HIV infections may be caused by one of two retroviruses, HIV-1 or HIV-2. HIV-1 has caused a worldwide epidemic, but HIV-2 tends to be limited to West Africa.
HIV progressively destroys some types of white blood cells called CD4+ lymphocytes. Lymphocytes help defend the body against foreign cells, infectious organisms, and cancer (see Biology of the Immune System: Lymphocytes). Thus, when HIV destroys CD4+ lymphocytes, people become susceptible to attack by many other infectious organisms. Many of the complications of HIV infection, including death, usually result from these other infections and not from HIV infection directly.
Acquired immunodeficiency syndrome (AIDS) is the most severe form of HIV infection. HIV infection is considered to be AIDS when at least one serious complicating illness develops or the number (count) of CD4+ lymphocytes decreases substantially.
HIV-1 originated in West-Central Africa in the first half of the 20th century when a closely related chimpanzee virus first infected humans. The global spread of HIV-1 has been documented to have occurred in the 1970s, and AIDS was first recognized in 1981. In North America as of December 2007, about 1.3 million people had HIV infection, and about 46,000 to 56,000 new infections and 21,000 deaths occur each year. Worldwide, about 33.2 million people are estimated to be infected. There are about 2.5 million new infections and 2.1 million deaths each year. Most (95%) occur in developing countries. One half occur in women, and one in seven occur in children under 15 years old. In parts of Africa, more than 30% of people between the ages of 15 and 45 are infected, threatening to dramatically reduce the life expectancy of a whole generation.
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 occurs mainly through blood, semen, vaginal secretions, and breast milk. Although tears, urine, and saliva may contain low concentrations of HIV, transmission through these fluids is extremely rare, if it occurs at all. HIV is not transmitted by casual contact (such as touching, holding, or dry kissing) or 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.
HIV is transmitted in the following ways:
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 sexual intercourse. Sexual transmission of HIV is more likely if either partner has herpes, syphilis, or another sexually transmitted disease (STD) that causes breaks in the skin or inflammation of the genitals. However, HIV can be transmitted even if neither partner has another STD or obvious breaks in the skin. HIV transmission can also occur during oral sex, although it is 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. HIV transmission in Africa, the Caribbean, and Asia occurs primarily between heterosexuals, and HIV infection occurs equally among men and women. In the United States, about 30% of adults who have HIV infection are women. Before 1992, most American women with HIV were infected by injecting drugs with contaminated needles, but now most are infected through 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 the needle contains HIV-contaminated blood (as with a needle used to draw blood) rather than simply being coated with blood (as with a needle used to inject a drug or stitch a cut). 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 as soon after exposure as possible appears to reduce, but not eliminate, the risk of becoming infected from an accident in a health care setting and is recommended.
People with hemophilia used to require frequent infusions of whole blood or other blood products, and many became infected because the blood products they received were contaminated with HIV. AIDS became the leading cause of death among these people. However, since 1985 in most developed countries, all blood collected for transfusion is 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 (which is carefully screened for HIV and other bloodborne viruses in most developed countries) is estimated to be less than 1 in 600,000.
Mothers and Children: HIV infection in a large number of women of childbearing age has led to an increase in HIV infection among children (see Viral Infections: Human Immunodeficiency Virus (HIV) Infection). In about 30 to 50% of pregnancies involving women infected with HIV who are not treated, HIV is transmitted to the fetus through the placenta or at birth during passage through the birth canal. Infants also can contract HIV through breast milk. The risk from breastfeeding depends on the duration of breastfeeding but may be as high as 75%.
Drug treatment of infected pregnant women during the 2nd and 3rd trimesters of pregnancy along with drugs given by vein during delivery can reduce the risk of transmission by about two thirds or more. Delivery by cesarean section and treating the mother at delivery and the baby for several weeks after birth with drugs also reduce the risk. Infected mothers should not breastfeed if they live in countries where formula feeding is safe and affordable. However, in countries where infectious diseases and malnutrition are common causes of infant mortality, and safe, affordable infant formula is not available, the World Health Organization recommends that mothers breastfeed. In such cases, the protection from potentially fatal infections afforded by breastfeeding may counterbalance the risk of HIV transmission.
