Acquired immune deficiency syndrome, or AIDS, is a recently recognized disease. It is caused by infection with the human immunodeficiency virus (HIV), which attacks selected cells in the IMMUNE SYSTEM and produces defects in function. These defects may not be apparent for years. They lead, however, to a severe suppression of the immune system’s ability to resist harmful organisms. This leaves the body open to invasion by various infections, which are therefore called opportunistic diseases, and to the development of unusual cancers.
The virus also tends to reach certain brain cells. This leads to so-called neuropsychiatric abnormalities, or psychological disturbances caused by physical damage to nerve cells. Since the first AIDS cases were reported in 1981, through mid-1994 more than 402,000 AIDS cases and more than 241,000 deaths have been reported in the United States alone. This is only the tip of the iceberg of HIV infection, however. It is estimated that nearly 1 million Americans had been infected with the virus through the mid-1990s but had not yet developed clinical symptoms.
In addition, although the vast majority of documented cases have occurred in the United States, AIDS cases have also been reported in almost every country in the world. Sub-Saharan Africa in particular appears to suffer a heavy burden of this illness. No cure or vaccine now exists for AIDS. Many of those infected with HIV may not even be aware that they carry and can spread the virus. Combating it is a major challenge to biomedical scientists and health-care providers. HIV infection and AIDS represent among the most pressing public-policy and public-health problems worldwide.
Definition of AIDS The U. S. CENTERS FOR DISEASE CONTROL AND PREVENTION has established criteria for defining cases of AIDS that are based on laboratory evidence such as T4 cell count, the presence of certain opportunistic diseases, and a range of other conditions. The opportunistic diseases are generally the most prominent and life-threatening clinical manifestations of AIDS. It is now recognized, however, that neuropsychiatric manifestations of HIV infection of the brain are also common. Other complications of HIV infection include fever, diarrhea, severe weight loss, and swollen lymph nodes.
When HIV-infected persons experience some of the above symptoms but do not meet full criteria for AIDS, they are given the diagnosis of AIDS-related complex, or ARC. The growing feeling is that ARC and HIV infection without symptoms should not be viewed as distinct entities but, rather, as stages of an irreversible progression toward AIDS. Historical Background In the late 1970s, certain rare cancers and a variety of serious infections were recognized to be occurring in increasing numbers of previously healthy persons.
Strikingly, these were disorders that would hardly ever threaten persons with normally functioning immune systems. First formally described in 1981, AIDS was observed predominantly to be affecting homosexual and bisexual men. Soon thereafter, intravenous drug users, hemophiliacs, and recipients of blood transfusions were recognized as being at increased risk for disease as well. It was also noted that sexual partners of persons with AIDS could contract the disease. Further study of AIDS patients revealed marked depletion of certain white BLOOD cells, called T4 lymphocytes.
These cells play a crucial role in coordinating the body’s immune defenses against invading organisms. It was presumed that this defect in AIDS patients was acquired in a common manner. Then, in 1983, a virus that attacks T4 cells was separately discovered by Robert Gallo at the U. S. National Institutes of Health and Luc Montagnier at France’s Pasteur Institute. The virus was at first given various names: human lymphotropic virus (HTLV) III, lymphadenopathy-associated virus (LAV), and AIDS-associated retrovirus (ARV).
It is now officially called human immunodeficiency virus (HIV), and considerable evidence demonstrates that it is indeed the causative agent for AIDS. A second strain that has been identified, HIV-2, is thus far relatively rare outside of Africa. Little is known about the biological and geographical origins of HIV. Apparently, however, this is the first time in modern history that the virus has spread widely among human beings. Related viruses have been observed in animal populations, such as certain African monkeys, but these do not appear to produce disease in humans. The Nature of the Virus HIV is an RNARETROVIRUS.
Viewed in an electron microscope, it has a dense cylindrical core that encases two molecules of viral RNA genetic material. A spherical outer envelope surrounds the core. Like all retroviruses, HIV possesses a special enzyme, called reverse transcriptase, that is able to make a DNA copy of the viral RNA. This enables the virus to reverse the normal flow of genetic information (see GENETIC CODE) and to incorporate its viral genes into the genetic material of its host. The virus may then remain in a latent form for a variable and often lengthy period of time until it is reactivated.
