When was AIDS first described?

AIDS (acquired immunodeficiency syndrome) was first reported in the United States in 1981 and has since become a major worldwide epidemic. AIDS is caused by HIV (human immunodeficiency virus). By killing or damaging cells of the body's immune system, HIV progressively destroys the body's ability to fight infections and certain cancers. People diagnosed with AIDS may get life-threatening diseases called opportunistic infections, which are caused by microbes such as viruses or bacteria that usually do not make healthy people sick.

More than 900,000 cases of AIDS have been reported in the United States since 1981. As many as 950,000 Americans may be infected with HIV, one-quarter of whom are unaware of their infection. The epidemic is growing most rapidly among minority populations and is a leading killer of African-American males ages 25 to 44. According to the U.S. Centers for Disease Control and Prevention (CDC), AIDS affects nearly seven times more African Americans and three times more Hispanics than whites. In recent years, an increasing number of African-American women and children are being affected by HIV/AIDS. In 2003, two-thirds of U.S. AIDS cases in both women and children were among African-Americans.

Transmission

HIV is spread most commonly by having unprotected sex with an infected partner. The virus can enter the body through the lining of the vagina, vulva, penis, rectum, or mouth during sex.

Risky behavior

HIV can infect anyone who practices risky behaviors such as:

* Sharing drug needles or syringes

* Having sexual contact, including oral, with an infected person without using a condom

* Having sexual contact with someone whose HIV status is unknown

Infected blood

HIV also is spread through contact with infected blood. Before donated blood was screened for evidence of HIV infection and before heat-treating techniques to destroy HIV in blood products were introduced, HIV was transmitted through transfusions of contaminated blood or blood components. Today, because of blood screening and heat treatment, the risk of getting HIV from such transfusions is extremely small.

Contaminated needles

HIV is frequently spread among injection drug users by the sharing of needles or syringes contaminated with very small quantities of blood from someone infected with the virus.

It is rare, however, for a patient to give HIV to a health care worker or vice-versa by accidental sticks with contaminated needles or other medical instruments.

Mother-to-child transmission

Women can transmit HIV to their babies during pregnancy or birth. Approximately one-quarter to one-third of all untreated pregnant women infected with HIV will pass the infection to their babies. HIV also can be spread to babies through the breast milk of mothers infected with the virus. If the mother takes certain drugs during pregnancy, she can significantly reduce the chances that her baby will get infected with HIV. If health care providers treat HIV-infected pregnant women and deliver their babies by cesarean section, the chances of the baby being infected can be reduced to a rate of 1 percent. HIV infection of newborns has been almost eradicated in the United States due to appropriate treatment.

A study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) in Uganda found a highly effective and safe drug for preventing transmission of HIV from an infected mother to her newborn. Independent studies have also confirmed this finding. This regimen is more affordable and practical than any other examined to date. Results from the study show that a single oral dose of the antiretroviral drug nevirapine (NVP) given to an HIV-infected woman in labor and another to her baby within 3 days of birth reduces the transmission rate of HIV by half compared with a similar short course of AZT (Azidothymidine). For more information on preventing transmission from mother to child, go to http://aidsinfo.nih.gov/guidelines.

Saliva

Although researchers have found HIV in the saliva of infected people, there is no evidence that the virus is spread by contact with saliva. Laboratory studies reveal that saliva has natural properties that limit the power of HIV to infect, and the amount of virus in saliva appears to be very low. Research studies of people infected with HIV have found no evidence that the virus is spread to others through saliva by kissing. The lining of the mouth, however, can be infected by HIV, and instances of HIV transmission through oral intercourse have been reported.

Scientists have found no evidence that HIV is spread through sweat, tears, urine, or feces.

Casual contact

Studies of families of HIV-infected people have shown clearly that HIV is not spread through casual contact such as the sharing of food utensils, towels and bedding, swimming pools, telephones, or toilet seats.

HIV is not spread by biting insects such as mosquitoes or bedbugs.

Sexually transmitted infections

If you have a sexually transmitted infection (STI) such as syphilis, genital herpes, chlamydial infection, gonorrhea, or bacterial vaginosis appears, you may be more susceptible to getting HIV infection during sex with infected partners.

Early symptoms of HIV infection

If you are like many people, you will not have any symptoms when you first become infected with HIV. You may, however, have a flu-like illness within a month or two after exposure to the virus. This illness may include:

* Fever

* Headache

* Tiredness

* Enlarged lymph nodes (glands of the immune system easily felt in the neck and groin)

These symptoms usually disappear within a week to a month and are often mistaken for those of another viral infection. During this period, people are very infectious, and HIV is present in large quantities in genital fluids.

More persistent or severe symptoms may not appear for 10 years or more after HIV first enters the body in adults, or within 2 years in children born with HIV infection. This period of 'asymptomatic' infection varies greatly in each individual. Some people may begin to have symptoms within a few months, while others may be symptom-free for more than 10 years.

Even during the asymptomatic period, the virus is actively multiplying, infecting, and killing cells of the immune system. The virus can also hide within infected cells and lay dormant. The most obvious effect of HIV infection is a decline in the number of CD4 positive T (CD4+) cells found in the blood-the immune system's key infection fighters. The virus slowly disables or destroys these cells without causing symptoms.

As the immune system worsens, a variety of complications start to take over. For many people, the first signs of infection are large lymph nodes or 'swollen glands' that may be enlarged for more than 3 months. Other symptoms often experienced months to years before the onset of AIDS include:

* Lack of energy

* Weight loss

* Frequent fevers and sweats

* Persistent or frequent yeast infections (oral or vaginal)

* Persistent skin rashes or flaky skin

* Pelvic inflammatory disease in women that does not respond to treatment

* Short-term memory loss

Some people develop frequent and severe herpes infections that cause mouth, genital, or anal sores, or a painful nerve disease called shingles. Children may grow slowly or be sick a lot.

What is AIDS?

The term AIDS applies to the most advanced stages of HIV infection. CDC developed official criteria for the definition of AIDS and is responsible for tracking the spread of AIDS in the United States.

CDC's definition of AIDS includes all HIV-infected people who have fewer than 200 CD4+ T cells per cubic millimeter of blood. (Healthy adults usually have CD4+ T-cell counts of 1,000 or more.) In addition, the definition includes 26 clinical conditions that affect people with advanced HIV disease. Most of these conditions are opportunistic infections that generally do not affect healthy people. In people with AIDS, these infections are often severe and sometimes fatal because the immune system is so ravaged by HIV that the body cannot fight off certain bacteria, viruses, fungi, parasites, and other microbes.

Symptoms of opportunistic infections common in people with AIDS include:

* Coughing and shortness of breath

* Seizures and lack of coordination

* Difficult or painful swallowing

* Mental symptoms such as confusion and forgetfulness

* Severe and persistent diarrhea

* Fever

* Vision loss

* Nausea, abdominal cramps, and vomiting

* Weight loss and extreme fatigue

* Severe headaches

* Coma

Children with AIDS may get the same opportunistic infections as do adults with the disease. In addition, they also have severe forms of the typically common childhood bacterial infections, such as conjunctivitis (pink eye), ear infections, and tonsillitis.

People with AIDS are also particularly prone to developing various cancers, especially those caused by viruses such as Kaposi's sarcoma and cervical cancer, or cancers of the immune system known as lymphomas. These cancers are usually more aggressive and difficult to treat in people with AIDS. Signs of Kaposi's sarcoma in light-skinned people are round brown, reddish, or purple spots that develop in the skin or in the mouth. In dark-skinned people, the spots are more pigmented.

During the course of HIV infection, most people experience a gradual decline in the number of CD4+ T cells, although some may have abrupt and dramatic drops in their CD4+ T-cell counts. A person with CD4+ T cells above 200 may experience some of the early symptoms of HIV disease. Others may have no symptoms even though their CD4+ T-cell count is below 200.

Many people are so debilitated by the symptoms of AIDS that they cannot hold a steady job or do household chores. Other people with AIDS may experience phases of intense life-threatening illness followed by phases in which they function normally.

A small number of people first infected with HIV 10 or more years ago have not developed symptoms of AIDS. Scientists are trying to determine what factors may account for their lack of progression to AIDS, such as

* Whether their immune systems have particular characteristics

* Whether they were infected with a less aggressive strain of the virus

* If their genes may protect them from the effects of HIV

Scientists hope that understanding the body's natural method of controlling infection may lead to ideas for protective HIV vaccines and use of vaccines to prevent the disease from progressing.

How is AIDS diagnosed?

Because early HIV infection often causes no symptoms, your health care provider usually can diagnose it by testing your blood for the presence of antibodies (disease-fighting proteins) to HIV. HIV antibodies generally do not reach noticeable levels in the blood for 1 to 3 months following infection. It may take the antibodies as long as 6 months to be produced in quantities large enough to show up in standard blood tests. Hence, to determine whether you have been recently infected (acute infection), your health care provider can screen you for the presence of HIV genetic material. Direct screening of HIV is extremely critical in order to prevent transmission of HIV from recently infected individuals.

If you have been exposed to the virus, you should get an HIV test as soon as you are likely to develop antibodies to the virus-within 6 weeks to 12 months after possible exposure to the virus. By getting tested early, if infected, you can discuss with your health care provider when you should start treatment to help your immune system combat HIV and help prevent the emergence of certain opportunistic infections (see section on treatment below). Early testing also alerts you to avoid high-risk behaviors that could spread the virus to others.

Most health care providers can do HIV testing and will usually offer you counseling at the same time. Of course, you can be tested anonymously at many sites if you are concerned about confidentiality.

Health care providers diagnose HIV infection by using two different types of antibody tests: ELISA and Western Blot. If you are highly likely to be infected with HIV but have been tested negative for both tests, your health care provider may request additional tests. You also may be told to repeat antibody testing at a later date, when antibodies to HIV are more likely to have developed.

Babies born to mothers infected with HIV may or may not be infected with the virus, but all carry their mothers' antibodies to HIV for several months. If these babies lack symptoms, a doctor cannot make a definitive diagnosis of HIV infection using standard antibody. Health care providers are using new technologies to detect HIV to more accurately determine HIV infection in infants between ages 3 months and 15 months. They are evaluating a number of blood tests to determine which ones are best for diagnosing HIV infection in babies younger than 3 months.

How are the treatment options for AIDS?

When AIDS first surfaced in the United States, there were no medicines to combat the underlying immune deficiency and few treatments existed for the opportunistic diseases that resulted. Researchers, however, have developed drugs to fight both HIV infection and its associated infections and cancers.

HIV therapy

The U.S. Food and Drug Administration (FDA) has approved a number of drugs for treating HIV infection. The first group of drugs used to treat HIV infection, called nucleoside reverse transcriptase (RT) inhibitors, interrupts an early stage of the virus making copies of itself. These drugs may slow the spread of HIV in the body and delay the start of opportunistic infections. This class of drugs, called nucleoside analogs, include:

* AZT (Azidothymidine)

* ddC (zalcitabine)

* ddI (dideoxyinosine)

* d4T (stavudine)

* 3TC (lamivudine)

* Abacavir (ziagen)

* Tenofovir (viread)

* Emtriva (emtricitabine)

Health care providers can prescribe non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as:

* Delavridine (Rescriptor)

* Nevirapine (Viramune)

* Efravirenz (Sustiva) (in combination with other antiretroviral drugs)

FDA also has approved a second class of drugs for treating HIV infection. These drugs, called protease inhibitors, interrupt the virus from making copies of itself at a later step in its life cycle. They include:

* Ritonavir (Norvir)

* Saquinivir (Invirase)

* Indinavir (Crixivan)

* Amprenivir (Agenerase)

* Nelfinavir (Viracept)

* Lopinavir (Kaletra)

* Atazanavir (Reyataz)

* Fosamprenavir (Lexiva)

FDA also has introduced a third new class of drugs, known at fusion inhibitors, to treat HIV infection. Fuzeon (enfuvirtide or T-20), the first approved fusion inhibitor, works by interfering with HIV-1's ability to enter into cells by blocking the merging of the virus with the cell membranes. This inhibition blocks HIV's ability to enter and infect the human immune cells. Fuzeon is designed for use in combination with other anti-HIV treatment. It reduces the level of HIV infection in the blood and may be active against HIV that has become resistant to current antiviral treatment schedules.

Because HIV can become resistant to any of these drugs, health care providers must use a combination treatment to effectively suppress the virus. When multiple drugs (three or more) are used in combination, it is referred to as highly active antiretroviral therapy, or HAART, and can be used by people who are newly infected with HIV as well as people with AIDS.

Researchers have credited HAART as being a major factor in significantly reducing the number of deaths from AIDS in this country. While HAART is not a cure for AIDS, it has greatly improved the health of many people with AIDS and it reduces the amount of virus circulating in the blood to nearly undetectable levels. Researchers, however, have shown that HIV remains present in hiding places, such as the lymph nodes, brain, testes, and retina of the eye, even in people who have been treated.

Side effects

Despite the beneficial effects of HAART, there are side effects associated with the use of antiviral drugs that can be severe. Some of the nucleoside RT inhibitors may cause a decrease of red or white blood cells, especially when taken in the later stages of the disease. Some may also cause inflammation of the pancreas and painful nerve damage. There have been reports of complications and other severe reactions, including death, to some of the antiretroviral nucleoside analogs when used alone or in combination. Therefore, health care experts recommend that you be routinely seen and followed by your health care provider if you are on antiretroviral therapy.

The most common side effects associated with protease inhibitors include nausea, diarrhea, and other gastrointestinal symptoms. In addition, protease inhibitors can interact with other drugs resulting in serious side effects. Fuzeon may also cause severe allergic reactions such as pneumonia, trouble breathing, chills and fever, skin rash, blood in urine, vomiting, and low blood pressure. Local skin reactions are also possible since it is given as an injection underneath the skin.

If you are taking HIV drugs, you should contact your health care provider immediately if you have any of these symptoms.

Opportunistic infections

A number of available drugs help treat opportunistic infections. These drugs include:

* Foscarnet and ganciclovir to treat CMV (cytomegalovirus) eye infections

* Fluconazole to treat yeast and other fungal infections

* TMP/SMX (trimethoprim/sulfamethoxazole) or pentamidine to treat PCP (Pneumocystis carinii pneumonia)

Cancers

Health care providers use radiation, chemotherapy, or injections of alpha interferon-a genetically engineered protein that occurs naturally in the human body-to treat Kaposi's sarcoma or other cancers associated with HIV infection.

AIDS prevention strategies

Because no vaccine for HIV is available, the only way to prevent infection by the virus is to avoid behaviors that put you at risk of infection, such as sharing needles and having unprotected sex.

Many people infected with HIV have no symptoms. Therefore, there is no way of knowing with certainty whether your sexual partner is infected unless he or she has repeatedly tested negative for the virus and has not engaged in any risky behavior. You should either abstain from having sex or use male latex condoms or female polyurethane condoms, which may offer partial protection, during oral, anal, or vaginal sex. Only water-based lubricants should be used with male latex condoms.

Although some laboratory evidence shows that spermicides can kill HIV, researchers have not found that these products can prevent you from getting HIV.