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| What Is the Risk of HIV Transmission During Sexual Activities? | | Risk | Activity | | None (unless sores are present) | Dry kissing Body-to-body rubbing and massage Use of inserted sexual devices that are not shared with others Stimulation of the genitals by a partner if there is no contact with semen or vaginal fluids Bathing or showering together Contact with feces or urine if the skin is intact | | Theoretical (extremely low risk unless sores are present) | Wet kissing Oral sex done to a male (fellatio) if ejaculation does not occur and a condom is used Oral sex done to a female (cunnilingus) if a barrier is used Oral-anal contact Vaginal or anal penetration by a hand with or without a glove Use of inserted sexual devices that are shared but are disinfected | | Low | Oral sex done to an infected male with or without ingestion of semen if a condom is not used or is used incorrectly (risk is less if oral sex is done to an uninfected male by an infected person) Oral sex done to a female if no barrier is used Vaginal or anal intercourse if a condom is used correctly (for example, using only water-based lubricants and not spilling any semen) Use of inserted sexual devices that are shared but are not disinfected | | High | Vaginal or anal intercourse with or without ejaculation if a condom is not used or is used incorrectly | |
Mechanism of Infection
Once in the body, HIV attaches to several types of white blood cells. The most important are certain helper T lymphocytes. Helper T lymphocytes activate and coordinate other cells of the immune system. On their surface, these lymphocytes have a receptor called CD4, which enables HIV to attach to them. Thus, these helper lymphocytes are designated as CD4+.
HIV stores its genetic information as ribonucleic acid (RNA). Once inside a CD4+ lymphocyte, the virus uses an enzyme called reverse transcriptase to make a copy of its RNA, but the copy is made as deoxyribonucleic acid (DNA). HIV mutates easily at this point because reverse transcriptase is prone to making errors during the conversion of viral RNA to DNA. These mutations make HIV more difficult to control—by the body's immune system and by drugs.
The viral DNA copy is incorporated into the DNA of the infected lymphocyte. The lymphocyte's own genetic machinery then reproduces (replicates) the virus. Eventually, the lymphocyte is destroyed. 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, the blood and genital fluids contain many viruses, and the number of CD4+ lymphocytes may be reduced substantially. Because the number of viruses in blood and genital fluids is so large so soon after HIV infection, newly infected people can readily spread HIV to other people.
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| Simplified Life Cycle of the Human Immunodeficiency Virus |  | | Like all viruses, human immunodeficiency virus (HIV) reproduces (replicates) using the genetic machinery of the cell it infects, usually a CD4+ lymphocyte. -
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 to DNA. The RNA is converted by an enzyme 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 of the infected cell now produces RNA as well as proteins that are needed to assembly a new HIV. -
A new virus is assembled from RNA and short pieces of protein. -
The virus pushes (buds) through the membrane of the cell, wrapping itself in a fragment of the cell membrane and pinching off from the infected cell. -
To be able to infect other cells, the budded virus must mature. It becomes mature when another HIV enzyme (HIV protease) cuts structural proteins in the virus, causing them to rearrange.
Drugs used to treat HIV infection were developed based on the life cycle of HIV. These drugs inhibit the three enzymes (reverse transcriptase, integrase, and protease) that the virus uses to replicate and the attachment process by which HIV enters cells. | |
When HIV infection destroys CD4+ lymphocytes, it weakens the body's immune system, which protects against many infections and cancers. This weakening 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 after infection, the body produces lymphocytes and antibodies that help lower the amount of HIV in the blood and keep the infection under control. For this reason, untreated HIV infection continues for an average of about 10 years (ranging from 2 to 20 years) before causing symptoms.
CD4 Count: The number of CD4+ lymphocytes in blood (the CD4 count) helps determine how well the immune system can protect the body from infections and how severe the damage done by HIV is. Healthy people have a CD4 count of about 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 3 to 6 months, the CD4 count stops falling so quickly, but without treatment, it usually continues to decline at rates that vary from slow to rapid.
If the CD4 count falls below about 200 cells per microliter of blood, the immune system becomes less able to fight certain infections (such as the fungal infection that causes Pneumocystis jiroveci pneumonia). These infections do not usually appear in people with a healthy immune system. Such infections are called opportunistic infections because they take advantage of a weakened immune system. 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.
Viral Load: The amount of HIV virus in the blood (specifically the number of copies of HIV RNA) is called the viral load. Viral load represents how quickly HIV is replicating. When people are first infected, the viral load increases rapidly. Then, even without treatment, it drops to a lower level, which remains fairly constant, called the set point. This level varies widely from person to person. Viral load also indicates how contagious the infection is and how fast the infection is likely to worsen. During successful treatment, the viral load decreases to a very low or undetectable level. However, inactive (latent) HIV is still present within cells and if treatment is stopped, it will start replicating. An increase in the viral load during treatment indicates that the HIV has developed resistance to drug treatment, that people are not taking the drugs, or both.