Further knowledge of the mechanisms and triggers of the activation process is important to the efforts being made to control HIV infection. A critical step in HIV infection is the binding of the virus to a receptor on the cell it attacks, enabling it to gain entrance. A molecule called CD4, found on the surface of the T4 cell, serves as a receptor, and almost any other cell with the CD4 surface molecule can become infected with HIV. Research has shown that a coreceptor called CD26 helps the HIV virus invade cells.
Thus blood cells known as monocytes and macrophages are very important additional targets. Modes of Transmission Researchers have isolated HIV from a number of body fluids, including blood, semen, saliva, tears, urine, cerebrospinal fluid, breast milk, and cervical and vaginal secretions. Strong evidence indicates, however, that HIV is transmitted only through three primary routes: sexual intercourse, whether vaginal or anal, with an infected individual; exposure to infected blood or blood products; and from an infected mother to her child before or during birth.
At least 97 percent of U. S. AIDS cases have been transmitted through one of these routes, with transmission between homosexual men accounting for about 53 percent of the cases. Heterosexual transmission in the United States accounts for about 7 percent of cases but is on the increase; it is a significant mode of transmission in Africa and Asia. About 25 percent of AIDS cases occur in intravenous drug users exposed to HIV-infected blood through shared needles.
Current practices of screening blood donors and testing all donated blood and plasma for HIV antibodies have reduced the number of cumulative cases caused by transfusion to about 1 percent. The number of new cases of AIDS in women of reproductive age is increasing at an alarming rate. AIDS has become the leading cause of death for women between the ages of 20 and 40 in the major cities of North and South America, Western Europe, and sub-Saharan Africa. In the United States, AIDS has hit hardest among black and Hispanic women, who represent 17 percent of the female population but make up 74 percent of women with AIDS.
AIDS is also having a devastating impact on infant mortality, since over 89 percent of HIV-infected children under the age of 13 acquired HIV from their infected mothers. Between 24 and 33 percent of children born to infected women will develop the disease. No scientific evidence supports transmission of HIV through ordinary nonsexual contact. Careful studies show that despite prolonged household contact with infected individuals, family members have not become infected–except through the routes described above.
Health-care workers have been infected with HIV from exposure to contaminated blood or by accidentally sticking themselves with contaminated needles. Clinical Signs Following infection with HIV, an individual may show no symptoms at all or may develop an acute but transient mononucleosislike illness. The period between initial infection and the development of AIDS is currently observed to vary from about 6 months to 11 years. Various estimates indicate that somewhere between 26 to 46 percent of the infected individuals will go on to develop full-blown AIDS within a little more than seven years following infection.
Once AIDS sets in, the clinical course generally follows a rapid decline; most people with AIDS die within three years. Opportunistic Infections and Cancers Because the T4 cell is involved in almost all immune responses, its depletion renders the body highly susceptible to opportunistic infections and tumorous growths. The most predominant and threatening complication is Pneumocystis carinii PNEUMONIA, which is frequently the first infection to occur and is the most common cause of death.
Other infections include the parasites Toxoplasma gondii (see TOXOPLASMOSIS) and Cryptosporidiosis; fungi such as Candida (see CANDIDIASIS) and Cryptococcus (see FUNGAL DISEASES); mycobacteria such as Mycobacterium avium, intracellulare, and tuberculosis (see TUBERCULOSIS); and viruses such as cytomegalovirus and herpes simplex and zoster (see HERPES). Increased susceptibility to bacterial infection is noted particularly among children with AIDS. Many AIDS patients develop CANCERS, including Kaposi’s sarcoma (KS), non- Hodgkin’s lymphoma, and HODGKIN’S DISEASE.
KS occurs in patients who manifest hardly any evidence of immunological impairment, indicating that other factors may also be at work. Among the non-Hodgkin’s lymphomas are immunoblastic and Burkitt’s-type as well as primary brain lymphomas. These tumors tend to be unusually aggressive and poorly responsive to chemotherapy, particularly in AIDS patients who have already experienced opportunistic infections. Other HIV-Related Disorders and Cofactors Neuropsychiatric manifestations occur in about 60 percent of HIV-infected persons.