How does HIV cause AIDS?

Overview

Untreated HIV disease is characterized by a gradual deterioration of immune function. Most notably, crucial immune cells called CD4 positive (CD4+) T cells are disabled and killed during the typical course of infection. These cells, sometimes called 'T-helper cells,' play a central role in the immune response, signaling other cells in the immune system to perform their special functions.

A healthy, uninfected person usually has 800 to 1,200 CD4+ T cells per cubic millimeter (mm3) of blood. During untreated HIV infection, the number of these cells in a person's blood progressively declines. When the CD4+ T cell count falls below 200/mm3, a person becomes particularly vulnerable to the opportunistic infections and cancers that typify AIDS, the end stage of HIV disease. People with AIDS often suffer infections of the lungs, intestinal tract, brain, eyes, and other organs, as well as debilitating weight loss, diarrhea, neurologic conditions, and cancers such as Kaposi's sarcoma and certain types of lymphomas.

Most scientists think that HIV causes AIDS by directly inducing the death of CD4+ T cells or interfering with their normal function, and by triggering other events that weaken a person's immune function. For example, the network of signaling molecules that normally regulates a person's immune response is disrupted during HIV disease, impairing a person's ability to fight other infections. The HIV-mediated destruction of the lymph nodes and related immunologic organs also plays a major role in causing the immunosuppression seen in people with AIDS. Immunosuppression by HIV is confirmed by the fact that medicines, which interfere with the HIV lifecycle, preserve CD4+ T cells and immune function as well as delay clinical illness.

Scope of the HIV epidemic

Although HIV was first identified in 1983, studies of previously stored blood samples indicate that the virus entered the U.S. population sometime in the late 1970s. In the United States, 886,575 cases of AIDS, and 501,669 deaths among people with AIDS had been reported to the CDC by the end of 2002. Approximately 40,000 new HIV infections occur each year in the United States, 70 percent of them among men and 30 percent among women. Of the new infections, approximately 40 percent are from male-to-male contact, 30 percent from heterosexual contact, and 25 percent from injection drug use. Minority groups in the United States have also been disproportionately affected by the epidemic.

Worldwide, an estimated 38 million people were living with HIV/AIDS as of December 2003, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) . Through 2003, cumulative AIDS-associated deaths worldwide numbered more than 20 million. Globally, approximately 5 million new HIV infections and approximately 3 million AIDS-related deaths, including an estimated 490,000 children under 15 years old, occurred in the year 2003 alone.

Retroviruses

HIV belongs to a class of viruses called retroviruses. Retroviruses are RNA (ribonucleic acid) viruses, and in order to replicate (duplicate). they must make a DNA (deoxyribonucleic acid) copy of their RNA. It is the DNA genes that allow the virus to replicate.

Like all viruses, HIV can replicate only inside cells, commandeering the cell's machinery to reproduce. Only HIV and other retroviruses, however, once inside a cell, use an enzyme called reverse transcriptase to convert their RNA into DNA, which can be incorporated into the host cell's genes.

Slow viruses

HIV belongs to a subgroup of retroviruses known as lentiviruses, or 'slow' viruses. The course of infection with these viruses is characterized by a long interval between initial infection and the onset of serious symptoms.

Other lentiviruses infect nonhuman species. For example, the feline immunodeficiency virus (FIV) infects cats and the simian immunodeficiency virus (SIV) infects monkeys and other nonhuman primates. Like HIV in humans, these animal viruses primarily infect immune system cells, often causing immune deficiency and AIDS-like symptoms. These viruses and their hosts have provided researchers with useful, albeit imperfect, models of the HIV disease process in people.

Structure of HIV

HIV has a diameter of 1/10,000 of a millimeter and is spherical in shape. The outer coat of the virus, known as the viral envelope, is composed of two layers of fatty molecules called lipids, taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Evidence from NIAID-supported research indicates that HIV may enter and exit cells through special areas of the cell membrane known as 'lipid rafts.' These rafts are high in cholesterol and glycolipids and may provide a new target for blocking HIV.

Embedded in the viral envelope are proteins from the host cell, as well as 72 copies (on average) of a complex HIV protein (frequently called 'spikes') that protrudes through the surface of the virus particle (virion). This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure in the viral envelope. Much of the research to develop a vaccine against HIV has focused on these envelope proteins.

The viral core

Within the envelope of a mature HIV particle is a bullet-shaped core or capsid, made of 2,000 copies of another viral protein, p24. The capsid surrounds two single strands of HIV RNA, each of which has a copy of the virus's nine genes. Three of these genes, gag, pol, and env, contain information needed to make structural proteins for new virus particles. The env gene, for example, codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41, the components of Env.

Six regulatory genes, tat, rev, nef, vif, vpr, and vpu, contain information necessary to produce proteins that control the ability of HIV to infect a cell, produce new copies of virus, or cause disease. The protein encoded by nef, for instance, appears necessary for the virus to replicate efficiently, and the vpu-encoded protein influences the release of new virus particles from infected cells. Recently, researchers discovered that Vif (the protein encoded by the vif gene) interacts with an antiviral defense protein in host cells (APOBEC3G), causing inactivation of the antiviral effect and enhancing HIV replication. This interaction may serve as a new target for antiviral drugs.

The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.

The core of HIV also includes a protein called p7, the HIV nucleocapsid protein. Three enzymes carry out later steps in the virus's life cycle: reverse transcriptase, integrase, and protease. Another HIV protein called p17, or the HIV matrix protein, lies between the viral core and the viral envelope.

Entry of HIV into cells

Infection typically begins when an HIV particle, which contains two copies of the HIV RNA, encounters a cell with a surface molecule called cluster designation 4 (CD4). Cells carrying this molecule are known as CD4+ cells.

One or more of the virus's gp120 molecules binds tightly to CD4 molecule(s) on the cell's surface. The binding of gp120 to CD4 results in a conformational change in the gp120 molecule allowing it to bind to a second molecule on the cell surface known as a co-receptor. The envelope of the virus and the cell membrane then fuse, leading to entry of the virus into the cell. The gp41 of the envelope is critical to the fusion process. Drugs that block either the binding or the fusion process are being developed and tested in clinical trials. The Food and Drug Administration (FDA) has approved one of the so-called fusion inhibitors, T20, for use in HIV-infected people.

Studies have identified multiple coreceptors for different types of HIV strains. These coreceptors are promising targets for new anti-HIV drugs, some of which are now being tested in preclinical and clinical studies. Agents that block the co-receptors are showing particular promise as potential microbicides that could be used in gels or creams to prevent HIV transmission. In the early stage of HIV disease, most people harbor viruses that use, in addition to CD4, a receptor called CCR5 to enter their target cells. With disease progression, the spectrum of co-receptor usage expands in approximately 50 percent of patients to include other receptors, notably a molecule called CXCR4. Virus that uses CCR5 is called R5 HIV and virus that uses CXCR4 is called X4 HIV.

Although CD4+ T cells appear to be the main targets of HIV, other immune system cells with and without CD4 molecules on their surfaces are infected as well. Among these are long-lived cells called monocytes and macrophages , which apparently can harbor large quantities of the virus without being killed, thus acting as reservoirs of HIV. CD4+ T cells also serve as important reservoirs of HIV; a small proportion of these cells harbor HIV in a stable, inactive form. Normal immune processes may activate these cells, resulting in the production of new HIV virions.

Cell-to-cell spread of HIV also can occur through the CD4-mediated fusion of an infected cell with an uninfected cell.

Reverse transcription

In the cytoplasm of the cell, HIV reverse transcriptase converts viral RNA into DNA, the nucleic acid form in which the cell carries its genes. Fifteen of the 26 antiviral drugs approved in the United States for treating people with HIV infection work by interfering with this stage of the viral life cycle.

Integration

The newly made HIV DNA moves to the cell's nucleus, where it is spliced into the host's DNA with the help of HIV integrase. HIV DNA that enters the DNA of the cell is called a provirus. Several drugs that target the integrase enzyme are in the early stages of development and are being investigated for their potential as antiretroviral agents.

Transcription

For a provirus to produce new viruses, RNA copies must be made that can be read by the host cell's protein-making machinery. These copies are called messenger RNA (mRNA), and production of mRNA is called transcription, a process that involves the host cell's own enzymes. Viral genes in concert with the cellular machinery control this process; the tat gene, for example, encodes a protein that accelerates transcription. Genomic RNA is also transcribed for later incorporation in the budding virion (see below).

Cytokines, proteins involved in the normal regulation of the immune response, also may regulate transcription. Molecules such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, secreted in elevated levels by the cells of HIV-infected people, may help to activate HIV proviruses. Other infections, by organisms such as Mycobacterium tuberculosis , also may enhance transcription by inducing the secretion of cytokines.

Translation

After HIV mRNA is processed in the cell's nucleus, it is transported to the cytoplasm. HIV proteins are critical to this process; for example, a protein encoded by the rev gene allows mRNA encoding HIV structural proteins to be transferred from the nucleus to the cytoplasm. Without the rev protein, structural proteins are not made. In the cytoplasm, the virus co-opts the cell's protein-making machinery-including structures called ribosomes-to make long chains of viral proteins and enzymes, using HIV mRNA as a template. This process is called translation.

Assembly and budding

Newly made HIV core proteins, enzymes, and genomic RNA gather inside the cell and an immature viral particle forms and buds off from the cell, acquiring an envelope that includes both cellular and HIV proteins from the cell membrane. During this part of the viral life cycle, the core of the virus is immature and the virus is not yet infectious. The long chains of proteins and enzymes that make up the immature viral core are now cut into smaller pieces by a viral enzyme called protease.

This step results in infectious viral particles. Drugs called protease inhibitors interfere with this step of the viral life cycle. FDA has approved eight such drugs-saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, fosamprenavir, atazanavir, and lopinavir-for marketing in the United States. Recently, an HIV inhibitor that targets a unique step in the viral life cycle, very late in the process of viral maturation, has been identified and is currently undergoing further development.

Recently, researchers have discovered that virus budding from the host cell is much more complex than previously thought. Binding between the HIV Gag protein and molecules in the cell directs the accumulation of HIV components in special intracellular sacks, called multivesicular bodies (MVB), that normally function to carry proteins out of the cell. In this way, HIV actively hitch-hikes out of the cell in the MVB by hijacking normal cell machinery and mechanisms. Discovery of this budding pathway has revealed several potential points for intervening in the viral replication cycle.

Transmission of HIV

Among adults, HIV is spread most commonly during sexual intercourse with an infected partner. During intercourse, the virus can enter the body through the mucosal linings of the vagina, vulva, penis, or rectum or, rarely, via the mouth and possibly the upper gastrointestinal tract after oral sex. The likelihood of transmission is increased by factors that may damage these linings, especially other sexually transmitted infections that cause ulcers or inflammation.

Research suggests that immune system cells of the dendritic cell type, which live in the mucosa, may begin the infection process after sexual exposure by binding to and carrying the virus from the site of infection to the lymph nodes where other immune system cells become infected. A molecule on the surface of dendritic cells, DC-SIGN, may be critical for this transmission process.

HIV also can be transmitted by contact with infected blood, most often by the sharing of needles or syringes contaminated with minute quantities of blood containing the virus. The risk of acquiring HIV from blood transfusions is extremely small in the United States, as all blood products in this country are screened routinely for evidence of the virus.

Almost all HIV-infected children in the United States get the virus from their mothers before or during birth. In the United States, approximately 25 percent of pregnant HIV-infected women not receiving antiretroviral therapy have passed on the virus to their babies. In 1994, researchers showed that a specific regimen of the drug AZT (zidovudine) can reduce the risk of transmission of HIV from mother to baby by two-thirds. The use of combinations of antiretroviral drugs and simpler drug regimens has further reduced the rate of mother-to-child HIV transmission in the United States.

In developing countries, cheap and simple antiviral drug regimens have been proven to significantly reduce mother-to-child transmission at birth in resource-poor settings. Unfortunately, the virus also may be transmitted from an HIV-infected mother to her infant via breastfeeding. Moreover, due to the use of medicines to prevent transmission at delivery, breastfeeding may become the most common mode of HIV infection in infants. Thus, development of affordable alternatives to breastfeeding is greatly needed.

Early events in HIV infection

Once it enters the body, HIV infects a large number of CD4+ cells and replicates rapidly. During this acute or primary phase of infection, the blood contains many viral particles that spread throughout the body, seeding various organs, particularly the lymphoid organs.

Two to 4 weeks after exposure to the virus, up to 70 percent of HIV-infected people suffer flu-like symptoms related to the acute infection. Their immune system fights back with killer T cells (CD8+ T cells) and B-cell-produced antibodies , which dramatically reduce HIV levels. A person's CD4+ T cell count may rebound somewhat and even approach its original level. A person may then remain free of HIV-related symptoms for years despite continuous replication of HIV in the lymphoid organs that had been seeded during the acute phase of infection.

One reason that HIV is unique is the fact that despite the body's aggressive immune responses, which are sufficient to clear most viral infections, some HIV invariably escapes. This is due in large part to the high rate of mutations that occur during the process of HIV replication. Even when the virus does not avoid the immune system by mutating, the body's best soldiers in the fight against HIV-certain subsets of killer T cells that recognize HIV-may be depleted or become dysfunctional.

In addition, early in the course of HIV infection, people may lose HIV-specific CD4+ T cell responses that normally slow the replication of viruses. Such responses include the secretion of interferons and other antiviral factors, and the orchestration of CD8+ T cells.

Finally, the virus may hide within the chromosomes of an infected cell and be shielded from surveillance by the immune system. Such cells can be considered as a latent reservoir of the virus. Because the antiviral agents currently in our therapeutic arsenal attack actively replicating virus, they are not effective against hidden, inactive viral DNA (so-called provirus). New strategies to purge this latent reservoir of HIV have become one of the major goals for current research efforts.

Course of HIV infection

Among people enrolled in large epidemiologic studies in Western countries, the median time from infection with HIV to the development of AIDS-related symptoms has been approximately 10 to 12 years in the absence of antiretroviral therapy. Researchers, however, have observed a wide variation in disease progression. Approximately 10 percent of HIV-infected people in these studies have progressed to AIDS within the first 2 to 3 years following infection, while up to 5 percent of individuals in the studies have stable CD4+ T cell counts and no symptoms even after 12 or more years.

Factors such as age or genetic differences among individuals, the level of virulence of an individual strain of virus, and co-infection with other microbes may influence the rate and severity of disease progression. Drugs that fight the infections associated with AIDS have improved and prolonged the lives of HIV-infected people by preventing or treating conditions such as Pneumocystis carinii pneumonia, cytomegalovirus disease, and diseases caused by a number of fungi.

HIV co-receptors and disease progression

Recent research has shown that most infecting strains of HIV use a co-receptor molecule called CCR5, in addition to the CD4 molecule, to enter certain of its target cells. HIV-infected people with a specific mutation in one of their two copies of the gene for this receptor may have a slower disease course than people with two normal copies of the gene. Rare individuals with two mutant copies of the CCR5 gene appear, in most cases, to be completely protected from HIV infection. Mutations in the gene for other HIV co-receptors also may influence the rate of disease progression.