Symptoms
When initially infected, many people have no noticeable symptoms, but within a few weeks, fever, rashes, swollen lymph nodes, fatigue, and a variety of less common symptoms may develop. Symptoms of initial (primary) HIV infection last from a few days to 1 to 2 weeks. The symptoms disappear, but lymph nodes often remain enlarged, felt as small, painless lumps in the neck, under the arms, or in the groin. People can be infected with HIV infection for years—even a decade or longer—before developing symptoms. However, the first symptoms may be those of AIDS. AIDS is defined as the development of very serious opportunistic infections or cancer—the ones that usually develop only in people with a CD count of less than 200. Before AIDS develops, many people feel well, although some develop a variety of vague symptoms such as weight loss, fatigue, recurring fever or diarrhea, anemia, and thrush (a fungal infection of the mouth or vagina).
Symptoms of AIDS are usually those of the specific opportunistic infections and cancers that develop. For example, people may have white patches in their mouth due to a fungal (candidal) infection or pain and rash due to herpes zoster.
However, HIV can also cause symptoms when it directly infects parts of the body:
HIV is probably directly responsible for a substantial loss of weight (AIDS wasting) in some people. Wasting in people with AIDS may also be caused by a series of infections or by an untreated, persistent digestive tract infection.
Kaposi's sarcoma, a cancer caused by another sexually transmitted type of herpesvirus (see Skin Cancers: Kaposi's Sarcoma), appears as painless, red to purple, raised patches on the skin. It affects many people with AIDS, especially homosexual men. Cancers of the immune system (lymphomas, typically non-Hodgkin lymphoma) may develop, sometimes first appearing in the brain. When the brain is affected, these cancers can cause weakness of an arm or a leg, headache, confusion, or personality changes. Having AIDS increases the risk of other cancers. Homosexual men are prone to developing cancer of the rectum due to the same human papillomaviruses (HPV) that cause cancer of the cervix in women.
Usually, death is caused by the cumulative effects of opportunistic infections or cancers, wasting, and dementia.
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| Common Opportunistic Infections Associated With AIDS | | Infection | Description | Symptoms | | Candidal esophagitis | A yeast infection of the esophagus | Painful swallowing and burning in the chest | | Pneumocystis jiroveci pneumonia | An infection of the lungs with the fungus Pneumocystis jiroveci | Difficulty breathing, cough, and fever | | Toxoplasmosis | Infection with the parasite Toxoplasma gondii usually in the brain | Headache, confusion, lethargy, and seizures | | Tuberculosis | Infection of the lungs and sometimes other organs with tuberculosis bacteria | Cough, fevers, night sweats, weight loss, and chest pain | | Mycobacterium avium complex infection | Infection of the intestine or lungs with a bacteria that resembles tuberculosis bacteria | Fever, weight loss, diarrhea, and cough | | Cryptosporidiosis | Infection of the intestine with the parasite Cryptosporidium | Diarrhea, abdominal pain, and weight loss | | Cryptococcal meningitis | Infection of the lining of the brain with the yeast Cryptococcus | Headache, fever, and confusion | | Cytomegalovirus infection | Infection of the eyes or intestinal tract with cytomegalovirus | Eye: Clouding of vision or blindness Intestinal tract: Diarrhea and weight loss | |
Diagnosis
Doctors usually ask about risk factors for HIV infection, such as occupational exposure, high-risk sexual activities, injecting street drugs, and about symptoms, such as fatigue, rashes, and weight loss. They do a physical examination to check for signs of opportunistic infections, such as swollen lymph nodes and white patches inside the mouth (indicating thrush). Early diagnosis is important because it may help infected people live longer, be healthier, and be less likely to transmit HIV to other people.
If doctors suspect HIV infection, simple, accurate, screening tests that detect antibodies to HIV are done. Tests may be done on a blood sample in the laboratory or on a blood or saliva sample in the doctor's office. If screening test results are positive, they are confirmed by a more accurate, specific test such as the Western blot. Often, these tests are not positive in the first weeks up to 2 months after initial HIV infection because antibodies to HIV are not yet being produced. Specific tests include the following:
Other tests, such as tests to measure viral load or P24 antigen, detect HIV in the blood sooner after infection than tests that detect antibodies to HIV. However, the P24 antigen test has difficulty detecting low levels of the antigen. Anyone who is concerned about being infected with HIV can request to be tested. Such testing is confidential.
