Human immunodeficiency virus (HIV) infection is an infection by one of two viruses, HIV-1 and HIV-2. The HIV viruses progressively destroy some types of white blood cells called lymphocytes. Lymphocytes are an important part of the body's immune defenses (see Biology of the Immune System: Lymphocytes). When lymphocytes are destroyed, the body becomes susceptible to attack by many other infectious organisms. Many of the complications of HIV infection, including death, are usually the result of these other infections and not of the HIV infection itself.

Acquired immunodeficiency syndrome (AIDS) is the most severe form of HIV infection. A person with HIV infection is considered to have AIDS when at least one complicating illness develops or his ability to defend against infection significantly declines as measured by a low CD4+ lymphocyte count.

HIV infection and AIDS have reached epidemic proportions. Through December 2000, more than 770,000 cases of AIDS and 448,000 deaths were reported in the United States. At the end of 2000, 36 million people worldwide were infected with HIV. More than 800,000 people in the United States are thought to be infected with HIV, and 40,000 new infections occur in this country each year. In parts of Africa, more than 30% of the adult population (between the ages of 15 and 45) is infected, threatening to nearly eliminate a whole generation.

Infections with HIV-1 and HIV-2 are serious and tend to occur in different regions. HIV-1 is most common in the Western Hemisphere; Europe; Asia; and Central, South, and East Africa. HIV-2 is common in West Africa, although many people there are infected with HIV-1.

What Is a Retrovirus? The human immunodeficiency virus (HIV) is a retrovirus, which like many other viruses stores its genetic information as RNA rather than as DNA. When the virus enters a targeted host cell, it releases its RNA and an enzyme (reverse transcriptase), and then makes DNA using the viral RNA as a pattern. The viral DNA is then incorporated into the host cell DNA. This reverses the pattern of human cells, which copy RNA from the pattern of human DNA (thus, the term “retro” for “backward”). Other RNA viruses, such as polio or measles, do not make DNA copies but simply copy their own RNA. Each time a host cell divides, it makes a new copy of the integrated viral DNA along with its own genes. The viral DNA can either lie latent (hidden) and do no damage or activate to take over the functions of the cell, causing the cell to produce new viruses. These new viruses are released from the infected cell to invade other cells.

Transmission of Infection

The transmission of HIV requires contact with a body fluid that contains the virus or infected cells. HIV can appear in nearly any body fluid, but transmission mainly comes from blood, semen, vaginal secretions, and breast milk. Although low concentrations of HIV are also present in tears, urine, and saliva, transmission from these fluids is extremely rare.

HIV is transmitted in the following ways:

• Sexual contact with an infected person, during which the mucous membrane lining the mouth, vagina, penis, or rectum is exposed to contaminated body fluids (unprotected sex)
• Injection or infusion of contaminated blood, as occurs with blood transfusions, the sharing of needles, or an accidental prick from an HIV-contaminated needle
• Transfer of the virus from an infected mother to a child before birth, during birth, or after birth through the mother's milk

Susceptibility to HIV infection increases when the skin or a mucous membrane is torn or damaged—even minimally—as can happen during vigorous vaginal or anal intercourse. Sexual transmission of HIV is more likely if either partner has herpes, syphilis, or another sexually transmitted disease (STD) that produces breaks in the skin or inflammation of the genitals. However, HIV can be transmitted even if neither partner has other STDs or obvious breaks in the skin. HIV transmission also can occur during oral sex, although it is far less common than during vaginal or anal intercourse.

In the United States, Europe, and Australia, HIV has mainly been transmitted through male homosexual contact and the sharing of needles among injecting drug users, but transmission through heterosexual contact has been rapidly increasing. In 2000, 42% of new HIV infections in the United States developed in homosexual men, 33% in heterosexual men and women, and 25% in injecting drug users. HIV transmission in Africa, the Caribbean, and Asia occurs primarily between heterosexuals, and HIV infection occurs equally among men and women. Through December 2000, more than 17% of the adults in the United States reported to have AIDS were women. HIV infection is increasing at a faster rate among women than among men. In areas of the United States where HIV infection is reported, 31% of new HIV infections occur in women. Before 1992, most American women with HIV were infected by injecting drugs with contaminated needles. In 2000, however, 75% of women were infected by sexual contact.