Viral burden and disease progression

Numerous studies show that people with high levels of HIV in their bloodstream are more likely to develop new AIDS-related symptoms or die than those with lower levels of virus. For instance, in the Multicenter AIDS Cohort Study (MACS), investigators showed that the level of HIV in an untreated person's plasma 6 months to a year after infection-the so-called viral 'set point'-is highly predictive of the rate of disease progression; that is, patients with high levels of virus are much more likely to get sicker faster than those with low levels of virus. The MACS and other studies have provided the rationale for providing aggressive antiretroviral therapy to HIV-infected people, as well as for routinely using newly available blood tests to measure viral load when initiating, monitoring, and modifying anti-HIV therapy.

Potent combinations of three or more anti-HIV drugs known as highly active antiretroviral therapy, or HAART, can reduce a person's 'viral burden' (amount of virus in the circulating blood) to very low levels and in many cases delay the progression of HIV disease for prolonged periods. Before the introduction of HAART therapy, 85 percent of patients survived an average of 3 years following AIDS diagnosis. Today, 95 percent of patients who start therapy before they get AIDS survive on average 3 years following their first AIDS diagnosis. For those who start HAART after their first AIDS event, survival is still very high at 85 percent, averaging 3 years after AIDS diagnosis.

Antiretroviral regimens, however, have yet to completely and permanently suppress the virus in HIV-infected people. Recent studies have shown that, in addition to the latent HIV reservoir discussed above, HIV persists in a replication-competent form in resting CD4+ T cells even in people receiving aggressive antiretroviral therapy who have no readily detectable HIV in their blood. Investigators around the world are working to develop the next generation of anti-HIV drugs that can stop HIV, even in these biological scenarios.

A treatment goal, along with reduction of viral burden, is the reconstitution of the person's immune system, which may have become sufficiently damaged that it cannot replenish itself. Various strategies for assisting the immune system in this regard are being tested in clinical trials in tandem with HAART, such as the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) trial exploring the effects of the T cell growth factor, IL-2.

Lymph nodes

Although HIV-infected people often show an extended period of clinical latency with little evidence of disease, the virus is never truly completely latent although individual cells may be latently infected. Researchers have shown that even early in disease, HIV actively replicates within the lymph nodes and related organs, where large amounts of virus become trapped in networks of specialized cells with long, tentacle-like extensions. These cells are called follicular dendritic cells (FDCs). FDCs are located in hot spots of immune activity in lymphoid tissue called germinal centers. They act like flypaper, trapping invading pathogens (including HIV) and holding them until B cells come along to start an immune response.

Over a period of years, even when little virus is readily detectable in the blood, significant amounts of virus accumulate in the lymphoid tissue, both within infected cells and bound to FDCs. In and around the germinal centers, numerous CD4+ T cells are probably activated by the increased production of cytokines such as TNF-alpha and IL-6 by immune system cells within the lymphoid tissue. Activation allows uninfected cells to be more easily infected and increases replication of HIV in already infected cells.

While greater quantities of certain cytokines such as TNF-alpha and IL-6 are secreted during HIV infection, other cytokines with key roles in the regulation of normal immune function may be secreted in decreased amounts. For example, CD4+ T cells may lose their capacity to produce IL-2, a cytokine that enhances the growth of other T cells and helps to stimulate other cells' response to invaders. Infected cells also have low levels of receptors for IL-2, which may reduce their ability to respond to signals from other cells.

Breakdown of lymph node architecture

Ultimately, with chronic cell activation and secretion of inflammatory cytokines, the fine and complex inner structure of the lymph node breaks down and is replaced by scar tissue. Without this structure, cells in the lymph node cannot communicate and the immune system cannot function properly. Investigators also have reported recently that this scarring reduces the ability of the immune system to replenish itself following antiretroviral therapy that reduces the viral burden.

CD8+ T cells

CD8+ T cells are critically important in the immune response to HIV. These cells attack and kill infected cells that are producing virus. Thus, vaccine efforts are directed toward eliciting or enhancing these killer T cells, as well as eliciting antibodies that will neutralize the infectivity of HIV.

CD8+ T cells also appear to secrete soluble factors that suppress HIV replication. Several molecules, including RANTES, MIP-1alpha, MIP-1beta, and MDC appear to block HIV replication by occupying the coreceptors necessary for many strains of HIV to enter their target cells. There may be other immune system molecules-including the so-called CD8 antiviral factor (CAF), the defensins (type of antimicrobials), and others yet undiscovered-that can suppress HIV replication to some degree.

Replication and mutation

HIV replicates rapidly; several billion new virus particles may be produced every day. In addition, the HIV reverse transcriptase enzyme makes many mistakes while making DNA copies from HIV RNA. As a consequence, many variants or strains of HIV develop in a person, some of which may escape destruction by antibodies or killer T cells. Additionally, different strains of HIV can recombine to produce a wide range of variants.

During the course of HIV disease, viral strains emerge in an infected person that differ widely in their ability to infect and kill different cell types, as well as in their rate of replication. Scientists are investigating why strains of HIV from people with advanced disease appear to be more virulent and infect more cell types than strains obtained earlier from the same person. Part of the explanation may be the expanded ability of the virus to use other co-receptors, such as CXCR4.

Immunology

Researchers around the world are studying how HIV destroys or disables CD4+ T cells, and many think that a number of mechanisms may occur simultaneously in an HIV-infected person. Data suggest that billions of CD4+ T cells may be destroyed every day, eventually overwhelming the immune system's capacity to regenerate.

Direct cell killing

Infected CD4+ T cells may be killed directly when large amounts of virus are produced and bud out from the cell surface, disrupting the cell membrane, or when viral proteins and nucleic acids collect inside the cell, interfering with cellular machinery.

Apoptosis

Infected CD4+ T cells may be killed when the regulation of cell function is distorted by HIV proteins, probably leading to cell suicide by a process known as programmed cell death or apoptosis. Recent reports indicate that apoptosis occurs to a greater extent in HIV-infected people, both in their bloodstream and lymph nodes. Apoptosis is closely associated with the aberrant cellular activation seen in HIV disease.

Uninfected cells also may undergo apoptosis. Investigators have shown in cell cultures that the HIV envelope alone or bound to antibodies sends an inappropriate signal to CD4+ T cells causing them to undergo apoptosis, even if not infected by HIV.

Innocent bystanders

Uninfected cells may die in an innocent bystander scenario: HIV particles may bind to the cell surface, giving them the appearance of an infected cell and marking them for destruction by killer T cells after antibody attaches to the viral particle on the cell. This process is called antibody-dependent cellular cytotoxicity.

Killer T cells also may mistakenly destroy uninfected cells that have consumed HIV particles and that display HIV fragments on their surfaces. Alternatively, because HIV envelope proteins bear some resemblance to certain molecules that may appear on CD4+ T cells, the body's immune responses may mistakenly damage such cells as well.

Anergy

Researchers have shown in cell cultures that CD4+ T cells can be turned off by activation signals from HIV that leaves them unable to respond to further immune stimulation. This inactivated state is known as anergy.

Damage to precursor cells

Studies suggest that HIV also destroys precursor cells that mature to have special immune functions, as well as the microenvironment of the bone marrow and the thymus needed for developing such cells. These organs probably lose the ability to regenerate, further compounding the suppression of the immune system.

Central nervous system

Although monocytes and macrophages can be infected by HIV, they appear to be relatively resistant to being killed by the virus. These cells, however, travel throughout the body and carry HIV to various organs, including the brain, which may serve as a hiding place or 'reservoir' for the virus that may be relatively resistant to most anti-HIV drugs.

Neurologic manifestations of HIV disease are seen in up to 50 percent of HIV-infected people, to varying degrees of severity. People infected with HIV often experience

* Cognitive symptoms, including impaired short-term memory, reduced concentration, and mental slowing

* Motor symptoms such as fine motor clumsiness or slowness, tremor, and leg weakness

* Behavioral symptoms including apathy, social withdrawal, irritability, depression, and personality change

More serious neurologic manifestations in HIV disease typically occur in patients with high viral loads, generally when a person has advanced HIV disease or AIDS.

Neurologic manifestations of HIV disease are the subject of many research projects. Current evidence suggests that although nerve cells do not become infected with HIV, supportive cells within the brain, such as astrocytes and microglia (as well as monocyte/macrophages that have migrated to the brain) can be infected with the virus. Researchers postulate that infection of these cells can cause a disruption of normal neurologic functions by altering cytokine levels, by delivering aberrant signals, and by causing the release of toxic products in the brain. The use of anti-HIV drugs frequently reduces the severity of neurologic symptoms, but in many cases does not, for reasons that are unclear. The impact of long-term therapy and long-term HIV disease on neurologic function is also unknown and under intensive study.

Role of immune activation in HIV disease

During a normal immune response, many parts of the immune system are mobilized to fight an invader. CD4+ T cells, for instance, may quickly multiply and increase their cytokine secretion, thereby signaling other cells to perform their special functions. Scavenger cells called macrophages may double in size and develop numerous organelles , including lysosomes that contain digestive enzymes used to process ingested pathogens. Once the immune system clears the foreign antigen, it returns to a relative state of quiescence.

Paradoxically, although it ultimately causes immune deficiency, HIV disease for most of its course is characterized by immune system hyperactivation, which has negative consequences. As noted above, HIV replication and spread are much more efficient in activated CD4+ cells. Chronic immune system activation during HIV disease also may result in a massive stimulation of B cells, impairing the ability of these cells to make antibodies against other pathogens.

Chronic immune activation also can result in apoptosis, and an increased production of cytokines that not only may increase HIV replication but also have other deleterious effects. Increased levels of TNF-alpha, for example, may be at least partly responsible for the severe weight loss or wasting syndrome seen in many HIV-infected people.

The persistence of HIV and HIV replication plays an important role in the chronic state of immune activation seen in HIV-infected people. In addition, researchers have shown that infections with other organisms activate immune system cells and increase production of the virus in HIV-infected people. Chronic immune activation due to persistent infections, or the cumulative effects of multiple episodes of immune activation and bursts of virus production, likely contribute to the progression of HIV disease.

HAART therapy

The clinical spectrum of disease among people with HIV has changed dramatically in the era of HAART. NIAID and its grantees are actively studying the new clinical syndrome of disease among persons on long term-therapy. Research is concentrating on the impact of HIV over the long term, the toxicity of the medicines used to control HIV, and the effects of aging on HIV disease progression. People with HIV have a variety of conditions including diabetes, heart disease, neurocognitive decline, and cancers that may, or may not, be directly due to HIV or its treatment. Long-term studies of people with HIV in the United States and abroad are underway.

HIV Infection in Adolescents and Young Adults in the U.S.

Overview

There is a rising concern about the effects of HIV/AIDS among adolescents and young adults between ages of 13 to 24 in the United States. The CDC reported 40,049 cumulative cases of AIDS among people ages 13 to 24 through 2004. Since the epidemic began, an estimated 10,129 adolescents and young adults with AIDS have died and the proportion diagnosed with AIDS has also increased. Likewise, the proportion of adolescents and young adults with an AIDS diagnosis has increased from 3.9 percent in 1999 to 4.2 percent in 2004.

Moreover, African-American and Hispanic adolescents have been disproportionately affected by the HIV/AIDS epidemic. Between the ages of 13 and 19, African-Americans and Hispanics accounted for 66 percent and 21 percent, respectively, of the reported AIDS cases in 2003.

Because the average duration from HIV infection to the development of AIDS is 10 years, most adults with AIDS were likely infected as adolescents or young adults. In 2004, an estimated 4,883 were diagnosed with HIV/AIDS, while an estimated 18,293 were living with HIV/AIDS. However, health experts estimate the number of adolescents and adults living with HIV infection to be much higher.

Modes of transmission

Most HIV-infected adolescents and young adults are exposed to the virus through sexual intercourse. Recent HIV surveillance data suggest that the majority of HIV-infected adolescent and young adult males are infected through sex with men. Only a small percentage of males appear to be exposed by injection drug use and/or heterosexual contact. These data also suggest that adolescent and young adult females infected with HIV were exposed through heterosexual contact, with a very small percentage through injection drug use. In addition, there is an increasing number of children who were infected as infants that are now surviving to adolescence.

Sexually transmitted infections (STIs) and HIV

Approximately 25 percent of cases of STIs reported in the United States each year are among teenagers. This is particularly significant because the risk of HIV transmission increases substantially if either partner is infected with an STI. Discharge of pus and mucus as a result of STIs such as gonorrhea or chlamydia also increase the risk of HIV transmission three- to five-fold. Likewise, STI-induced ulcers from syphilis or genital herpes increase the risk of HIV transmission nine-fold.

Care and treatment

Because many adolescents and young adults tend to think they are invincible, this belief may cause them to engage in risky behavior, delay HIV testing, and if they test positive, delay or refuse treatment. The inability to link them to medical care can lead to increased transmission of HIV. Health care providers report that many young people, when they learn they are HIV-positive, take several months to accept their diagnosis and return for treatment.

Health care providers may be able to help young people understand their situation during visits by

* Ensuring confidentiality

* Explaining the information clearly

* Eliciting questions

* Emphasizing the success of newly available treatments

HIV Infection in Minority Populations

Overview

HIV/AIDS continues to disproportionately affect minorities. Racial and ethnic minority populations in the United States, primarily African Americans and Hispanics, constitute 58 percent of the more than 928,188 cases of AIDS reported to the CDC since the epidemic began in 1981. African Americans make up 50 percent of all AIDS cases reported in the United States, yet according to the U.S. Census Bureau, they comprise only 12 percent of the U.S. population. Hispanics represent 15 percent of all AIDS cases in the United States and are approximately 13 percent of the U.S. population.

Injection drug use is a major factor in the spread of HIV in minority communities. Other factors contributing to the spread of HIV/AIDS in these communities include men who have sex with men (MSM) and increasingly, heterosexual transmission.

According to the CDC

* As of December 2003, African Americans and Hispanics represented 64 percent of males living with AIDS and 83 percent of those in females.

* As of December 2003, 67 percent of all women reported with AIDS are African American and 16 percent are Hispanic.

* African-American children represent almost 71 percent of all pediatric AIDS cases.

* Of the 59 pediatric AIDS cases reported in 2003, 40 were in African Americans and 7 were in Hispanics.

* AIDS is the leading cause of death among African-American men ages 25-44.

HIV Infection in Infants and Children

Overview

The National Institute of Allergy and Infectious Diseases (NIAID) has a lead role in research devoted to children infected with HIV (human immunodeficiency virus), the virus that causes AIDS (acquired immunodeficiency syndrome). NIAID-supported researchers are developing and refining treatments to prolong the survival and improve the quality of life of HIV-infected infants and children through the Pediatric AIDS Clinical Trials Group (PACTG). The PACTG is a nationwide clinical trials network jointly sponsored by NIAID and the National Institute of Child Health and Human Development (NICHD). NIAID also supports research on ways to prevent mother-to-child transmission (MTCT) of HIV through the PACTG and its HIV Prevention Trials Network (HPTN), a global clinical trials network designed to test promising nonvaccine strategies to prevent the spread of HIV/AIDS.