If HIV infection is diagnosed, blood tests should be done regularly to measure the CD4 count and viral load. When the CD4 count is low, serious infections are more likely to develop and to make people ill. Viral load helps predict how fast the CD4 count is likely to decrease over the next few years. These two measurements help doctors determine when to start antiretroviral drugs, what effects treatment is likely to have, and whether other drugs may be needed to prevent complicating infections. With successful treatment, the viral load falls to very low levels within weeks, and the CD4 count begins a long, slow recovery toward normal levels.
Doctors may do other tests to check for disorders that commonly occur in people with HIV infection. For example, a bone marrow examination may be done to check for disorders (such as lymphomas) that affect the production of blood cells in the bone marrow. A spinal tap (lumbar puncture) or computed tomography (CT) or magnetic resonance imaging (MRI) of the head may be done to check for disorders that affect the brain or spinal cord.
AIDS is diagnosed when the CD4 count falls below 200 cells per microliter of blood or when extreme wasting or certain serious opportunistic infections or cancers develop.
Prevention
Transmission of HIV through its most common routes—sexual contact or sharing of needles—is almost completely preventable. However, the measures required for prevention—sexual abstinence or condom use (see Sexually Transmitted Diseases: How to Use a Condom
) 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 put themselves at risk of HIV infection. Also, safe sex practices are not foolproof. For example, 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 been elusive. Research continues, but in recent clinical trials, several promising vaccines have not proved useful.
Other measures can help. Circumcision of men, an inexpensive, safe procedure, appears to reduce the risk of infection by about half.
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. Surfaces contaminated with HIV 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 latex gloves, masks, and eye shields. These universal precautions apply to body fluids from all people, not just those from people 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 anti-HIV drugs (antiretroviral drugs) for a short time. These drugs must be started as soon as possible after the exposure. Taking two or three drugs for 4 weeks is currently recommended. Because the risk of infection varies, doctors and infected people make decisions about preventive treatment individually based on the type of exposure
Treatment
Antiretroviral Drugs: Several classes of drugs are used to treat HIV infection. All of the drugs, called antiretroviral drugs, block the activity of one of the enzymes HIV needs to replicate inside human cells. These drugs include the following:
These prevent the virus from replicating. If replication is sufficiently slowed, the destruction of CD4+ lymphocytes by HIV is decreased dramatically and the CD4 count begins to increase. As a result, much of the damage to the immune system caused by HIV can be reversed. Doctors can detect this reversal by measuring the CD4 count, which begins to return toward normal levels.
HIV invariably develops resistance to any of these drugs when they are used alone. Resistance develops after a few days to several months of use, depending on the drug and the virus. HIV varies because of mutations that occur when it replicates. Treatment is most effective when at least two or three drugs are given in combination—usually one of the following combinations:
These combinations of drugs are often referred to as highly active antiretroviral therapy (HAART). HAART is used because
HAART can delay or prevent AIDS in HIV-infected people, thus extending their life.
Combinations of HIV drugs have unpleasant and serious side effects. Metabolism of fats may be disturbed, probably primarily by protease inhibitors. Fat slowly accumulates in the abdomen (central obesity) and breasts of women and is lost from the face, arms, and legs. Blood levels of cholesterol and triglycerides (two types of fat in the blood) are increased, increasing the risk of heart attacks and strokes. Many drugs cause rashes (skin reactions). Some skin reactions can be very dangerous, especially if the drug causing the reaction is nevirapine .
Nucleoside reverse transcriptase inhibitors damage mitochondria, which help the cell generate energy. Side effects include anemia, foot pain caused by nerve damage (neuropathy), liver damage that uncommonly progresses to severe liver failure, and heart damage that can result in heart failure. Individual drugs differ in their tendency to cause these problems. Careful monitoring and changes of drugs can usually prevent serious problems.
When HAART is successful, it can cause the immune reconstitution inflammatory syndrome. In this syndrome, symptoms of various infections worsen because immune responses improve (are reconstituted), increasing inflammation (see Biology of Infectious Disease: Inflammation), or sometimes because parts of dead viruses persist, triggering immune responses.
Drug treatment is beneficial only if the drugs are taken on schedule. Missed doses allow the virus to replicate and develop resistance. No treatments can eliminate the virus from the body, although the HIV level often decreases so much that it cannot be detected. An undetectable level is the goal of treatment. If treatment is stopped, the HIV level increases, and the CD4 count begins to fall.