A health care worker who is accidentally pricked with an HIV-contaminated needle has about a 1 in 300 chance of contracting HIV. The risk increases if the needle penetrates deeply or if contaminated blood is injected. Infected fluid splashing into the mouth or eyes has less than a 1 in 1,000 chance of causing infection. Taking a combination of antiretroviral drugs soon after exposure appears to reduce, but not eliminate, the risk of becoming infected and is recommended.

People with hemophilia require frequent infusions of whole blood or other blood products. Before 1985, many people with hemophilia in the United States became infected with HIV because the blood products they received were contaminated with HIV. AIDS became the leading cause of death among these people. Since 1985, all blood collected for transfusion has been tested for HIV, and when possible, some blood products are treated with heat to eliminate the risk of HIV infection. The current risk of HIV infection from a single blood transfusion is estimated to be less than 1 in 500,000.

HIV infection in a large number of women of childbearing age has led to HIV infection in children (see Viral Infections: Human Immunodeficiency Virus (HIV) Infection). In about 25 to 35% of the pregnancies involving women infected with HIV, the virus is transmitted to the fetus through the placenta or, more commonly, at birth during passage through the birth canal. Infants who are breastfed can contract HIV infection through breast milk. A few children contract HIV infection through sexual abuse.

HIV is not transmitted by casual contact or even by close, nonsexual contact at work, school, or home. No case of HIV transmission has been traced to the coughing or sneezing of an infected person or to a mosquito bite. Transmission from an infected doctor or dentist to a patient is extremely rare.

The HIV Transmission Risk of Several Sexual Activities No risk (unless sores are present) Dry kissing Body-to-body rubbing and massage Using unshared inserted sexual devices Being masturbated by a partner, without semen or vaginal fluids Bathing and showering together Contact of intact skin with feces or urine Theoretical risk (extremely low risk unless sores are present) Wet kissing Oral sex performed on male (no ejaculation, with or without a condom) Oral sex performed on female (with barrier) Oral-anal contact Digital vaginal or anal penetration, with or without a glove Using shared but disinfected inserted sexual devices Low risk Oral sex performed on male (with ejaculation, with or without ingestion of semen) Oral sex performed on female (no barrier) Vaginal or anal intercourse (with proper use of a condom) Using shared but not disinfected inserted sexual devices High risk Vaginal or anal intercourse (with or without ejaculation, condom not used or used improperly)

Mechanism of Infection

Once in the body, HIV attaches to several types of white blood cells, the most important being the helper T lymphocyte. Helper T lymphocytes activate and coordinate other cells of the immune system. These lymphocytes have a receptor protein called CD4 in their outer membrane (and are therefore designated as CD4+). HIV has its genetic material encoded in RNA. Once inside a CD4+ lymphocyte, the virus turns its RNA into DNA by means of an enzyme called reverse transcriptase. The viral DNA is incorporated into the DNA of the infected lymphocyte. The lymphocyte's own machinery then reproduces (replicates) the virus inside the cell, eventually destroying the cell. The thousands of new viruses produced by each infected cell infect other lymphocytes and can destroy them as well. Within a few days or weeks, enough HIV may be produced to reduce numbers of lymphocytes substantially and enable the person to spread the HIV infection to others.