In this era of antiretroviral therapy, epidemiologic studies such as NIAID's Women and Infant's Transmission Study (WITS) are examining risk factors for transmission as well as the course of HIV disease in pregnant women and their babies. Researchers have helped illuminate the mechanisms of HIV transmission, the distinct features of pediatric HIV infection, and how the course of disease and the usefulness of therapies can differ in children and adults.

A global problem

According to UNAIDS (The Joint United Nations Programme on HIV/AIDS) at the end of 2003, an estimated 2.5 million children worldwide under age 15 were living with HIV/AIDS. Approximately 500,000 children under 15 had died from the virus or associated causes in that year alone. As HIV infection rates rise in the general population, new infections are increasingly concentrating in younger age groups.

December 2003 UNAIDS/World Health Organization (WHO) worldwide statistics show:

* 700,000 children under age 15 were newly infected with HIV

* Thirteen percent of all new HIV infections were in children under age 15

* Three million children in sub-Saharan Africa, the region with the highest number of cases, are living with HIV

More than 95 percent of all HIV-infected people now live in developing countries, which have also suffered 95 percent of all deaths from AIDS. In those countries with the highest prevalence, UNAIDS predicts that, between 2000 and 2020, 68 million people will die prematurely as a result of AIDS. In seven sub-Saharan African countries, mortality due to HIV/AIDS in children under age five has increased by 20 to 40 percent. Life expectancy for a child born in Botswana, the country with the highest HIV prevalence in the world, has dropped below 40 years-a level not seen in that country since before 1950.

The United States has a relatively small percentage of the world's children living with HIV/AIDS. From the beginning of the epidemic through the end of 2002, 9,300 American children under age 13 had been reported to the CDC as living with HIV/AIDS. The vast majority of HIV-infected children acquire the virus from their mothers before or during birth or through breast feeding. Because of the widespread use of AZT and other highly active antiretroviral therapy (HAART) in HIV-infected pregnant women in the United States, only 92 new cases of pediatric AIDS were reported in 2002. More than three times that number are infected with HIV but have not yet developed AIDS.

* The U.S. city with the highest rate of pediatric AIDS through 2002 was New York City, followed by Miami, FL, and Washington, DC.

* The disease disproportionately affects children in minority groups, especially African Americans. Out of 9,300 cases in children under 13 reported to the CDC through December 2002, 59 percent were black/non-Hispanic, 23 percent were Hispanic, 17 percent were white/non-Hispanic, and less than 1 percent were in other minority groups.

New anti-HIV drug therapies and promotion of voluntary testing continue to positively effect the death rate. CDC reported a drop of 68 percent from 1998 to 2002 in the estimated number of children who died from AIDS.

Transmission

Almost all HIV-infected children acquire the virus from their mothers before or during birth or through breastfeeding. In the United States, approximately 25 percent of pregnant HIV-infected women not receiving AZT therapy have passed on the virus to their babies. The rate is significantly higher in developing countries.

Prior to 1985 when screening of the nation's blood supply for HIV began, some children as well as adults were infected through transfusions with blood or blood products contaminated with HIV. A small number of children also have been infected through sexual or physical abuse by HIV-infected adults.

Pregnancy and birth

Most MTCT, estimated to cause more than 90 percent of infections worldwide in infants and children, probably occurs late in pregnancy or during birth. Although the precise mechanisms are unknown, scientists think HIV may be transmitted when maternal blood enters the fetal circulation or by mucosal exposure to virus during labor and delivery. The role of the placenta in maternal-fetal transmission is unclear and the focus of ongoing research.

The risk of MTCT is significantly increased if the mother has advanced HIV disease, increased levels of HIV in her bloodstream, or fewer numbers of the immune system cells-CD4+ T cells-that are the main targets of HIV.

Other factors that may increase the risk are maternal drug use, severe inflammation of fetal membranes, or a prolonged period between membrane rupture and delivery. A study sponsored by NIAID and others found that HIV-infected women who gave birth more than 4 hours after the rupture of the fetal membranes were nearly twice as likely to transmit HIV to their infants, as compared to women who delivered within 4 hours of membrane rupture.

Breastfeeding

HIV also may be transmitted from a nursing mother to her infant. Studies have suggested that breastfeeding introduces an additional risk of HIV transmission of approximately 10 to 14 percent among women with chronic HIV infection. In developing countries, an estimated one-third to one-half of all HIV infections are transmitted through breastfeeding.

WHO recommends that all HIV-infected women be advised about both the risks and benefits of breastfeeding for their infants so they can make informed decisions. In countries where safe alternatives to breastfeeding are readily available and economically feasible, this alternative should be encouraged. In general, in developing countries where safe alternatives to breastfeeding are not readily available, the benefits of breastfeeding in terms of decreased illness and death due to other infectious diseases greatly outweigh the potential risk of HIV transmission.

Preventing mother-to-child transmission

In 1994, a landmark study conducted by the PACTG demonstrated that AZT, given to HIV-infected women who had very little or no prior antiretroviral therapy and CD4+ T-cell counts above 200/mm3, reduced the risk of MTCT by two-thirds, from 25 percent to 8 percent. In the study, AZT therapy was initiated in the second or third trimester and continued during labor, and infants were treated for 6 weeks following birth. AZT produced no serious side effects in mothers or infants. Long-term follow up of the infants and mothers is ongoing.

A few years later, another PACTG study found that the risk of transmitting HIV from an HIV-positive mother to her newborn infant could be reduced to 1.5 percent in those women who received antiretroviral treatment and appropriate medical and obstetrical care during pregnancy.

Combination therapies have been shown to be beneficial in treating HIV-infected adults, and current guidelines have been designed accordingly. In HIV-infected pregnant women, the safety and pharmacology of these potent drug combinations need to be better understood, and NIAID is conducting studies in this area.

The AZT regimen is not available in much of the world because of its high cost and logistical requirements. The cost of a short-course AZT regimen is substantially lower, but is still prohibitive in many countries. International agencies are studying whether there may be innovative ways to provide AZT at lower cost, for example, through reductions in drug prices to developing countries or partnerships with industry. As a result, NIAID continues to evaluate other strategies that may be simpler and less costly to prevent MTCT in various settings. In September 1999, one such study demonstrated that short-course therapy with nevirapine lowered the risk of HIV-1 transmission during the first 14 to16 weeks of life by nearly 50 percent compared to AZT in a breastfeeding population. As a follow up, NIAID released a final report on additional data showing that the results of nevirapine were sustained after 18 months. These findings have significant implications because this simple, inexpensive regimen offers a potential cost-effective alternative for decreasing MTCT in developing countries.

In addition, in April 1999 the International Perinatal HIV Group reported that elective caesarian section delivery can help reduce vertical transmission of HIV, though it is not without risk to certain women. When AZT treatment is combined with elective caesarian delivery, a transmission rate of 2 percent has been reported.

Because a significant amount of MTCT occurs around the time of birth, and the risk of maternal-fetal transmission depends, in part, on the amount of HIV in the mother's blood, it may be possible to reduce transmission using drug therapy only around the time of birth. NIAID has planned other studies that will assess the effectiveness of this approach as well as the role of new antiretrovirals, microbicides and other innovative strategies in reducing the risk of MTCT of HIV.

Diagnosis

HIV infection is often difficult to diagnose in very young children. Infected babies, especially in the first few months of life, often appear normal and may show no telltale signs allowing for a definitive diagnosis of HIV infection. Moreover, all children born to infected mothers have antibodies to HIV, made by the mother's immune system, that cross the placenta to the baby's bloodstream before birth and persist for up to 18 months. Because these maternal antibodies reflect the mother's but not the infant's infection status, the test for HIV infection is not useful in newborns or young infants.

In recent years, investigators have demonstrated the utility of highly accurate blood tests in diagnosing HIV infection in children 6 months of age and younger. One laboratory technique, called polymerase chain reaction (PCR), can detect minute quantities of the virus in an infant's blood. Another procedure allows physicians to culture a sample of an infant's blood and test it for the presence of HIV.

Currently, PCR assays or HIV culture techniques can identify at birth about one-third of infants who finally and ultimately prove to be HIV infected. With these techniques, approximately 90 percent of HIV-infected infants are identifiable by 2 months of age, and 95 percent by 3 months of age. One innovative new approach to both RNA and DNA PCR testing uses dried blood spot specimens, which should make it much simpler to gather and store specimens in field settings.

Disease progression

Researchers have observed two general patterns of illness in HIV-infected children. About 20 percent of children develop serious disease in the first year of life; most of these children die by age 4. The remaining 80 percent of infected children have a slower rate of disease progression, many not developing the most serious symptoms of AIDS until school entry or even adolescence. A report from a large European registry of HIV-infected children indicated that half of the children with perinatally acquired HIV disease were alive at age nine. Another study of 42 perinatally HIV-infected children, who survived beyond 9 years of age, found about one-quarter of the children to be asymptomatic with relatively intact immune systems.

The factors responsible for the wide variation observed in the rate of disease progression in HIV-infected children are a major focus of the NIAID pediatric AIDS research effort. WITS is a multisite perinatal HIV study. It has found that maternal factors, including Vitamin A level and CD4+ T-cell counts during pregnancy, as well as infant viral load and CD4+ T-cell counts in the first several months of life, can help identify those infants at risk for rapid disease progression who may benefit from early aggressive therapy.

Signs and symptoms

Many children with HIV infection do not gain weight or grow normally. HIV-infected children frequently are slow to reach important milestones in motor skills and mental development such as crawling, walking, and talking. As the disease progresses, many children develop neurologic problems such as difficulty walking, poor school performance, seizures, and other symptoms of HIV encephalopathy (a brain disorder).

Like adults with HIV infection, children with HIV develop life-threatening opportunistic infections (OIs), although the incidence of various OIs differs in adults and children.

* Toxoplasmosis (a parasitic disease) is seen less frequently in HIV-infected children than in HIV-infected adults, while serious bacterial infections occur more commonly in children than in adults.

* Pneumocystis carinii pneumonia (PCP) is the leading cause of death in HIV-infected children with AIDS. PCP, as well as cytomegalovirus (CMV) disease, usually are primary infections in children, whereas in adults these diseases result from the reactivation of latent infections.

* A lung disease called lymphocytic interstitial pneumonitis (LIP), rarely seen in adults, occurs more frequently in HIV-infected children. This condition, like PCP, can make breathing progressively more difficult and often results in hospitalization.

* Severe candidiasis, a yeast infection that can cause unrelenting diaper rash and infections in the mouth and throat that make eating difficult, is found frequently in HIV-infected children.

* As children with HIV become sicker, they may suffer from chronic diarrhea due to opportunistic pathogens.

Children with HIV suffer the usual childhood infections more frequently and more severely than uninfected children. These infections can cause seizures, fever, pneumonia, recurrent colds, diarrhea, dehydration, and other problems that often result in extended hospital stays and nutritional problems.

Treatment

While the basic principles that guide treatment of pediatric HIV infection are the same as for an HIV-infected adult, there are a number of unique scientific and medical concerns that are important to consider in treating children with HIV infection. These range from differences in age-related issues such as CD4+ T-cell counts and drug metabolism to requirements for special formulations and treatment regimens that are appropriate for infants through adolescents. As in adults, treating HIV-infected children today is a complex task of using potent combinations of antiretroviral agents to maximally suppress viral replication. NIAID investigators are defining the best treatments for pediatric patients.

NIAID-supported researchers are focusing not only on the development of new antiretroviral products but also on the critical question of how to best use the treatments that are currently available, especially in resource-poor nations. Treatment strategy questions should be designed to identify, for example, the best initial therapy, when failing regimens should be modified, and strategies to address the antiretroviral needs of children with advanced disease. Another high priority is the long-term assessment of these strategies to determine sustained antiretroviral benefits as well as to monitor for potential adverse consequences of treatment. Current guidelines for the use of antiretroviral agents in pediatric HIV infection is available at http://www.aidsinfo.nih.gov/guidelines.

Problems in families

A mother and child with HIV usually are not the only family members with the disease. Often, the mother's sexual partner is infected, and other children in the family may be infected as well. Frequently, a parent with AIDS does not survive to care for his or her HIV-infected child.

In the countries hardest hit by the AIDS epidemic, some 14 million children under 15 around the world have been orphaned by AIDS-80 percent of them (11 million) in sub-Saharan Africa alone. The rate is expected to increase. One in three of these orphans is under age five. Communities and extended families are struggling with and often overwhelmed by the vast number of children orphaned by AIDS. Many orphans and other children from families devastated by AIDS face multiple risks, such as forced relocation, violence, living on the streets, drug use, and even commercial sex. Other children suffer because sexuality education and services are not available to them or not effectively communicated to them. Living in a country undergoing political turmoil or can also raise the risk of a child becoming HIV-infected.

In the United States, most children living with HIV/AIDS live in inner cities, where poverty, illicit drug use, poor housing, and limited access to and use of medical care and social services add to the challenges of HIV disease.

One encouraging note is, according to UNAIDS, that where information, training, and services to help prevent HIV infection are made available and affordable, young people are more likely to make use of them than their elders.

Management of the complex medical and social problems of families affected by HIV requires a multidisciplinary case management team, integrating medical, social, mental health, and educational services. NIAID provides special funding to many of its clinical research sites to provide for services, such as transportation, day care, and the expertise of social workers, crucial to families devastated by HIV.

HIV Infection in Women

Overview

The number of women with HIV (human immunodeficiency virus) infection and AIDS (acquired immunodeficiency syndrome) has increased steadily worldwide. By the end of 2005, according to the World Health Organization (WHO), 17.5 million women worldwide were infected with HIV.

According to the CDC, between 2000 through 2004, the estimated number of AIDS cases in the United States increased 10 percent among females and 7 percent among males. In 2004, women accounted for 27 percent of the 44,615 newly reported AIDS cases among adults and adolescents. HIV disproportionately affects African-American and Hispanic women. Together they represent less than 25 percent of all U.S. women, yet they account for more than 79 percent of AIDS cases in women.

Worldwide, more than 90 percent of all adolescent and adult HIV infections have resulted from heterosexual intercourse. Women are particularly vulnerable to heterosexual transmission of HIV due to substantial mucosal exposure to seminal fluids. This biological fact amplifies the risk of HIV transmission when coupled with the high prevalence of non-consensual sex, sex without condom use, and the unknown and/or high-risk behaviors of their partners.

Women suffer from the same complications of AIDS that afflict men but also suffer gender-specific manifestations of HIV disease, such as recurrent vaginal yeast infections, severe pelvic inflammatory disease (PID), and an increased risk of precancerous changes in the cervix including probable increased rates of cervical cancer. Women also exhibit different characteristics from men for many of the same complications of antiretroviral therapy, such as metabolic abnormalities.

Frequently, women with HIV infection have great difficulty accessing health care and carry a heavy burden of caring for children and other family members who may also be HIV-infected. They often lack social support and face other challenges that may interfere with their ability to obtain or adhere to treatment.

