AIDS

/aydz/, n. Pathol.

a disease of the immune system characterized by increased susceptibility to opportunistic infections, as pneumocystis carinii pneumonia and candidiasis, to certain cancers, as Kaposi's sarcoma, and to neurological disorders: caused by a retrovirus and transmitted chiefly through blood or blood products that enter the body's bloodstream, esp. by sexual contact or contaminated hypodermic needles. Cf. AIDS virus.

[1982; a(cquired) i(mmune) d(eficiency) s(yndrome)]

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in full acquired immunodeficiency syndrome

Fatal transmissible disorder caused by HIV.

AIDS, the last stage of HIV infection, is defined by the appearance of potentially lethal opportunistic infections. The first AIDS cases were identified in 1981, HIV was isolated in 1983, and blood tests were developed by 1985. In 2002 approximately 40,000,000 people worldwide were living with HIV, and more than 25,000,000 had died of AIDS. In the U.S. some 2,000,000 people had been infected with HIV, 800,000 had been diagnosed with AIDS, and 450,000 had died. Sub-Saharan Africa remains the focus of infection, but the number of cases in South and Southeast Asia and elsewhere continues to mount at an alarming rate as well. An initial acute illness usually resolves within weeks. Infected persons then generally have few or no symptoms for about 10 years. As the immune system deteriorates, they develop diseases such as Pneumocystis carinii pneumonia, cytomegalovirus (CMV), lymphoma, or Kaposi sarcoma.

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▪ disease

Introduction

byname of  acquired immunodeficiency syndrome 

      transmissible disease of the immune system caused by the human immunodeficiency virus (HIV). HIV is a lentivirus (literally meaning “slow virus”; a member of the retrovirus family) that slowly attacks and destroys the immune system, the body's defense against infection, leaving an individual vulnerable to a variety of other infections and certain malignancies that eventually cause death. AIDS is the final stage of HIV infection, during which time fatal infections and cancers frequently arise.

The emergence of HIV/AIDS

      Details of the origin of HIV remain unclear; however, a lentivirus that is genetically similar to HIV has been found in chimpanzees (chimpanzee) in western equatorial Africa. This virus, known as simian immunodeficiency virus (SIV), does not readily cause disease in chimpanzees. However, AIDS is a zoonosis, an infection that is shared by humans and lower vertebrate animals. The practice of hunting, butchering, and eating the meat of chimpanzees may have allowed transmission of the virus to humans, probably in the late 19th century or early 20th century.

      Genetic studies of a pandemic strain of HIV, known as HIV-1 group M, have indicated that the virus emerged between 1884 and 1924 in central and western Africa. Researchers estimate that this strain of the virus began spreading throughout these areas in the late 1950s. Later, in the mid-1960s, an evolved strain called HIV-1 group M subtype B spread from Africa to Haiti. In Haiti this subtype acquired unique characteristics, presumably through the process of genetic recombination. Sometime between 1969 and 1972, the virus migrated from Haiti to the United States. The virus spread within the United States for about a decade before it was discovered in the early 1980s. The worldwide spread of HIV-1 was likely facilitated by several factors, including increasing urbanization and long-distance travel in Africa, international travel, changing sexual mores, and intravenous drug use.

      In 1981 investigators in New York and California reported the first official case of AIDS. Initially, most cases of AIDS in the United States were diagnosed in homosexual (homosexuality) men, who contracted the virus primarily through sexual contact, and in intravenous drug users (drug use), who became infected mainly by sharing contaminated hypodermic needles. In 1983 French and American researchers isolated the causative agent, HIV. (In 2008 French virologists Françoise Barré-Sinoussi and Luc Montagnier were awarded the Nobel Prize for Physiology or Medicine for their discovery of HIV.) By 1985 serological tests to detect the virus had been developed. According to the 2007 United Nations report on AIDS, an estimated 33.2 million people were living with HIV, approximately 2.5 million people were newly infected with HIV, and about 2.1 million people died of AIDS. Relative to previous years, the statistics for 2007 reflect a decrease in the annual number of new infections and deaths from AIDS and an increase in the overall number of people living with AIDS. Some 25 million people have died of the disease since 1981.