Simplified Life Cycle of the Human Immunodeficiency Virus Like all viruses, human immunodeficiency virus (HIV) reproduces (replicates) using the genetic machinery of its host cell, usually a CD4+ lymphocyte. Currently licensed drugs inhibit two critical enzymes (reverse transcriptase and protease) that the virus uses to replicate. Drugs targeted at a third enzyme, integrase, are being developed. HIV first attaches to and penetrates its target cell. HIV releases RNA, the genetic code of the virus, into the cell. For the virus to replicate, its RNA must be converted into DNA; the enzyme that performs the conversion is called reverse transcriptase. HIV mutates easily at this point, because reverse transcriptase is prone to errors during the conversion of viral RNA to DNA. The viral DNA enters the cell's nucleus. With the help of an enzyme called integrase, the viral DNA becomes integrated with the cell's DNA. The DNA now replicates and reproduces RNA and proteins. The proteins are in the form of a long chain that must be cut into pieces after the virus leaves the cell. A new virus is assembled from RNA and short pieces of protein. The virus buds through the membrane of the cell, wrapping itself in a fragment of the cell membrane (envelope). To be able to infect other cells, the budded virus must mature. It becomes mature when another viral enzyme (HIV protease) cuts structural proteins within the virus, causing them to rearrange.

Because HIV infection destroys CD4+ lymphocytes, it weakens the body's system for protecting itself against certain infections and cancers. This weakening of the immune system is part of the reason that the body is unable to eliminate HIV infection once it has started. However, the immune system is able to mount some response. Within a month or two of infection, the body produces lymphocytes and antibodies that help to lower the amount of HIV in the blood and keep the infection under control. For this reason, HIV infection can continue for a long time in some people before it causes serious problems.

Because the number of CD4+ lymphocytes in the blood helps determine the ability of the immune system to protect the body from infections, it is a good measure of the severity of the damage done by HIV infection. A healthy person has a CD4+ lymphocyte count of roughly 800 to 1,300 cells per microliter of blood. Typically, 40 to 60% of CD4+ lymphocytes are destroyed in the first few months of infection. After about 6 months, the CD4+ count stops falling so quickly, but it continues to decline.

If the CD4+ count falls below about 200 cells per microliter of blood, the immune system becomes less able to fight certain infections (for example, the fungal infection that causes Pneumocystis carinii pneumonia [PCP]). These infections do not usually appear in people with a healthy immune system and are called opportunistic infections. A count below about 50 cells per microliter of blood is particularly dangerous, because additional opportunistic infections that can rapidly cause severe weight loss, blindness, or death commonly occur.

The amount of virus in the blood is called the viral load. In the first few months after infection, a large number of virus particles circulate in the blood. The infection is very contagious at this stage. Later, the viral load drops to a lower level that remains constant for some time. This level is an important indicator of how contagious a person's infection is and how fast the disease is likely to progress. Doctors measure the viral load during treatment, because a decreasing or very low level indicates that treatment is working. The goal of treatment is to lower the viral load to the point where it is undetectable (suppressed) in the blood, although some virus is probably still present. A rise in the viral load may indicate the development of drug resistance or failure to take the drugs.

Symptoms

Most people experience no noticeable symptoms upon initial infection. However, fever, rashes, swollen lymph nodes, fatigue, and a variety of less common symptoms may develop within a few weeks of HIV infection and last a few weeks. The symptoms disappear, although the lymph nodes may stay enlarged. An infected person is able to spread the virus soon after becoming infected; this is true even if there are no symptoms.

A person can have HIV infection for years—even a decade or longer—before developing AIDS. Before AIDS develops, many people feel well, although some develop a variety of nonspecific symptoms. These symptoms include swollen lymph nodes, weight loss, fatigue, recurring fever or diarrhea, anemia, and thrush (a fungal infection of the mouth).

The main symptoms of AIDS are those of the specific opportunistic infections and cancers that develop. HIV can also directly infect the brain, causing memory loss, weakness, difficulty walking, and difficulty in thinking and concentrating (dementia). In some people, HIV is probably directly responsible for AIDS wasting, which is a significant loss of weight with or without an obvious cause. Wasting in people with AIDS may also be caused by a series of infections or an untreated infection (such as tuberculosis) that persists. Kidney failure, which may be a direct effect of HIV, is more common in blacks than in whites.