Current research

To confront the growing problem of HIV infection and AIDS in women, the National Institute of Allergy and Infectious Diseases (NIAID) has made woman-focused research an important component of the Institute's AIDS research program.

NIAID is studying the course of HIV/AIDS disease in women through the Women's Interagency HIV Study (WIHS) and supports clinical trials to investigate gender-specific differences in disease progression, complications, and treatment though the Adult AIDS Clinical Trials Group (ACTG), the Pediatric AIDS Clinical Trials Group (PACTG), and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The HIV Prevention Trials Network (HPTN) investigates non- vaccine prevention strategies.

Natural History and Epidemiological Research

NIAID supports studies in the United States and abroad of the natural history and manifestations of HIV infection in both non-pregnant and pregnant women, as well as the factors that influence the transmission of HIV to women through WIHS. WIHS is a multi-site, prospective cohort of predominantly minority HIV-infected and uninfected women and is currently f ollowing 2,441 women. The study recently increased enrollment to evaluate clinical outcomes in the era of highly active antiretroviral therapy (HAART), including time to develop AIDS, impact of resistance to antiretroviral therapy, the effect of co-infections such as hepatitis C and human papillomavirus (HPV), the effects of metabolic abnormalities and toxicities, the impact of hormonal factors on HIV disease, and the impact of aging on HIV disease, which includes assessing neurocognitive functioning and physical impairment.

Recently, WIHS implemented an intensive protocol to evaluate cardiovascular manifestations of HIV among women. This study was the outgrowth of a workshop held in May 2003 that was co- sponsored by NIAID and the National Heart, Lung and Blood Institute. So that gender comparisons can be made, a similar investigation is taking place in the Multi-center AIDS Cohort Study, a cohort of men who have sex with men, and the Tri-Service AIDS Clinical Consortium, a cohort of HIV-infected U.S. military personnel.

Topical microbicides

Because HIV is spread predominantly through sexual transmission, the development of chemical, biological, and physical barriers that can be used intravaginally or intrarectally to inactivate HIV and other sexually transmitted infection (STI) pathogens is critically important for controlling HIV infection.

Scientists are developing and testing new chemical and biological compounds that women could apply before intercourse to protect themselves against HIV and other sexually transmitted organisms. These include creams or gels, known as topical microbicides, that ideally would be non-irritating, inexpensive, and unobtrusive. The research effort for developing topical microbicides includes basic research, preclinical product development, and clinical evaluation.

To clinically evaluate the safety of vaginal formulations of microbicide products, NIAID is supporting the adaptation of imaging technology (Optical Coherence Tomography) developed for other indications, among other techniques, and is examining the potential relevance of specific parameters, such as endometrial toxicity and vaginal innate immunity. NIAID-supported researchers continue to evaluate microbicide candidates for safety in animal models (pig tailed macaques), coordinate the results with other testing to facilitate product development, and test safety and efficacy in clinical trials. At present, NIAID is supporting the development and evaluation of 23 compounds and/or combinations through its Integrated Preclinical/Clinical Program for HIV Topical Microbicides. Some of the new products in development include a combination product using dendrimer and BufferGel, both of which have entered into clinical testing separately and the use bioengineered Lactobacillus expressing a broad range of protein-based microbicides.

In February 2005, NIAID initiated a multicenter clinical trial (HPTN 035) to examine the safety and preliminary effectiveness of BufferGel and PRO2000/5 Gel (P) to prevent HIV infection. The trial, which is the first microbicide safety and effectiveness trial of this magnitude to be supported by NIAID, is being conducted through the HPTN and represents a partnership among various research institutions in Africa and the United States. The primary objective of the trial is to evaluate the safety and effectiveness of BufferGel and PRO2000/5 Gel (P) when applied intravaginally by women at risk for sexually-transmitted HIV infection. Women are currently being enrolled at sites in Philadelphia, Pennsylvania; Lilongwe and Blantrye, Malawi; and Durban and Hlabisa, South Africa, Harare and Chitungwiza, Zimbabwe, and Lusaka, Zambia.

Another study, the HIV Prevention Preparedness Study (HPTN 055) was conducted in Zambia, South Africa, and Tanzania to assess the ability of sites to recruit and retain participants for future efficacy trials of topical microbicides. This study has helped obtain reliable data on HIV seroprevalence and seroincidence in the target populations.

Recently, NIAID-funded investigators demonstrated that combination microbicides may be more efficient than single microbicides at preventing vaginal transmission of simian HIV(SHIV) in rhesus macaques. This has important implications for future microbicide research because it is highly possible that first generation microbicides may at best be only 30 to 50 percent effective, given the complexity of HIV transmission. Thus, combinations resulting in additive or synergistic inhibition of HIV transmission could offer the potential to reduce individual microbicide concentrations resulting in a more potent and cost effective microbicide strategy. This study, which was the first to investigate the efficacy of combination microbicides, had a goal of achieving at least 50 percent protection for the monkeys. It was not only achieved, but was surpassed, in some cases, with certain combinations. This study demonstrates that combination microbicides can result in what appears to be synergistic inhibition of virus transmission in monkeys and offers support for the hypothesis that optimization of combination microbicides could result in enhanced microbicide strategies.

Another finding recently released provided proof that disrupting how the virus attaches itself to cells completely protected monkeys that were vaginally exposed to SHIV. This was done with the use of PSC-RANTES, a chemically modified form of a protein called RANTES, that works by targeting a protein in the body called C-C chemokine receptor 5 (CCR5), a receptor on human cells to which HIV binds. In addition to CD4, there are co-receptors, such as CCR5 and CXCR4. Sexual transmission of HIV is thought to predominantly involve CCR5. HIV needs CCR5 to achieve infection of any given cell.

For the virus to be transmitted during heterosexual intercourse-the primary method the virus is spread in many parts of the world-the virus must attach to CCR5 in cells within the vaginal mucosa. When these cells were protected with a topical microbicide containing a high enough concentration of PSC-RANTES, however, the virus could not attach to them, thus preventing transmission. This work represents the first demonstration of significant protection through a range of doses for any protein-based microbicide and demonstrated that it was possible to achieve in vivo concentrations of protein microbicides that could afford 100 percent protection of exposed individuals.

To further develop vaginal microbicides, NIAID entered into an agreement with the International Partnership for Microbicides (IPM) earlier this year to share information and expertise. This agreement draws on complementary strengths of the two organizations. NIAID brings funding resources and expertise in topical microbicide discovery and early product development for HIV and other STIs to the partnership, while IPM has enhanced capacity to design optimal microbicide formulations, manufacture pilot lots of microbicides for clinical testing, and implement clinical trials.

NIAID's Topical Microbicide Strategic Plan, which details long-range plans for advancing microbicide concepts from the laboratory to clinical trials, is available on NIAID's Web site at www.niaid.nih.gov/publications/topical_microbicide_strategic_plan.pdf.

Transmission of HIV to women

In the United States, most women are infected with HIV during sex with an HIV-infected man or while using HIV-contaminated syringes for the injection of drugs such as heroin, cocaine, and amphetamines. Of the new HIV infections diagnosed among women in the United States in 2004, CDC estimated 70 percent were attributed to heterosexual contact and 28 percent to injection drug use.

In this country, studies have shown that during unprotected heterosexual intercourse with an HIV-infected partner, women have a greater risk of becoming infected than uninfected men who have heterosexual intercourse with an HIV-infected woman. In other parts of the world, however, this is not necessarily true. In Uganda, for example, one study demonstrated that the risk of HIV transmission from woman to man was the same as from man to woman. This difference may be due to the lack of circumcision in Ugandan men.

Studies in both the United States and abroad have demonstrated that STIs, particularly infections that cause ulcerations of the vagina (for example, genital herpes, syphilis, and chancroid), greatly increase a woman's risk of becoming infected with HIV. NIAID-sponsored cohort studies in the United States have also found a number of other factors to be associated with an increased risk of heterosexual HIV transmission, including alcohol use, history of childhood sexual abuse, current domestic abuse, and use of crack/cocaine.

Consistent and correct use of male latex condoms greatly reduces the risk of becoming infected with HIV. In studies of heterosexual couples, in which one individual was HIV-positive and the other uninfected and regular condom use was reported, the rate of HIV transmission was extremely low.

Studies examining the use of antiretroviral drugs to try to prevent transmission are also underway. For example, the HPTN (HPTN 052) has a study examining serodiscordant couples with CD4 counts above 300 cells to determine whether HAART, when given to the infected partner along with prevention counseling and interventions like condoms, prevents HIV transmission to the uninfected partner better than prevention counseling and prevention services alone.

Mother-to-child transmission of HIV

In the United States, approximately 25 percent of pregnant HIV-infected women who do not receive AZT or a combination of antiretroviral therapies pass the virus to their babies. If women do receive a combination of antiretroviral therapies during pregnancy, however, the risk of HIV transmission to the newborn drops below 2 percent. (There were 84 infected infants born in the US in 2004 http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2004report/table23.htm.)

The risk of mother-to-child transmission is significantly increased if the mother has advanced HIV disease, high amounts of HIV in her bloodstream, or fewer-than-normal amounts of the CD4+ T cells.

Other factors that may increase the risk include:

* Drug use, such as heroin or crack/cocaine

* Severe inflammation of fetal membranes

* A prolonged period between membrane rupture and delivery

Most mother-to-child transmission, an estimated 50 to 70 percent, probably occurs late in pregnancy or during birth. Although the exact ways the virus is transmitted are unknown, scientists think it may happen when the mother's blood enters fetal circulation or by mucosal exposure to the virus during labor and delivery. One NIAID-sponsored study also found that HIV-infected women who gave birth more than 4 hours after rupture of the fetal membranes were nearly twice as likely to transmit HIV to their babies, as compared to women who delivered within 4 hours of membrane rupture. In the same study, HIV-infected women who used heroin or crack/cocaine during pregnancy were also twice as likely to transmit HIV to their babies as compared to HIV-infected women who did not use drugs.

NIAID supports research on mother-to-child transmission through the PACTG, ACTG, and HPTN, and until recently, through the Women and Infants Transmission Study (WITS), a prospective cohort study that has followed HIV-infected mothers and their children since 1988. Since that time, WITS researchers have examined factors that contribute to perinatal transmission, evaluated disease progression and contributing factors during pregnancy and postpartum in HIV-infected women and their infants, and evaluated diagnostic tools for determining HIV status in infants. Sponsored by NIAID, the National Institute of Child Health and Human Development, and the National Institute on Drug Abuse, WITS will be phasing out over the coming year.

The first regimen to prevent mother-to-child transmission was identified in a landmark study conducted in 1994 by the PACTG. A specific regimen of AZT (azidothymidine) given to an HIV-infected woman during pregnancy and to her baby after birth was shown to reduce mother-to-child HIV transmission by two-thirds.

In another NIAID-sponsored study (HIVNET 012) in Uganda, researchers identified a highly effective and safe drug regimen for preventing transmission of HIV from an infected mother to her newborn that is more affordable and practical than any other course of therapy examined to date. The study demonstrated that a single oral dose of the antiretroviral drug, nevirapine (NVP), given to an HIV-infected woman in labor and another dose given to her baby within 3 days of birth reduces the transmission rate by about half compared with a course of AZT given only during labor and delivery. Additional data from this study demonstrated the continued benefit and safety of NVP in reducing mother-to-child transmission up to 18 months, even in a breastfeeding population. This study suggests that women in the United States who are identified as HIV-infected very late in pregnancy or at the time of labor and delivery could lower the rates of HIV transmission to their babies by following a NVP-containing regimen.

Data from HIVNET 012 also showed that resistance to NVP was present in approximately 19 percent of women 6 to 8 weeks after the single dose of NVP. After 12 to 24 months, there was no NVP resistance detectable in these women using standard methods of HIV resistance testing. Nevertheless, these data are of concern because preliminary data from a small, uncontrolled trial presented at the 2004 Retrovirus Conference in San Francisco by Jourdain et al. showed that women who had received previous single dose NVP had poorer virologic outcome when treated with HAART than women who had never received NVP.

Studies are now underway to examine the effects of exposure to single dose nevirapine (SD NVP) on future treatment options for women and children. One study currently open to enrollment in Africa is evaluating the effect of previous exposure to SD NVP on the mother's future treatment options (Optimal Combined Therapy after Nevirapine Exposure, ACTG 5208). A similar trial for infants is in development (PACTG 1060). Strategies to minimize viral resistance after SD NVP are also being explored in two other studies. The first study will compare the impact of three antiretroviral strategies administered on reducing NVP resistance following SD NVP, and the second will examine the pharmacokinetics and incidence of NVP resistance in women who receive SD NVP alone or in combination with one of two other regimens.

The HPTN is also conducting a study to compare three antiretroviral regimens for post-exposure prophylaxis of HIV-uninfected infants born to HIV-infected women whose HIV status was unknown at the time of delivery and who were therefore not exposed to a prenatal or perinatal antiretroviral regimen (HPTN 040).

HIV may also be transmitted from a nursing mother to her child. A series of studies have determined that breastfeeding increases the risk of HIV transmission by about 14 percent. Currently, the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommends that HIV-positive women be educated and counseled so they can make an informed decision about how to best feed their children.

Research to identify effective strategies for reducing the risk of transmission through breastfeeding is underway in areas of the world where the benefits of breastfeeding outweigh the risks. This includes early weaning strategies as well as evaluating drugs or vaccines to reduce the risk of transmission from breastfeeding.

To further evaluate ways to prevent HIV transmission during breastfeeding, the HPTN is initiating a study of NVP for breastfeeding infants of HIV-infected mothers (HPTN 046). Similarly, an investigator-initiated study for preventing MTCT is underway in Ethiopia and Uganda to evaluate a 6-week regimen of NVP administered to HIV-uninfected infants born to HIV-infected breastfeeding mothers. In Uganda, another component of the study will be added to passively immunize the breastfeeding children with HIV immune globulin (HIV-Ig).

Signs and symptoms of HIV infection

Many manifestations of HIV infection are similar in men and women. Both men and women with HIV may have non-specific symptoms even early in disease, including low-grade fevers, night sweats, fatigue, and weight loss. Anti-HIV therapies, as well as treatments for other infections associated with HIV, appear to be similarly effective in men and women. Other conditions, however, occur in different frequencies in men and women. HIV-infected men, for instance, are eight times more likely than HIV-infected women to develop a skin cancer known as Kaposi's sarcoma. In some studies, women had higher rates of herpes simplex infections than men.

Data from several studies conducted by the Community Programs for Clinical Research on AIDS (CPCRA) found that HIV-infected women were also more likely than HIV-infected men to develop bacterial pneumonia. This finding may be explained by factors such as a delay in seeking care among HIV-infected women as compared to men, and less access to anti-HIV therapies or preventive therapies for Pneumocystis carinii pneumonia, or PCP.

Woman-specific symptoms of HIV infection

Women also experience HIV-associated gynecologic problems, many of which occur in uninfected women but with less frequency or severity.