It is now well established that HIV can exist and proliferate within the brain, spinal cord, and peripheral nerves. This results in a broad range of symptoms, including meningoencephalitis (see ENCEPHALITIS) and DEMENTIA. Evidence thus far indicates that circulating HIV-infected blood cells of the kind called monocytes may be responsible for the initiation of infection in the brain. There is little evidence to support direct infection of neuron tissue by HIV. Blood-cell abnormalities of HIV patients include ANEMIA, reduced white-blood- cell counts, and platelet deficiencies.
Researchers have also been able to show direct infection of bone-marrow cells–the precursors of circulating blood cells–and the proliferation of the virus within these cells. Thus bone marrow may represent an important reservoir of HIV in an infected person and provide a potential mechanism for spreading the virus through the body. Other HIV-related syndromes include nephritis (see KIDNEY DISEASE), ARTHRITIS, and lung inflammation (pneumonitis). Certain cofactors appear to play an important role in HIV infection and AIDS by increasing susceptibility to infection and by enhancing viral-disease activity.
Other sexually transmitted diseases appear to be of particular significance. Damage to genital skin and mucous membranes may facilitate transmission of the virus. In addition, laboratory studies show that certain other microbes frequently found in AIDS patients, such as mycoplasmas, also probably act as cofactors. Treatment of HIV Two major avenues are being pursued by biomedical scientists in the fight against HIV infection and AIDS. One strategy is to develop a vaccine that can induce neutralizing antibodies against HIV and protect uninfected individuals if exposed to the virus itself.
The second approach involves the discovery and development of therapeutic agents against HIV infection and AIDS. At present no vaccine exists to protect against infection, although recent advances have led some experts to predict that a vaccine should be available within the next ten years. Obstacles still remain, however, primarily because of the variability of the virus itself. Many different strains of HIV exist, and even within a given individual’s body the virus can undergo mutations rapidly and easily. A number of candidate vaccines were in the early phases of testing in human volunteers by the early 1990s around the world.
Progress is also being made in the treatment of HIV infection. The focus has been on two major areas: antiviral drugs with a direct effect against the causative agent; and immunomodulators, or substances that act to reconstitute or enhance immune-system function. Efforts to develop and improve treatments of specific opportunistic infections and tumors continue, and more new drugs have been approved. Because of the complex life cycle of HIV, however, the successful development of antiviral and immune-enhancement therapies represents an enormous scientific challenge.
Unlike most known disease-producing microorganisms, HIV infects the very cells that are intended to lead the immune system’s attack against invaders. This makes it technically very hard to kill the virus without destroying the already threatened immune system. Furthermore, there may be several important reservoirs in the body for HIV that will be difficult to deal with while not causing fundamental damage to the host cells involved. For example, macrophage cells can support HIV replication while harboring the virus from the body’s immune surveillance.
Circulating blood cells of the kind called macrophages appear to play an important role in the propagation of HIV throughout the body, including the brain. In seeking effective therapies, other important considerations are involved. Thus, since the brain is an important target of HIV infection, an effective anti-HIV agent should be able to cross the blood-brain barrier (see BRAIN). It would also be desirable if therapies could be taken orally, since it is likely that AIDS drugs would have to be taken for a long period and perhaps a lifetime.
Dozens of agents have been tested in humans, but only two have been licensed by the U. S. Food and Drug Administration (FDA): azidothymidine (AZT) and dideoxyinosine (DDI). AZT interferes with virus replication and has been found to prolong life in some patients, but its ability to delay the onset of full-blown AIDS in persons with no symptoms has been questioned. AZT’s potentially toxic side effects may preclude uses in many cases. DDI acts similarly but is recommended for those who cannot tolerate AZT. Other drugs are in clinical trials.
Some drugs are available to fight major opportunistic infections. Eye infections can be treated with ganciclovir or foscarnet, which also helps patients live longer, while aerosolized pentamidine fights Pneumocystis carinii pneumonia and protects the patient from AIDS dementia. The slow process of FDA approval of new AIDS drugs has developed into a political issue. AIDS activists are demanding that the government speed up authorization by postponing certain tests comparing efficacy and ability to prolong life until after the drug is on the market.
While a faster approval rate may expose patients to unforeseen side effects, activists argue that patients with life-threatening diseases who have no alternative therapy should still be entitled to choose these drugs. Efforts at Prevention In the absence of an effective vaccine or therapy, education and risk reduction remain the most powerful tools in the fight against AIDS. Because of the limited number of transmission routes, the further spread of AIDS could virtually be stopped by avoiding behaviors that place persons at risk.