Kaposi's sarcoma, a cancer that appears as painless, red to purple, raised patches on the skin, affects many people with AIDS, especially homosexual men. Cancers of the immune system (lymphomas, typically non-Hodgkin's lymphoma) may develop, sometimes first appearing in the brain, where they can cause confusion, personality changes, and memory loss. Women are prone to developing cancer of the cervix. Homosexual men are prone to developing cancer of the rectum.

Usually, death is caused by the cumulative effects of wasting, dementia, opportunistic infections, or cancers.

Common Opportunistic Infections Associated With AIDS Infection Description Symptoms Candida esophagitis A yeast infection of the esophagus Painful swallowing, burning in chest Pneumocystis carinii pneumonia An infection of the lungs with Pneumocystis fungus Difficulty breathing, cough, fever Toxoplasmosis Infection with the parasite Toxoplasma, which usually affects the brain Headache, confusion, lethargy, seizures Tuberculosis Infection of the lungs and sometimes other organs with tuberculosis bacteria Cough, fevers, night sweats, weight loss, chest pain Mycobacterium avium complex Infection of the intestines or lungs with a type of bacteria that resembles tuberculosis bacteria Fever, weight loss, diarrhea, cough Cryptosporidiosis Infection of the intestines with the parasite Cryptosporidium Diarrhea, abdominal pain, weight loss Cryptococcal meningitis Infection of the lining of the brain with the yeast Cryptococcus Headache, fever, confusion Cytomegalovirus infection Infection of the eyes or intestinal tract with cytomegalovirus Eye: blindness Intestinal tract: diarrhea, weight loss Progressive multifocal leukoencephalopathy Infection of the brain with a polyomavirus Weakness on one side of the body, loss of coordination or balance

Diagnosis

A relatively simple, accurate blood test that detects antibodies to HIV (ELISA test) is used to screen people for HIV infection. If the ELISA result is positive, it is confirmed with a more accurate test, usually the Western Blot. Both tests often are not positive in the first month or two after HIV infection because it takes the body that long to produce antibodies against the virus. Other tests (for example, viral load tests or P24 antigen) detect HIV in the blood much sooner after infection. P24 antigen is currently used along with other tests to screen blood donated for transfusions.

People diagnosed with HIV infection have their blood tested regularly to measure the CD4+ count and viral load. CD4+ counts indicate the health of a person's immune system and, when low, their chances of becoming ill from an infection. Viral load is a predictor of how fast the CD4+ count is likely to drop over the next year. Doctors use these two measurements to decide when to start drugs for both the treatment of HIV and the prevention of the complicating infections. Doctors also use these tests to monitor the effects of treatment. With successful treatment, the viral load falls to low levels within weeks and the CD4+ count begins a long, slow recovery toward normal levels. AIDS is diagnosed when the CD4+ count falls below 200 cells per microliter of blood, there is extreme wasting, or certain opportunistic infections and cancers develop.

Prevention

Because HIV is nearly always transmitted by sexual contact or the sharing of needles, infection is almost completely preventable. Unfortunately, the measures required for prevention—sexual abstinence or condom use (see Sexually Transmitted Diseases (STD):Introduction) and access to clean needles—are sometimes personally or socially unpopular. Many people have difficulty changing their addictive or sexual behaviors, so they continue to engage in behavior that puts them at risk for HIV infection. Additionally, safe sex practices are not foolproof: condoms can leak or break.

Vaccines for preventing HIV infection or slowing the progression of AIDS in people who are already infected have so far proved elusive. Research continues, and several promising vaccines are being tested.

Because HIV is not transmitted through the air or by casual contact (such as touching, holding, or dry kissing), hospitals and clinics do not isolate HIV-infected people unless they have another contagious infection. HIV-contaminated surfaces can easily be cleaned and disinfected because HIV is inactivated by heat and by common disinfectants such as hydrogen peroxide and alcohol. People who are likely to come into contact with blood or other body fluids at their job should wear protective gear, including latex gloves, masks, and eye shields. These universal precautions apply to body fluids from all people, not just those from someone with HIV, for two reasons: people with HIV may not know that they are infected, and other viruses can be transmitted by body fluids.