Vaginal yeast infections, common and easily treated in most women, often are particularly persistent and difficult to treat in HIV-infected women. Data from WIHS suggest that these infections are considerably more frequent in HIV-infected women. Health care providers commonly treat yeast infections with fluconazole. A CPCRA study demonstrated that weekly doses of fluconazole can also safely prevent oropharyngeal and vaginal, but not esophageal yeast infections, without resulting in drug resistance.

Other vaginal infections may occur more frequently and with greater severity in HIV-infected women, including bacterial vaginosis and common STIs such as gonorrhea, chlamydia, and trichomoniasis.

Severe herpes simplex virus ulcerations, which are sometimes unresponsive to therapy with the standard drug acyclovir, can severely compromise a woman's quality of life.

Idiopathic genital ulcers, with no evidence of an infectious organism or cancerous cells in the lesion, are a unique manifestation of HIV infection. These ulcers, for which there is no proven treatment, are sometimes confused with those caused by herpes simplex virus.

HPV infections, which cause genital warts and can lead to cervical cancer, occur more frequently in HIV-infected women. A precancerous condition associated with HPV, called cervical dysplasia, is also more common and more severe in HIV-infected women and more apt to recur after treatment.

PID appears to be more common and more aggressive in HIV-infected women than in uninfected women. PID may become a chronic and relapsing condition as a woman's immune system deteriorates.

Menstrual irregularities frequently are reported by HIV-infected women and are being actively studied by NIAID-supported scientists. Although menstrual irregularities were equally common in HIV-infected women and at-risk HIV-negative women in a WIHS survey, women with CD4+ T-cell counts below 50 per cubic millimeter (mm3) of blood were more likely to report no periods than were uninfected women, or HIV-infected women with higher CD4+ T-cell counts.

Gynecologic Screening

CDC currently recommends that HIV-positive women have a complete gynecologic evaluation, including a Pap smear, as part of their initial HIV evaluations, or upon entry to prenatal care, and another Pap smear 6 months later. If both smears are negative, annual screening is recommended thereafter in asymptomatic women. The agency also recommends more frequent screenings-every 6 months-for women with symptomatic HIV infection, prior abnormal Pap smears, or signs of HPV infection.

Early diagnosis

Some women in the United States have poor access to health care. In addition, women may not think they are at risk for HIV infection. They may not heed symptoms that could serve as warning signals of HIV infection, such as recurrent yeast infections. PID and the other symptoms discussed above should signal health care providers to offer women HIV testing with counseling.

Early diagnosis of HIV infection allows women to take full advantage of antiretroviral treatments and preventive medicines for opportunistic infections when their health care providers think it is appropriate. Both appropriate therapy and preventive drugs can forestall the development of AIDS-related symptoms and prolong life in HIV-infected women as well as men. Early diagnosis also allows women to make informed reproductive choices. Health care providers should be alert to early signs of HIV infection in women. In addition, all women should consider HIV testing if they have engaged in behaviors that put them at risk of infection.

Survival

Women whose HIV infections are detected early and receive appropriate treatment survive as long as HIV-infected men. Although several studies have shown HIV-infected women to have shorter survival times than men, this may be because women are less likely than men to be diagnosed early.

In an analysis of several studies involving more than 4,500 people with HIV infection, women were 33 percent more likely than men to die within the study period. The investigators could not definitively identify the reasons for excess mortality among women in this study, but they speculated that poorer access to or use of health care resources among HIV-infected women as compared to men, domestic violence, homelessness, and lack of social supports may have been important factors.

The evidence that HIV causes AIDS

Background

The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981 and has since become a major worldwide pandemic. AIDS is caused by the human immunodeficiency virus (HIV). By leading to the destruction and/or functional impairment of cells of the immune system, notably CD4+ T cells, HIV progressively destroys the body's ability to fight infections and certain cancers.

An HIV-infected person is diagnosed with AIDS when his or her immune system is seriously compromised and manifestations of HIV infection are severe. The CDC currently defines AIDS in an adult or adolescent age 13 years or older as the presence of one of 26 conditions indicative of severe immunosuppression associated with HIV infection, such as Pneumocystis carinii pneumonia (PCP), a condition extraordinarily rare in people without HIV infection. Most other AIDS-defining conditions are also 'opportunistic infections' which rarely cause harm in healthy individuals. A diagnosis of AIDS also is given to HIV-infected individuals when their CD4+ T-cell count falls below 200 cells/cubic millimeter (mm3) of blood. Healthy adults usually have CD4+ T-cell counts of 600-1,500/mm3 of blood. In HIV-infected children younger than 13 years, the CDC definition of AIDS is similar to that in adolescents and adults, except for the addition of certain infections commonly seen in pediatric patients with HIV. (CDC. MMWR 1992;41(RR-17):1; CDC. MMWR 1994;43(RR-12):1).

In many developing countries, where diagnostic facilities may be minimal, healthcare workers use a World Health Organization (WHO) AIDS case definiton based on the presence of clinical signs associated with immune deficiency and the exclusion of other known causes of immunosuppression, such as cancer or malnutrition. An expanded WHO AIDS case definition, with a broader spectrum of clinical manifestations of HIV infection, is employed in settings where HIV antibody tests are available (WHO. Wkly Epidemiol Rec. 1994;69:273).

As of the end of 2000, an estimated 36.1 million people worldwide - 34.7 million adults and 1.4 million children younger than 15 years - were living with HIV/AIDS. Through 2000, cumulative HIV/AIDS-associated deaths worldwide numbered approximately 21.8 million - 17.5 million adults and 4.3 million children younger than 15 years. In the United States, an estimated 800,000 to 900,000 people are living with HIV infection. As of December 31, 1999, 733,374 cases of AIDS and 430,441 AIDS-related deaths had been reported to the CDC. AIDS is the fifth leading cause of death among all adults aged 25 to 44 in the United States. Among African-Americans in the 25 to 44 age group, AIDS is the leading cause of death for men and the second leading cause of death for women (UNAIDS. AIDS epidemic update: December 2000; CDC. HIV/AIDS Surveillance Report 1999;11[2]:1; CDC. MMWR 1999;48[RR13]:1).

HIV fulfills Koch's postulates as the cause of AIDS.

Among many criteria used over the years to prove the link between putative pathogenic (disease-causing) agents and disease, perhaps the most-cited are Koch's postulates, developed in the late 19th century. Koch's postulates have been variously interpreted by many scientists, and modifications have been suggested to accommodate new technologies, particularly with regard to viruses (Harden. Pubbl Stn Zool Napoli [II] 1992;14:249; O'Brien, Goedert. Curr Opin Immunol 1996;8:613). However, the basic tenets remain the same, and for more than a century Koch's postulates, as listed below, have served as the litmus test for determining the cause of any epidemic disease:

1. Epidemiological association: the suspected cause must be strongly associated with the disease.

2. Isolation: the suspected pathogen can be isolated - and propagated - outside the host.

3. Transmission pathogenesis: transfer of the suspected pathogen to an uninfected host, man or animal, produces the disease in that host.

With regard to postulate #1, numerous studies from around the world show that virtually all AIDS patients are HIV-seropositive; that is they carry antibodies that indicate HIV infection. With regard to postulate #2, modern culture techniques have allowed the isolation of HIV in virtually all AIDS patients, as well as in almost all HIV-seropositive individuals with both early- and late-stage disease. In addition, the polymerase chain (PCR) and other sophisticated molecular techniques have enabled researchers to document the presence of HIV genes in virtually all patients with AIDS, as well as in individuals in earlier stages of HIV disease.

Postulate #3 has been fulfilled in tragic incidents involving three laboratory workers with no other risk factors who have developed AIDS or severe immunosuppression after accidental exposure to concentrated, cloned HIV in the laboratory. In all three cases, HIV was isolated from the infected individual, sequenced and shown to be the infecting strain of virus. In another tragic incident, transmission of HIV from a Florida dentist to six patients has been documented by genetic analyses of virus isolated from both the dentist and the patients. The dentist and three of the patients developed AIDS and died, and at least one of the other patients has developed AIDS. Five of the patients had no HIV risk factors other than multiple visits to the dentist for invasive procedures (O'Brien, Goedert. Curr Opin Immunol 1996;8:613; O'Brien, 1997; Ciesielski et al. Ann Intern Med 1994;121:886).

In addition, through December 1999, the CDC had received reports of 56 health care workers in the United States with documented, occupationally acquired HIV infection, of whom 25 have developed AIDS in the absence of other risk factors. The development of AIDS following known HIV seroconversion also has been repeatedly observed in pediatric and adult blood transfusion cases, in mother-to-child transmission, and in studies of hemophilia, injection-drug use and sexual transmission in which seroconversion can be documented using serial blood samples (CDC. HIV AIDS Surveillance Report 1999;11[2]:1; AIDS Knowledge Base, 1999). For example, in a 10-year study in the Netherlands, researchers followed 11 children who had become infected with HIV as neonates by small aliquots of plasma from a single HIV-infected donor. During the 10-year period, eight of the children died of AIDS. Of the remaining three children, all showed a progressive decline in cellular immunity, and two of the three had symptoms probably related to HIV infection (van den Berg et al. Acta Paediatr 1994;83:17).

Koch's postulates also have been fulfilled in animal models of human AIDS. Chimpanzees experimentally infected with HIV have developed severe immunosuppression and AIDS. In severe combined immunodeficiency (SCID) mice given a human immune system, HIV produces similar patterns of cell killing and pathogenesis as seen in people. HIV-2, a less virulent variant of HIV which causes AIDS in people, also causes an AIDS-like syndrome in baboons. More than a dozen strains of simian immunodeficiency virus (SIV), a close cousin of HIV, cause AIDS in Asian macaques. In addition, chimeric viruses known as SHIVs, which contain an SIV backbone with various HIV genes in place of the corresponding SIV genes, cause AIDS in macaques. Further strengthening the association of these viruses with AIDS, researchers have shown that SIV/SHIVs isolated from animals with AIDS cause AIDS when transmitted to uninfected animals (O'Neil et al. J Infect Dis 2000;182:1051; Aldrovandi et al. Nature 1993;363:732; Liska et al. AIDS Res Hum Retroviruses 1999;15:445; Locher et al. Arch Pathol Lab Med 1998;22:523; Hirsch et al. Virus Res 1994;32:183; Joag et al. J Virol 1996;70:3189).

AIDS and HIV infection are invariably linked in time, place and population group.

Historically, the occurence of AIDS in human populations around the world has closely followed the appearance of HIV. In the United States, the first cases of AIDS were reported in 1981 among homosexual men in New York and California, and retrospective examination of frozen blood samples from a U.S. cohort of gay men showed the presence of HIV antibodies as early as 1978, but not before then. Subsequently, in every region, country and city where AIDS has appeared, evidence of HIV infection has preceded AIDS by just a few years (CDC. MMWR 1981;30:250; CDC. MMWR 1981;30:305; Jaffe et al. Ann Intern Med 1985;103:210; U.S. Census Bureau; UNAIDS).

Many studies agree that only a single factor, HIV, predicts whether a person will develop AIDS.

Other viral infections, bacterial infections, sexual behavior patterns and drug abuse patterns do not predict who develops AIDS. Individuals from diverse backgrounds, including heterosexual men and women, homosexual men and women, hemophiliacs, sexual partners of hemophiliacs and transfusion recipients, injection-drug users and infants have all developed AIDS, with the only common denominator being their infection with HIV (NIAID, 1995).

In cohort studies, severe immunosuppression and AIDS-defining illnesses occur almost exclusively in individuals who are HIV-infected.

For example, analysis of data from more than 8,000 participants in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) demonstrated that participants who were HIV-seropositive were 1,100 times more likely to develop an AIDS-associated illness than those who were HIV-seronegative. These overwhelming odds provide a clarity of association that is unusual in medical research.

In a Canadian cohort, investigators followed 715 homosexual men for a median of 8.6 years. Every case of AIDS in this cohort occurred in individuals who were HIV-seropositive. No AIDS-defining illnesses occurred in men who remained negative for HIV antibodies, despite the fact that these individuals had appreciable patterns of illicit drug use and receptive anal intercourse (Schechter et al. Lancet 1993;341:658).

Before the appearance of HIV, AIDS-related diseases such as PCP, KS and MAC were rare in developed countries; today, they are common in HIV-infected individuals.

Prior to the appearance of HIV, AIDS-related conditions such as Pneumocystis carinii pneumonia (PCP), Kaposi's sarcoma (KS) and disseminated infection with the Mycobacterium avium complex (MAC) were extraordinarily rare in the United States. In a 1967 survey, only 107 cases of PCP in the United States had been described in the medical literature, virtually all among individuals with underlying immunosuppressive conditions. Before the AIDS epidemic, the annual incidence of Kaposi's sarcoma in the United States was only 0.2 to 0.6 cases per million population, and only 32 individuals with disseminated MAC disease had been described in the medical literature (Safai. Ann NY Acad Sci 1984;437:373; Le Clair. Am Rev Respir Dis 1969;99:542; Masur. JAMA 1982;248:3013).

By the end of 1999, CDC had received reports of 166,368 HIV-infected patients in the United States with definitive diagnoses of PCP, 46,684 with definitive diagnoses of KS, and 41,873 with definitive diagnoses of disseminated MAC (personal communication).

In developing countries, patterns of both rare and endemic diseases have changed dramatically as HIV has spread, with a far greater toll now being exacted among the young and middle-aged, including well-educated members of the middle class.

In developing countries, the emergence of the HIV epidemic has dramatically changed patterns of disease in affected communities. As in developed countries, previously rare, 'opportunistic' diseases such as PCP and certain forms of meningitis have become more commonplace. In addition, as HIV seroprevalence rates have risen, there have been significant increases in the burden of endemic conditions such as tuberculosis (TB), particularly among young people. For example, as HIV seroprevalence increased sharply in Blantyre, Malawi from 1986 to 1995, tuberculosis admissions at the city's main hospital rose more than 400 percent, with the largest increase in cases among children and young adults. In the rural Hlabisa District of South Africa, admissions to tuberculosis wards increased 360 percent from 1992 to 1998, concomitant with a steep rise in HIV seroprevalence. High rates of mortality due to endemic conditions such as TB, diarrheal diseases and wasting syndromes, formerly confined to the elderly and malnourished, are now common among HIV-infected young and middle-aged people in many developing countries (UNAIDS, 2000; Harries et al. Int J Tuberc Lung Dis 1997;1:346; Floyd et al. JAMA 1999;282:1087).

In studies conducted in both developing and developed countries, death rates are markedly higher among HIV-seropositive individuals than among HIV-seronegative individuals.

For example, Nunn and colleagues (BMJ 1997;315:767) assessed the impact of HIV infection over five years in a rural population in the Masaka District of Uganda. Among 8,833 individuals of all ages who had an unambiguous result on testing for HIV-antibodies (either 2 or 3 different test kits were used for blood samples from each individual), HIV-seropositive people were 16 times more likely to die over five years than HIV-seronegative people (see table). Among individuals ages 25 to 34, HIV-seropositive people were 27 times more likely to die than HIV-seronegative people.