      People living in sub-Saharan Africa account for about 70 percent of all infections, and in some countries of the region the prevalence of HIV infection of inhabitants exceeded 10 percent of the population. Rates of infection are lower in other parts of the world, but different subtypes of the virus have spread to Europe, India, South and Southeast Asia, Latin America, and the Caribbean. Rates of infection have leveled off somewhat in the United States and Europe. In the United States nearly one million people are living with HIV/AIDS, and half of all new infections are among African Americans. In Asia the sharpest increases in HIV infections are found in China, Indonesia, and Vietnam. Access to retroviral treatment for AIDS remains limited in some areas of the world, although more people are receiving treatment today than in the past.

Groups and subtypes of HIV

      Genetic studies have led to a general classification system for HIV that is primarily based on the degree of similarity in viral gene sequence. The two major classes of HIV are HIV-1 and HIV-2. HIV-1 is divided into three groups, known as group M (main group), group O (outlier group), and group N (new group). Worldwide, HIV-1 group M causes the majority of HIV infections, and it is further subdivided into subtypes A through K, which differ in expression of viral genes, virulence, and mechanisms of transmission. In addition, some subtypes combine with one another to create recombinant subtypes. HIV-1 group M subtype B is the virus that spread from Africa to Haiti and eventually to the United States. Pandemic forms of subtype B are found in North and South America, Europe, Japan, and Australia. Subtypes A, C, and D are found in sub-Saharan Africa, although subtypes A and C are also found in Asia and some other parts of the world. Most other subtypes of group M are generally located in specific regions of Africa, South America, or Central America.

      HIV-2 is divided into groups A through E, with subtypes A and B being the most relevant to human infection. HIV-2, which is found primarily in western Africa, can cause AIDS, but it does so more slowly than HIV-1. There is some evidence that HIV-2 may have arisen from a form of SIV that infects African green monkeys.

Transmission

      HIV is transmitted by the direct transfer of bodily fluids, such as blood and blood products, semen and other genital secretions, or breast milk, from an infected person to an uninfected person. The primary means of transmission worldwide is sexual contact with an infected individual. HIV frequently is spread among intravenous drug users who share needles or syringes. Prior to the development of screening procedures and heat-treating techniques that destroy HIV in blood products, transmission also occurred through contaminated blood products; many people with hemophilia contracted HIV in this way. Today the risk of contracting HIV from a blood transfusion is extremely small. In rare cases transmission to health care workers may occur by an accidental stick with a needle used to obtain blood from an infected person. The virus also can be transmitted across the placenta or through the breast milk from mother to infant; administration of antiretroviral medications to both the mother and infant around the time of birth reduces the chance that the child will be infected with HIV. HIV is not spread by coughing, sneezing, or casual contact (e.g., shaking hands). HIV is fragile and cannot survive long outside of the body. Therefore, direct transfer of bodily fluids is required for transmission. Other sexually transmitted diseases, such as syphilis, genital herpes (herpes simplex), gonorrhea, and Chlamydia, increase the risk of contracting HIV through sexual contact, probably through the genital lesions that they cause.

Life cycle of HIV

      The main cellular target of HIV is a special class of white blood cells critical to the immune system known as helper T lymphocytes (lymphocyte), or helper T cells. Helper T cells are also called CD4+ T cells because they have on their surfaces a protein called CD4. Helper T cells play a central role in normal immune responses by producing factors that activate virtually all the other immune system cells. These include B lymphocytes, which produce antibodies (antibody) needed to fight infection; cytotoxic T lymphocytes, which kill cells infected with a virus; and macrophages and other effector cells, which attack invading pathogens. AIDS results from the loss of most of the helper T cells in the body.

      HIV is a retrovirus, one of a unique family of viruses that consist of genetic material in the form of RNA (instead of DNA) surrounded by a lipoprotein envelope. HIV cannot replicate on its own and instead relies on the mechanisms of the host cell to produce new viral particles. HIV infects helper T cells by means of a protein embedded in its envelope called gp120. The gp120 protein binds to a molecule called CD4 on the surface of the helper T cell, an event that initiates a complex set of reactions that allow the HIV genetic information into the cell. Entry of HIV into the host cell also requires the participation of a set of cell surface proteins that normally serve as receptors for chemokines (hormone-like mediators that attract immune system cells to particular sites in the body). It appears that the binding of gp120 to CD4 exposes a region of gp120 that interacts with the chemokine receptors. This interaction triggers a conformational change that exposes a region of the viral envelope protein gp41, which inserts itself into the membrane of the host cell so that it bridges the viral envelope and the cell membrane. An additional conformational change in gp41 pulls these two membranes together, allowing fusion to occur. After fusion the viral genetic information can enter the host cell.