The best time to start drug treatment is unclear. The benefit of starting treatment in people who are not very sick and whose CD4 count is still near normal is also unclear. However, people with a low CD4 count (below 200) or a high viral load should be treated, even if they have no symptoms. Before starting a treatment regimen, they are taught about the necessity of taking drugs as directed, not skipping any doses, and taking the drugs for the rest of their life. Taking the drugs as directed for a life time may be difficult because the drugs have many significant and unpleasant side effects and are very expensive. Because taking HIV drugs irregularly often leads to drug resistance, health care practitioners try to make sure that people are both willing and able to adhere to the treatment regimen.
Prevention of Opportunistic Infections: If the CD4 count is low, drugs to prevent opportunistic infections are routinely prescribed.
Other Drugs: 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 help people regain muscle tissue. If testosterone levels are reduced in men, testosterone injections or patches on the skin can increase the levels.
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| | | Drug* | Side Effects† | | Fusion inhibitors | | Enfuvirtide | Painful rash at the injection site and allergic (hypersensitivity) reactions (including rash, fever, chills, nausea, and low blood pressure) | | Mariviroc (a CCR-5 inhibitor) | Inadequate blood flow (ischemia) to the heart or heart attacks | | Integrase inhibitors | | Raltegravir | None | | Non-nucleoside reverse transcriptase inhibitors | | | Rash (occasionally severe or life threatening) and liver dysfunction | | Delavirdine | Side effects of the drug class | | Efavirenz | Dizziness, sleepiness, nightmares, confusion, agitation, forgetfulness, and euphoria | | Etravirine | Side effects of the drug class | | Nevirapine | Side effects of the drug class | | Nucleoside and nucleotide reverse transcriptase inhibitors | | | Lactic acidosis (buildup of lactic acid, a waste product of metabolism) and liver damage | | Abacavir | Fever, rash (occasionally severe or life threatening), loss of appetite, nausea, vomiting, and a low white blood count | | Didanosine (ddI) | Peripheral nerve damage, inflammation of the pancreas, nausea, and diarrhea | | Emtricitabine | Headache, nausea, diarrhea, and darkening of the skin (hyperpigmentation), especially on the palms and soles | | Lamivudine (3TC) | Headache, fatigue, and peripheral nerve damage | | Stavudine (d4T) | Peripheral nerve damage and loss of fat in the face, arms, and legs | | Tenofovir | Mild to moderate diarrhea, nausea, vomiting, kidney damage, and flatulence | | Zalcitabine (ddC) | Peripheral nerve damage, pancreas inflammation, and mouth sores | | Zidovudine (AZT) | Anemia, susceptibility to infection (resulting from bone marrow damage), headache, insomnia, weakness, and muscle aches | | Protease inhibitors | | | Nausea, vomiting, diarrhea, abdominal discomfort; increased levels of blood sugar and cholesterol (common), increased abdominal fat, liver dysfunction, and nail discoloration and deformity (ingrown nails) a bleeding tendency (in people with hemophilia, bleeding)) | | Amprenavir | Rash | | Darunavir | Headache, coldlike symptoms, severe rash, and fever | | Fosamprenavir | Rash | | Indinavir | Kidney stones | | Lopinavir | Mouth tingling and altered taste | | Nelfinavir | Side effects of the drug class | | Ritonavir | Mouth tingling and altered taste | | Saquinavir | Side effects of the drug class | | Tipranavir | Liver inflammation | | *All drugs are taken by mouth.†Side effects listed for the class of drug can occur when any drug in that class is used. | |
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 remain well for more than a decade. A few HIV-infected, untreated people have remained well for over 20 years. Why some people become ill so much sooner than others is not fully understood, but a number of genetic factors appear to influence both susceptibility to infection and progression to AIDS after infection.
If infected people are not treated, AIDS develops in many, as follows:
Early in the AIDS epidemic, most people with AIDS experienced a rapid decline in their quality of life after they were first hospitalized for the infection. Many spent much of their remaining time in the hospital and died within 2 years of developing AIDS. However, with current therapy, AIDS has become more manageable. Many people live for years after AIDS is diagnosed, and they continue to lead productive, active lives. Nevertheless, illness due to infections and the expense and side effects of drugs may reduce quality of life. If people cannot tolerate or take drugs consistently, AIDS progresses. Cure is not yet possible, although intensive research for a cure continues.
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