In another study in Uganda, 19,983 adults in the rural Rakai District were followed for 10 to 30 months (Sewankambo et al. AIDS 2000;14:2391). In this cohort, HIV-seropositive people were 20 times more likely to die than HIV-seronegative people during 31,432 person-years of observation.

Similar findings have emerged from other studies (Boerma et al. AIDS 1998;12(suppl 1):S3); for example,

* in Tanzania, HIV-seropositive people were 12.9 time more likely to die over two years than HIV-seronegative people (Borgdorff et al. Genitourin Med 1995;71:212)

* in Malawi, mortality over three years among children who survived the first year of life was 9.5 times higher among HIV-seropositive children than among HIV-seronegative children (Taha et al. Pediatr Infect Dis J 1999;18:689)

* in Rwanda, mortality was 21 times higher for HIV-seropositive children than for HIV-seronegative children after five years (Spira et al. Pediatrics 1999;14:e56). Among the mothers of these children, mortality was 9 times higher among HIV-seropositive women than among HIV-seronegative women in four years of follow-up (Leroy et al. J Acquir Immune Defic Syndr Hum Retrovirol 1995;9:415).

* in Cote d'Ivoire, HIV-seropositive individuals with pulmonary tuberculosis (TB) were 17 times more likely to die within six months than HIV-seronegative individuals with pulmonary TB (Ackah et al. Lancet 1995; 345:607).

* in the former Zaire (now the Democratic Republic of Congo), HIV-infected infants were 11 times more likely to die from diarrhea than uninfected infants (Thea et al. NEJM 1993;329:1696).

* in South Africa, the death rate for children hospitalized with severe lower respiratory tract infections was 6.5 times higher for HIV-infected infants than for uninfected children (Madhi et al. Clin Infect Dis 2000;31:170).

Kilmarx and colleagues (Lancet 2000; 356:770) recently reported data on HIV infection and mortality in a cohort of female commercial sex workers in Chiang Rai, Thailand. Among 500 women enrolled in the study between 1991 and 1994, the mortality rate through October 1998 among women who were HIV-infected at enrollment (59 deaths among 160 HIV-infected women) was 52.7 times higher than among women who remained uninfected with HIV (2 deaths among 306 uninfected women). The mortality rate among women who became infected during the study (7 deaths among 34 seroconverting women) was 22.5 higher than among persistently uninfected women. Among the HIV-infected women, only 3 of whom received antiretroviral medications, all reported causes of death were associated with immunosuppression, whereas the reported causes of death of the two uninfected women were postpartum amniotic embolism and gunshot wound.

Excess mortality among HIV-seropositive people also has been repeatedly observed in studies in developed countries, perhaps most dramatically among hemophiliacs. For example, Darby et al. (Nature 1995;377:79) studied 6,278 hemophiliacs living in the United Kingdom during the period 1977-91. Among 2,448 individuals with severe hemophilia, the annual death rate was stable at 8 per 1,000 during 1977-84. While death rates remained stable at 8 per 1,000 from 1985-1992 among HIV-seronegative persons with severe hemophilia, deaths rose steeply among those who had become HIV-seropositive following HIV-tainted transfusions during 1979-1986, reaching 81 per 1,000 in 1991-92. Among 3,830 individuals with mild or moderate hemophilia, the pattern was similar, with an initial death rate of 4 per 1,000 in 1977-84 that remained stable among HIV-seronegative individuals but rose to 85 per 1,000 in 1991-92 among seropositive individuals.

Similar data have emerged from the Multicenter Hemophilia Cohort Study. Among 1,028 hemophiliacs followed for a median of 10.3 years, HIV-infected individuals (n=321) were 11 times more likely to die than HIV-negative subjects (n=707), with the dose of Factor VIII having no effect on survival in either group (Goedert. Lancet 1995;346:1425).

In the Multicenter AIDS Cohort Study (MACS), a 16-year study of 5,622 homosexual and bisexual men, 1,668 of 2,761 HIV-seropositive men have died (60 percent), 1,547 after a diagnosis of AIDS. In contrast, among 2,861 HIV-seronegative participants, only 66 men (2.3 percent) have died (A. Munoz, MACS, personal communication).

HIV can be detected in virtually everyone with AIDS.

Recently developed sensitive testing methods, including the polymerase chain reaction (PCR) and improved culture techniques, have enabled researchers to find HIV in patients with AIDS with few exceptions. HIV has been repeatedly isolated from the blood, semen and vaginal secretions of patients with AIDS, findings consistent with the epidemiologic data demonstrating AIDS transmission via sexual activity and contact with infected blood (Hammer et al. J Clin Microbiol 1993;31:2557; Jackson et al. J Clin Microbiol 1990;28:16).

Numerous studies of HIV-infected people have shown that high levels of infectious HIV, viral antigens, and HIV nucleic acids (DNA and RNA) in the body predict immune system deterioration and an increased risk for developing AIDS. Conversely, patients with low levels of virus have a much lower risk of developing AIDS.

For example, in an anlysis of 1,604 HIV-infected men in the Multicenter AIDS Cohort Study (MACS), the risk of a patient developing AIDS with six years was strongly associated with levels of HIV RNA in the plasma as measured by a sensitive test known as the branched-DNA signal-amplification assay (bDNA):

Similar associations between increasing HIV RNA levels and a greater risk of disease progression have been observed in HIV-infected children in both developed and developing countries (Palumbo et al. JAMA 1998;279:756; Taha et al. AIDS 2000;14:453).

In the very small proportion of untreated HIV-infected individuals whose disease progresses very slowly, the amount of HIV in the blood and lymph nodes is significantly lower than in HIV-infected people whose disease progression is more typical (Pantaleo et al. NEJM 1995;332:209; Cao et al. NEJM 1995;332:201; Barker et al. Blood 1998;92:3105).

The availability of potent combinations of drugs that specifically block HIV replication has dramatically improved the prognosis for HIV-infected individuals. Such an effect would not be seen if HIV did not have a central role in causing AIDS.

Clinical trials have shown that potent three-drug combinations of anti-HIV drugs, known as highly active antiretroviral therapy (HAART), can significantly reduce the incidence of AIDS and death among HIV-infected individuals as compared to previously available HIV treatment regimens (Hammer et al. NEJM 1997;337:725; Cameron et al. Lancet 1998;351:543).

Use of these potent anti-HIV combination therapies has contributed to dramatic reductions in the incidence of AIDS and AIDS-related deaths in populations where these drugs are widely available, among both adults and children (Figure 1; CDC. HIV AIDS Surveillance Report 1999;11[2]:1; Palella et al. NEJM 1998;338:853; Mocroft et al. Lancet 1998;352:1725; Mocroft et al. Lancet 2000;356:291; Vittinghoff et al. J Infect Dis 1999;179:717; Detels et al. JAMA 1998;280:1497; de Martino et al. JAMA 2000;284:190; CASCADE Collaboration. Lancet 2000;355:1158; Hogg et al. CMAJ 1999;160:659; Schwarcz et al. Am J Epidemiol 2000;152:178; Kaplan et al. Clin Infect Dis 2000;30:S5; McNaghten et al. AIDS 1999;13:1687;).

For example, in a prospective study of more than 7,300 HIV-infected patients in 52 European outpatient clinics, the incidence of new AIDS-defining illnesses declined from 30.7 per 100 patient-years of observation in 1994 (before the availability of HAART) to 2.5 per 100 patient years in 1998, when the majority of patients received HAART (Mocroft et al. Lancet 2000;356:291).

Among HIV-infected patients who receive anti-HIV therapy, those whose viral loads are driven to low levels are much less likely to develop AIDS or die than patients who do not respond to therapy. Such an effect would not be seen if HIV did not have a central role in causing AIDS.

Clinical trials in both HIV-infected children and adults have demonstrated a link between a good virologic response to therapy (i.e. much less virus in the body) and a reduced risk of developing AIDS or dying (Montaner et al. AIDS 1998;12:F23; Palumbo et al. JAMA 1998;279:756; O'Brien et al. NEJM 1996;334:426; Katzenstein et al. NEJM 1996;335:1091; Marschner et al. J Infect Dis 1998;177:40; Hammer et al. NEJM 1997;337:725; Cameron et al. Lancet 1998;351:543).

This effect has also been seen in routine clinical practice. For example, in an analysis of 2,674 HIV-infected patients who started highly active antiretroviral therapy (HAART) in 1995-1998, 6.6 percent of patients who achieved and maintained undetectable viral loads (<400 copies/mL of blood) developed AIDS or died within 30 months, compared with 20.1 percent of patients who never achieved undetectable concentrations (Ledergerber et al. Lancet 1999;353:863).

Nearly everyone with AIDS has antibodies to HIV.

A survey of 230,179 AIDS patients in the United States revealed only 299 HIV-seronegative individuals. An evaluation of 172 of these 299 patients found 131 actually to be seropositive; an additional 34 died before their serostatus could be confirmed (Smith et al. N Engl J Med 1993;328:373).

Numerous serosurveys show that AIDS is common in populations where many individuals have HIV antibodies. Conversely, in populations with low seroprevalence of HIV antibodies, AIDS is extremely rare.

For example, in the southern African country of Zimbabwe (population 11.4 million), more than 25 percent of adults ages 15 to 49 are estimated to be HIV antibody-positive, based on numerous studies. As of November 1999, more than 74,000 cases of AIDS in Zimbabwe had been reported to the World Health Organization (WHO). In contrast, Madagascar, an island country off the southeast coast of Africa (population 15.1 million) with a very low HIV seroprevalence rate, reported only 37 cases of AIDS to WHO through November 1999. Yet, other sexually transmitted diseases, notably syphilis, are common in Madagascar, suggesting that conditions are ripe for the spread of HIV and AIDS if the virus becomes entrenched in that country (U.S. Census Bureau; UNAIDS, 2000; WHO. Wkly Epidemiol Rec 1999;74:1; Behets et al. Lancet 1996;347:831).

The specific immunologic profile that typifies AIDS - a persistently low CD4+ T-cell count - is extraordinarily rare in the absence of HIV infection or other known cause of immunosuppression.

For example, in the NIAID-supported Multicenter AIDS Cohort Study (MACS), 22,643 CD4+ T-cell determinations in 2,713 HIV-seronegative homosexual and bisexual men revealed only one individual with a CD4+ T-cell count persistently lower than 300 cells/mm3 of blood, and this individual was receiving immunosuppressive therapy. Similar results have been reported from other studies (Vermund et al. NEJM 1993;328:442; NIAID, 1995).

Newborn infants have no behavioral risk factors for AIDS, yet many children born to HIV-infected mothers have developed AIDS and died.

Only newborns who become HIV-infected before or during birth, during breastfeeding, or (rarely) following exposure to HIV-tainted blood or blood products after birth, go on to develop the profound immunosuppression that leads to AIDS. Babies who are not HIV-infected do not develop AIDS. In the United States, 8,718 cases of AIDS among children younger than age 13 had been reported to the CDC as of December 31, 1999. Cumulative U.S. AIDS deaths among individuals younger than age 15 numbered 5,044 through December 31, 1999. Globally, UNAIDS estimates that 480,000 child deaths due to AIDS occurred in 1999 alone (CDC. HIV/AIDS Surveillance Report 1999;11[2]:1; UNAIDS. AIDS epidemic update: June 2000).

Because many HIV-infected mothers abuse recreational drugs, some have argued that maternal drug use itself causes pediatric AIDS. However, studies have consistently shown that babies who are not HIV-infected do not develop AIDS, regardless of their mothers' drug use (European Collaborative Study. Lancet 1991;337:253; European Collaborative Study. Pediatr Infect Dis J 1997;16:1151; Abrams et al. Pediatrics 1995;96:451).

For example, a majority of the HIV-infected, pregnant women enrolled in the European Collaborative Study are current or former injection drug users. In this ongoing study, mothers and their babies are followed from birth in 10 centers in Europe. In a paper in Lancet, study investigators reported that none of 343 HIV-seronegative children born to HIV-seropositive mothers had developed AIDS or persistent immune deficiency. In contrast, among 64 seropositive children, 30 percent presented with AIDS within 6 months of age or with oral candidiasis followed rapidly by the onset of AIDS. By their first birthday, 17 percent died of HIV-related diseases (European Collaborative Study. Lancet 1991;337:253).

In a study in New York, investigators followed 84 HIV-infected and 248 HIV-uninfected infants, all born to HIV-seropositive mothers. The mothers of the two groups of infants were equally likely to be injection drug users (47 percent vs. 50 percent), and had similar rates of alcohol, tobacco, cocaine, heroin and methadone use. Of the 84 HIV-infected children, 22 died during a median follow-up period of 27.6 months, including 20 infants who died before their second birthday. Twenty-one of these deaths were classified as AIDS-related. Among the 248 uninfected children, only one death (due to child abuse) was reported during a median follow-up period of 26.1 months (Abrams et al. Pediatrics 1995;96:451).

The HIV-infected twin develops AIDS while the uninfected twin does not.

Because twins share an in utero environment and genetic relationships, similarities and differences between them can provide important insight into infectious diseases, including AIDS (Goedert. Acta Paediatr Supp 1997;421:56). Researchers have documented cases of HIV-infected mothers who have given birth to twins, one of whom is HIV-infected and the other not. The HIV-infected children developed AIDS, while the other children remained clinically and immunologically normal (Park et al. J Clin Microbiol 1987;25:1119; Menez-Bautista et al. Am J Dis Child 1986;140:678; Thomas et al. Pediatrics 1990;86:774; Young et al. Pediatr Infect Dis J 1990;9:454; Barlow and Mok. Arch Dis Child 1993;68:507; Guerrero Vazquez et al. An Esp Pediatr 1993;39:445).

Studies of transfusion-acquired AIDS cases have repeatedly led to the discovery of HIV in the patient as well as in the blood donor.

Numerous studies have shown an almost perfect correlation between the occurrence of AIDS in a blood recipient and donor, and evidence of homologous HIV strains in both the recipient and the donor (NIAID, 1995).

HIV is similar in genetic structure and morphology to other lentiviruses that often cause immunodeficiency in their animal hosts in addition to slow, progressive wasting disorders, neurodegeneration and death.

Like HIV in humans, animal viruses such as feline immunodeficiency virus (FIV) in cats, visna virus in sheep and simian immunodeficiency virus (SIV) in monkeys primarily infect cells of the immune system such as T cells and macrophages. For example, visna virus infects macrophages and causes a slowly progressive neurologic disease (Haase. Nature 1986;322:130).

HIV causes the death and dysfunction of CD4+ T lymphocytes in vitro and in vivo.

CD4+ T cell dysfunction and depletion are hallmarks of HIV disease. The recognition that HIV infects and destroys CD4+ T cells in vitro strongly suggests a direct link between HIV infection, CD4+ T cell depletion, and development of AIDS. A variety of mechanisms, both directly and indirectly related to HIV infection of CD4+ T cells, are likely responsible for the defects in CD4+ T cell function observed in HIV-infected people. Not only can HIV enter and kill CD4+ T cells directly, but several HIV gene products may interfere with the function of uninfected cells (NIAID, 1995; Pantaleo et al. NEJM 1993;328:327).