Education can help to achieve this, through development and dissemination of materials by local community groups, statewide organizations, and national governments. In 1988, for example, the U. S. Public Health Service produced a simple, straightforward brochure containing information about HIV infection and AIDS. The brochure was mailed to every household in the nation. Although behavior change is often very hard to achieve, studies have provided encouraging indications that such change is beginning to occur. In March 1983 the major U. S. lood-banking organizations instituted procedures to reduce the likelihood of HIV transmission by asking all individuals at increased risk of AIDS to stop donating blood. They expanded screening procedures to exclude anyone with a history of risk behavior for AIDS or symptoms suggestive of AIDS. In early 1985 blood banks began using a test to screen blood directly for antibodies to HIV. The presence of antibodies, which generally takes weeks or months to develop, means that a person has been infected by the virus. It does not indicate whether that individual has or will develop AIDS, although this is almost certain.
All blood intended for transfusion or the manufacture of blood products is now tested for the antibody. The procedure involves the use of the ELISA (enzyme- linked immunosorbent assay) screening test, with confirmation of positive results with a more specific test known as the Western Blot. Blood that tests positive is eliminated from the blood-donation pool. Tissue and organ banks use a similar process. The act of donating blood does not pose any risk of HIV infection, because sterile equipment is always used. Costs The AIDS epidemic is having a profound impact on many aspects of medicine and health care.
The U. S. Public Health Service estimates that in 1993, the lifetime cost of treating a person with AIDS from infection to death is approximately $119,000. Outpatient care, including medication, visits to doctors, home health aids, and long-term care, accounted for approximately 32 percent of the total cost. Persons exposed to HIV may have difficulty in obtaining adequate health- insurance coverage. Yearly AZT expenses can average approximately $6,000, although in 1989 the drug’s maker did offer to distribute AZT freely to HIV- infected children. The yearly expense for DDI is somewhat less at $2,000.
The effects of the epidemic on society at large are increasingly evident. AIDS tests are now required in the military services. Various proposals have been made for mandatory screening of other groups such as health-care workers. A number of nations, including the United States, have instituted stringent rules for testing long-term foreign visitors or potential immigrants for AIDS, as well as testing returning foreign nationals. In the United States one frequent phenomenon is the effort to keep school-age children with AIDS isolated from their classmates, if not out of school altogether.
Governmental and civil rights organizations have countered restrictive moves with a great deal of success. There is little doubt that the ultimate physical toll of the AIDS epidemic will be high, as will be its economic costs, however the social issues are resolved. Concerted efforts are under way to address the problem at many levels, and they offer hope for successful strategies to combat HIV-induced disease. Politics and AIDS In the United States, AIDS provoked a grass-roots political response, as well as government action.
First evident in urban gay men, AIDS moved an already politically organized gay community to create service, information, and political organizations, such as Gay Men’s Health Crisis (GMHC) and AIDS Coalition to Unleash Power (ACT UP). Those groups have lobbied the federal government for funding and favorable policies. ACT UP was formed in 1987 to urge speed in drug approval and to protest high prices for AIDS drugs. By successfully promoting reforms, ACT UP and other advocates have provided a model for other disease groups, particularly breast cancer advocates.
During the 1980s, AIDS groups accused the government of neglecting its duty in responding to AIDS. Critics cite government reluctance to promote condom use as a prevention method, and the fact that President Ronald Reagan did not mention AIDS publicly until April 1987, six years after the epidemic began. The epidemic’s spread to people of color, often drug users and their intimates, introduced race into the politics of AIDS. Competition for funding and influence arose between gay and minority groups. Disagreements emerged about prevention methods, in particular needle exchange programs.
Many African Americans and Hispanics viewed needle exchange as promoting drug use in their communities, while others cited its role in curbing HIV transmission. The AIDS activists have helped increase federal funding for AIDS from an initial $5. 6 million in 1982, to over $2 billion in 1992. The 1990 Americans with Disabilities Act included protection from discrimination for people with HIV; the Ryan White Comprehensive AIDS Resources Emergency Act was passed to provide funds to cities hard hit by AIDS.