People who have been exposed to HIV from a blood splash, needlestick, or sexual contact may reduce the chance of infection by taking a brief course of anti-HIV drugs. These drugs must be started as soon as possible after the exposure. Four weeks of preventive treatment with two or three drugs is currently recommended. Because the risk of infection varies, doctors and infected people make treatment decisions individually based on the type of exposure.

Strategies for Preventing the Transmission of HIV Abstain from sexual activity Use a latex condom for each act of intercourse with an infected partner or a partner whose HIV status is unknown (vaginal spermicides and sponges do not protect against HIV infection) If engaging in oral sex, withdraw before ejaculation; avoid brushing teeth for several hours before and after oral sex Newly monogamous couples should get tested for HIV and other sexually transmitted diseases (STDs) before engaging in unprotected sexual intercourse Never share needles or syringes Wear rubber gloves (preferably latex) when touching body fluids of a person who might be infected with HIV If exposed to HIV by needlestick, seek treatment to prevent infection

Treatment

Three classes of drugs are available to treat HIV infection: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. Both types of reverse transcriptase inhibitors work by interfering with the HIV enzyme reverse transcriptase, which converts viral RNA into DNA. Protease inhibitors interfere with the HIV enzyme protease, which is needed to activate certain proteins inside newly produced viruses. Failure to activate these proteins results in immature, defective HIV that does not infect new cells. None of these drugs kill HIV; they prevent the virus from replicating. If replication is sufficiently slowed, the destruction of CD4 cells by HIV is decreased dramatically and CD4+ counts begin to rise. The result can be reversal of much of the damage to the immune system caused by HIV.

HIV usually develops resistance to any of these drugs when they are used alone. Resistance can develop after a few days to several months of use, depending on the drug and the person. Therefore, treatment is most effective when at least two or three of the drugs are given in combination—usually one or two reverse transcriptase inhibitors plus a protease inhibitor. This combination of drugs is sometimes referred to as a "drug cocktail." Combinations of drugs are used for three reasons. First, combinations are more powerful than single drugs in reducing levels of HIV in the blood. Second, combinations help prevent the development of drug resistance. Third, some HIV drugs (like ritonavir) boost the blood levels of other HIV drugs (including most protease inhibitors) by slowing their removal from the body. Drug combinations have delayed the onset of AIDS in HIV-infected people, thus extending their lives.

Combinations of HIV drugs have both unpleasant and serious side effects. Disturbances in the metabolism of fats appear to be caused primarily by the protease inhibitors. Symptoms are the slow migration of body fat from the face, arms, and legs to the abdomen ("protease paunch") and sometimes to the breasts of women. Blood levels of cholesterol and triglycerides, two forms of fat in the blood, are increased—probably increasing the risk of future heart attacks and strokes.

Nucleoside reverse transcriptase inhibitors damage mitochondria, a critical site of energy generation in human cells. Their side effects include anemia, painful feet caused by nerve damage, and liver damage that rarely progresses to liver failure. Individual drugs differ in their tendency to cause these problems. Careful monitoring and changes of drugs can usually prevent serious problems.

Drug treatment is beneficial only when the drugs are taken on schedule. Missed doses allow the virus to replicate and develop resistance. The goal of combination therapy is to reduce the viral load so it is below detectable levels. No treatments have proven able to eliminate the virus from the body, although levels often fall below what can be measured; if treatment is stopped, viral load increases and CD4+ counts begin to fall.

It is not yet clear for which infected people drug treatment should be started, but people with low CD4+ counts or high viral loads require treatment, even if they have no symptoms. Because of the many significant and unpleasant side effects and because the drugs are very expensive, it is not easy for people with HIV infection to take the drugs for many years without fail. Because taking HIV drugs irregularly often leads to drug resistance, doctors try to ensure that anyone prescribed these drugs is both willing and able to adhere to the treatment schedule.