Answering the skeptics

MYTH: HIV antibody testing is unreliable.

FACT: Diagnosis of infection using antibody testing is one of the best-established concepts in medicine. HIV antibody tests exceed the performance of most other infectious disease tests in both sensitivity (the ability of the screening test to give a positive finding when the person tested truly has the disease ) and specificity (the ability of the test to give a negative finding when the subjects tested are free of the disease under study). Current HIV antibody tests have sensitivity and specificity in excess of 98% and are therefore extremely reliable WHO, 1998; Sloand et al. JAMA 1991;266:2861).

Progress in testing methodology has also enabled detection of viral genetic material, antigens and the virus itself in body fluids and cells. While not widely used for routine testing due to high cost and requirements in laboratory equipment, these direct testing techniques have confirmed the validity of the antibody tests (Jackson et al. J Clin Microbiol 1990;28:16; Busch et al. NEJM 1991;325:1; Silvester et al. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:411; Urassa et al. J Clin Virol 1999;14:25; Nkengasong et al. AIDS 1999;13:109; Samdal et al. Clin Diagn Virol 1996;7:55.

MYTH: There is no AIDS in Africa. AIDS is nothing more than a new name for old diseases.

FACT: The diseases that have come to be associated with AIDS in Africa - such as wasting syndrome, diarrheal diseases and TB - have long been severe burdens there. However, high rates of mortality from these diseases, formerly confined to the elderly and malnourished, are now common among HIV-infected young and middle-aged people, including well-educated members of the middle class (UNAIDS, 2000).

For example, in a study in Cote d'Ivoire, HIV-seropositive individuals with pulmonary tuberculosis (TB) were 17 times more likely to die within six months than HIV-seronegative individuals with pulmonary TB (Ackah et al. Lancet 1995; 345:607). In Malawi, mortality over three years among children who had received recommended childhood immunizations and who survived the first year of life was 9.5 times higher among HIV-seropositive children than among HIV-seronegative children. The leading causes of death were wasting and respiratory conditions (Taha et al. Pediatr Infect Dis J 1999;18:689). Elsewhere in Africa, findings are similar.

MYTH: HIV cannot be the cause of AIDS because researchers are unable to explain precisely how HIV destroys the immune system.

FACT: A great deal is known about the pathogenesis of HIV disease, even though important details remain to be elucidated. However, a complete understanding of the pathogenesis of a disease is not a prerequisite to knowing its cause. Most infectious agents have been associated with the disease they cause long before their pathogenic mechanisms have been discovered. Because research in pathogenesis is difficult when precise animal models are unavailable, the disease-causing mechanisms in many diseases, including tuberculosis and hepatitis B, are poorly understood. The critics' reasoning would lead to the conclusion that M. tuberculosis is not the cause of tuberculosis or that hepatitis B virus is not a cause of liver disease (Evans. Yale J Biol Med 1982;55:193).

MYTH: AZT and other antiretroviral drugs, not HIV, cause AIDS.

FACT: The vast majority of people with AIDS never received antiretroviral drugs, including those in developed countries prior to the licensure of AZT in 1987, and people in developing countries today where very few individuals have access to these medications (UNAIDS, 2000).

As with medications for any serious diseases, antiretroviral drugs can have toxic side effects. However, there is no evidence that antiretroviral drugs cause the severe immunosuppression that typifies AIDS, and abundant evidence that antiretroviral therapy, when used according to established guidelines, can improve the length and quality of life of HIV-infected individuals.

In the 1980s, clinical trials enrolling patients with AIDS found that AZT given as single-drug therapy conferred a modest (and short-lived) survival advantage compared to placebo. Among HIV-infected patients who had not yet developed AIDS, placebo-controlled trials found that AZT given as single-drug therapy delayed, for a year or two, the onset of AIDS-related illnesses. Significantly, long-term follow-up of these trials did not show a prolonged benefit of AZT, but also never indicated that the drug increased disease progression or mortality. The lack of excess AIDS cases and death in the AZT arms of these placebo-controlled trials effectively counters the argument that AZT causes AIDS (NIAID, 1995).

Subsequent clinical trials found that patients receiving two-drug combinations had up to 50 percent increases in time to progression to AIDS and in survival when compared to people receiving single-drug therapy. In more recent years, three-drug combination therapies have produced another 50 percent to 80 percent improvements in progression to AIDS and in survival when compared to two-drug regimens in clinical trials. Use of potent anti-HIV combination therapies has contributed to dramatic reductions in the incidence of AIDS and AIDS-related deaths in populations where these drugs are widely available, an effect which clearly would not be seen if antiretroviral drugs caused AIDS (Figure 1; CDC. HIV AIDS Surveillance Report 1999;11[2]:1; Palella et al. NEJM 1998;338:853; Mocroft et al. Lancet 1998;352:1725; Mocroft et al. Lancet 2000;356:291; Vittinghoff et al. J Infect Dis 1999;179:717; Detels et al. JAMA 1998;280:1497; de Martino et al. JAMA 2000;284:190; CASCADE Collaboration. Lancet 2000;355:1158; Hogg et al. CMAJ 1999;160:659; Schwarcz et al. Am J Epidemiol 2000;152:178; Kaplan et al. Clin Infect Dis 2000;30:S5; McNaghten et al. AIDS 1999;13:1687).

MYTH: Behavioral factors such as recreational drug use and multiple sexual partners account for AIDS.

FACT: The proposed behavioral causes of AIDS, such as multiple sexual partners and long-term recreational drug use, have existed for many years. The epidemic of AIDS, characterized by the occurrence of formerly rare opportunistic infections such as Pneumocystis carinii pneumonia (PCP) did not occur in the United States until a previously unknown human retrovirus - HIV - spread through certain communities (NIAID, 1995a; NIAID, 1995b).

Compelling evidence against the hypothesis that behavioral factors cause AIDS comes from recent studies that have followed cohorts of homosexual men for long periods of time and found that only HIV-seropositive men develop AIDS.

For example, in a prospectively studied cohort in Vancouver, 715 homosexual men were followed for a median of 8.6 years. Among 365 HIV-positive individuals, 136 developed AIDS. No AIDS-defining illnesses occurred among 350 seronegative men despite the fact that these men reported appreciable use of inhalable nitrites ('poppers') and other recreational drugs, and frequent receptive anal intercourse (Schechter et al. Lancet 1993;341:658).

Other studies show that among homosexual men and injection-drug users, the specific immune deficit that leads to AIDS - a progressive and sustained loss of CD4+ T cells - is extremely rare in the absence of other immunosuppressive conditions. For example, in the Multicenter AIDS Cohort Study, more than 22,000 T-cell determinations in 2,713 HIV-seronegative homosexual men revealed only one individual with a CD4+ T-cell count persistently lower than 300 cells/mm3 of blood, and this individual was receiving immunosuppressive therapy (Vermund et al. NEJM 1993;328:442).

In a survey of 229 HIV-seronegative injection-drug users in New York City, mean CD4+ T-cell counts of the group were consistently more than 1000 cells/mm3 of blood. Only two individuals had two CD4+ T-cell measurements of less than 300/mm3 of blood, one of whom died with cardiac disease and non-Hodgkin's lymphoma listed as the cause of death (Des Jarlais et al. J Acquir Immune Defic Syndr 1993;6:820).

MYTH: AIDS among transfusion recipients is due to underlying diseases that necessitated the transfusion, rather than to HIV.

FACT: This notion is contradicted by a report by the Transfusion Safety Study Group (TSSG), which compared HIV-negative and HIV-positive blood recipients who had been given transfusions for similar diseases. Approximately 3 years after the transfusion, the mean CD4+ T-cell count in 64 HIV-negative recipients was 850/mm3 of blood, while 111 HIV-seropositive individuals had average CD4+ T-cell counts of 375/mm3 of blood. By 1993, there were 37 cases of AIDS in the HIV-infected group, but not a single AIDS-defining illness in the HIV-seronegative transfusion recipients (Donegan et al. Ann Intern Med 1990;113:733; Cohen. Science 1994;266:1645).

MYTH: High usage of clotting factor concentrate, not HIV, leads to CD4+ T-cell depletion and AIDS in hemophiliacs.

FACT: This view is contradicted by many studies. For example, among HIV-seronegative patients with hemophilia A enrolled in the Transfusion Safety Study, no significant differences in CD4+ T-cell counts were noted between 79 patients with no or minimal factor treatment and 52 with the largest amount of lifetime treatments. Patients in both groups had CD4+ T cell-counts within the normal range (Hasset et al. Blood 1993;82:1351). In another report from the Transfusion Safety Study, no instances of AIDS-defining illnesses were seen among 402 HIV-seronegative hemophiliacs who had received factor therapy (Aledort et al. NEJM 1993;328:1128).

In a cohort in the United Kingdom, researchers matched 17 HIV-seropositive hemophiliacs with 17 HIV-seronegative hemophiliacs with regard to clotting factor concentrate usage over a ten-year period. During this time, 16 AIDS-defining clinical events occurred in 9 patients, all of whom were HIV-seropositive. No AIDS-defining illnesses occurred among the HIV-negative patients. In each pair, the mean CD4+ T cell count during follow-up was, on average, 500 cells/mm3 lower in the HIV-seropositive patient (Sabin et al. BMJ 1996;312:207).

Among HIV-infected hemophiliacs, Transfusion Safety Study investigators found that neither the purity nor the amount of Factor VIII therapy had a deleterious effect on CD4+ T cell counts (Gjerset et al., Blood 1994;84:1666). Similarly, the Multicenter Hemophilia Cohort Study found no association between the cumulative dose of plasma concentrate and incidence of AIDS among HIV-infected hemophiliacs (Goedert et al. NEJM 1989;321:1141.).

MYTH: The distribution of AIDS cases casts doubt on HIV as the cause. Viruses are not gender-specific, yet only a small proportion of AIDS cases are among women.

FACT: The distribution of AIDS cases, whether in the United States or elsewhere in the world, invariably mirrors the prevalence of HIV in a population. In the United States, HIV first appeared in populations of homosexual men and injection-drug users, a majority of whom are male. Because HIV is spread primarily through sex or by the exchange of HIV-contaminated needles during injection-drug use, it is not surprising that a majority of U.S. AIDS cases have occurred in men (U.S. Census Bureau, 1999; UNAIDS, 2000).

Increasingly, however, women in the United States are becoming HIV-infected, usually through the exchange of HIV-contaminated needles or sex with an HIV-infected male. The CDC estimates that 30 percent of new HIV infections in the United States in 1998 were in women. As the number of HIV-infected women has risen, so too has the number of female AIDS patients in the United States. Approximately 23 percent of U.S. adult/adolescent AIDS cases reported to the CDC in 1998 were among women. In 1998, AIDS was the fifth leading cause of death among women aged 25 to 44 in the United States, and the third leading cause of death among African-American women in that age group.

In Africa, HIV was first recognized in sexually active heterosexuals, and AIDS cases in Africa have occurred at least as frequently in women as in men. Overall, the worldwide distribution of HIV infection and AIDS between men and women is approximately 1 to 1 (U.S. Census Bureau, 1999; UNAIDS, 2000).

MYTH: HIV cannot be the cause of AIDS because the body develops a vigorous antibody response to the virus.

FACT: This reasoning ignores numerous examples of viruses other than HIV that can be pathogenic after evidence of immunity appears. Measles virus may persist for years in brain cells, eventually causing a chronic neurologic disease despite the presence of antibodies. Viruses such as cytomegalovirus, herpes simplex and varicella zoster may be activated after years of latency even in the presence of abundant antibodies. In animals, viral relatives of HIV with long and variable latency periods, such as visna virus in sheep, cause central nervous system damage even after the production of antibodies (NIAID, 1995).

Also, HIV is well recognized as being able to mutate to avoid the ongoing immune response of the host (Levy. Microbiol Rev 1993;57:183).

MYTH: Only a small number of CD4+ T cells are infected by HIV, not enough to damage the immune system.

FACT: New techniques such as the polymerase chain reaction (PCR) have enabled scientists to demonstrate that a much larger proportion of CD4+ T cells are infected than previously realized, particularly in lymphoid tissues. Macrophages and other cell types are also infected with HIV and serve as reservoirs for the virus. Although the fraction of CD4+ T cells that is infected with HIV at any given time is never extremely high (only a small subset of activated cells serve as ideal targets of infection), several groups have shown that rapid cycles of death of infected cells and infection of new target cells occur throughout the course of disease (Richman J Clin Invest 2000;105:565).

MYTH: HIV is not the cause of AIDS because many individuals with HIV have not developed AIDS.

FACT: HIV disease has a prolonged and variable course. The median period of time between infection with HIV and the onset of clinically apparent disease is approximately 10 years in industrialized countries, according to prospective studies of homosexual men in which dates of seroconversion are known. Similar estimates of asymptomatic periods have been made for HIV-infected blood-transfusion recipients, injection-drug users and adult hemophiliacs (Alcabes et al. Epidemiol Rev 1993;15:303).

As with many diseases, a number of factors can influence the course of HIV disease. Factors such as age or genetic differences between individuals, the level of virulence of the individual strain of virus, as well as exogenous influences such as co-infection with other microbes may determine the rate and severity of HIV disease expression. Similarly, some people infected with hepatitis B, for example, show no symptoms or only jaundice and clear their infection, while others suffer disease ranging from chronic liver inflammation to cirrhosis and hepatocellular carcinoma. Co-factors probably also determine why some smokers develop lung cancer while others do not (Evans. Yale J Biol Med 1982;55:193; Levy. Microbiol Rev 1993;57:183; Fauci. Nature 1996;384:529).

MYTH: Some people have many symptoms associated with AIDS but do not have HIV infection.

FACT: Most AIDS symptoms result from the development of opportunistic infections and cancers associated with severe immunosuppression secondary to HIV.

However, immunosuppression has many other potential causes. Individuals who take glucocorticoids and/or immunosuppressive drugs to prevent transplant rejection or for autoimmune diseases can have increased susceptibility to unusual infections, as do individuals with certain genetic conditions, severe malnutrition and certain kinds of cancers. There is no evidence suggesting that the numbers of such cases have risen, while abundant epidemiologic evidence shows a staggering rise in cases of immunosuppression among individuals who share one characteristic: HIV infection (NIAID, 1995; UNAIDS, 2000).

MYTH: The spectrum of AIDS-related infections seen in different populations proves that AIDS is actually many diseases not caused by HIV.

FACT: The diseases associated with AIDS, such as PCP and Mycobacterium avium complex (MAC), are not caused by HIV but rather result from the immunosuppression caused by HIV disease. As the immune system of an HIV-infected individual weakens, he or she becomes susceptible to the particular viral, fungal and bacterial infections common in the community. For example, HIV-infected people in certain midwestern and mid-Atlantic regions are much more likely than people in New York City to develop histoplasmosis, which is caused by a fungus. A person in Africa is exposed to different pathogens than is an individual in an American city. Children may be exposed to different infectious agents than adults (USPHS/IDSA, 2001).

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