People with low CD4+ counts are routinely prescribed drugs to prevent opportunistic infections. To prevent Pneumocystis pneumonia, the combination of sulfamethoxazole and trimethoprim is given when the CD4+ count drops below 200 cells per microliter of blood. This combination of drugs also prevents toxoplasmosis, which can damage the brain of a person with AIDS. For people with CD4+ counts below 50 cells per microliter of blood, azithromycin taken weekly or clarithromycin or rifabutin taken daily may prevent Mycobacterium avium infections. People recovering from cryptococcal meningitis or those experiencing repeated infections of the mouth, esophagus, or vagina with the fungus Candida may be given the antifungal drug fluconazole for prolonged periods. People with recurring episodes of herpes simplex infections of the mouth, lips, genitals, or rectum may require prolonged treatment with an antiviral drug (such as acyclovir) to prevent relapses.

Other drugs may help with the weakness and weight loss associated with AIDS. Megestrol and dronabinol (a marijuana derivative) stimulate appetite. Many people with AIDS claim that natural marijuana is even more effective, and use of marijuana for this purpose has been legalized in a few states. Anabolic steroids (such as testosterone) can also significantly reverse the loss of muscle tissue. Testosterone levels are reduced in some men and can be replaced by use of injections or patches on the skin.

Drugs For HIV Infection Type Drug Side Effects Non-nucleoside reverse transcriptase inhibitors   Delavirdine Rash, headaches   Efavirenz Dizziness, sleepiness, nightmares, confusion, agitation, forgetfulness, euphoria, rash   Nevirapine Rash (occasionally severe or life threatening), liver dysfunction Nucleoside and nucleotide reverse transcriptase inhibitors     All may cause lactic acidosis and liver damage   Abacavir Fever, rash (occasionally severe or life threatening), nausea and vomiting, low white blood count   Didanosine (ddl) Peripheral nerve damage, pancreas inflammation, nausea, diarrhea   Lamivudine (3TC) Headache, fatigue   Stavudine (d4T) Peripheral nerve damage, loss of facial fat   Tenofovir Mild to moderate diarrhea, nausea and vomiting, flatulence   Zalcitabine (ddC) Peripheral nerve damage, pancreas inflammation, mouth sores   Zidovudine (AZT) Anemia and susceptibility to infection (resulting from bone marrow toxicity), headache, insomnia, weakness, muscle aches Protease inhibitors     All produce nausea, vomiting, diarrhea, and abdominal discomfort; high blood sugar and cholesterol are common; increased abdominal fat ("protease paunch") may occur; bleeding in hemophilia; liver dysfunction   Amprenavir     Indinavir Kidney stones   Lopinavir Mouth tingling, altered taste   Nelfinavir     Ritonavir Mouth tingling, altered taste   Saquinavir

Prognosis

Exposure to HIV does not always lead to infection, and some people who have had repeated exposures over many years remain uninfected. Moreover, many infected people have remained well for more than a decade. Doctors do not fully understand why some people become ill so much sooner than others, but a number of genetic factors appear to influence both susceptibility to infection and progression to AIDS after infection.

Of the people infected with HIV who do not receive drug treatment, each year 1 to 2% develop AIDS for the first several years after infection. Every year thereafter, about 5% of the people with untreated HIV infection develop AIDS. Within 10 to 11 years of contracting HIV infection, half of the people who have not received treatment develop AIDS. Eventually, more than 95% of untreated infected people develop AIDS, and it is possible that they all will if they live long enough, although a few people have remained well for more than 15 years.

Early in the AIDS epidemic, many people with AIDS experienced a rapid decline in their quality of life after first being hospitalized for the infection—often spending much of their remaining time in the hospital. Most people died within 2 years of developing AIDS. However, current therapy has changed AIDS into a more stable, manageable disease. Many people have lived for years with AIDS, continuing to lead productive and active lives. Nevertheless, illness from infections and the expense and side effects of drugs may reduce quality of life. For people unable to tolerate or take drugs consistently, the natural progression of the disease resumes. Cure is not yet possible, although intensive research on a cure continues.

Last full review/revision February 2003