      Once the virus has infected a T cell, HIV copies its RNA into a double-stranded DNA copy by means of the viral enzyme reverse transcriptase; this process is called reverse transcription because it violates the usual way in which genetic information is transcribed. Because reverse transcriptase lacks the “proofreading” function that most DNA synthesizing enzymes have, many mutations (mutation) arise as the virus replicates, further hindering the ability of the immune system to combat the virus. These mutations allow the virus to evolve very rapidly, approximately one million times faster than the human genome evolves. This rapid evolution allows the virus to escape from antiviral immune responses and antiretroviral drugs. The next step in the virus life cycle is the integration of the viral genome into the host cell DNA. Integration occurs at essentially any accessible site in the host genome and results in the permanent acquisition of viral genes by the host cell. Under appropriate conditions these genes are transcribed into viral RNA molecules. Some viral RNA molecules are incorporated into new virus particles, while others are used as messenger RNA for the production of new viral proteins. Viral proteins assemble at the plasma membrane together with the genomic viral RNA to form a virus particle that buds from the surface of the infected cell, taking with it some of the host cell membrane that serves as the viral envelope. Embedded in this envelope are the gp120/gp41 complexes that allow attachment of the helper T cells in the next round of infection. Most infected cells die quickly (in about one day). The number of helper T cells that are lost through direct infection or other mechanisms exceeds the number of new cells produced by the immune system, eventually resulting in a decline in the number of helper T cells. Physicians follow the course of the disease by determining the number of helper T cells (CD4+ cells) in the blood. This measurement, called the CD4 count, provides a good indication of the status of the immune system. Physicians also measure the amount of virus in the bloodstream—i.e., the viral load—which provides an indication of how fast the virus is replicating and destroying helper T cells.

      Because of the high rate at which the genetic material of HIV mutates, the virus in each infected individual is slightly different. Genetic variants of HIV have been categorized into several major subtypes, or clades, which have different geographical distributions. Variation occurs throughout the genome but is especially pronounced in the gene encoding the gp120 protein. By constantly changing the structure of its predominant surface protein, the virus can avoid recognition by antibodies produced by the immune system.

Course of infection

      The course of HIV infection involves three stages: primary HIV infection, the asymptomatic phase, and AIDS. During the first stage the transmitted HIV replicates rapidly, and some persons may experience an acute flulike illness that usually persists for one to two weeks. During this time a variety of symptoms may occur, such as fever, enlarged lymph nodes, sore throat, muscle and joint pain, rash, and malaise. Standard HIV tests, which measure antibodies to the virus, are initially negative because HIV antibodies generally do not reach detectable levels in the blood until a few weeks after the onset of the acute illness. As the immune response to the virus develops, the level of HIV in the blood decreases.

      The second phase of HIV infection, the asymptomatic period, lasts an average of 10 years. During this period the virus continues to replicate, and there is a slow decrease in the CD4 count (the number of helper T cells). When the CD4 count falls to about 200 cells per microlitre of blood (in an uninfected adult it is typically about 1,000 cells per microlitre), patients begin to experience opportunistic infections—i.e., infections that arise only in individuals with a defective immune system. This is AIDS, the final stage of HIV infection. The most common opportunistic infections are Pneumocystis carinii pneumonia, tuberculosis, Mycobacterium avium infection, herpes simplex infection, bacterial pneumonia, toxoplasmosis, and cytomegalovirus infection. In addition, patients can develop dementia and certain cancers (cancer), including Kaposi sarcoma and lymphomas (lymphoma). Death ultimately results from the relentless attack of opportunistic pathogens or from the body's inability to fight off malignancies.

      A small proportion of individuals infected with HIV have survived longer than 10 years without developing AIDS. It was suspected for many years that such individuals mount a more vigorous immune response to the virus, but scientists could not explain why. Then, in 2006, a variation called a single nucleotide polymorphism, or SNP, in the HLA-G gene— human leukocyte antigen G, a gene that codes for a molecule that stimulates immune response—was identified in a subset of female prostitutes who had remained HIV-negative despite having had sexual contact with more than 500 HIV-positive men. In 2007 scientists identified three additional SNPs responsible for an estimated 15 percent of the variability in viral load and disease progression between HIV-infected individuals. Two of these SNPs are located in genes that code for HLA-B and HLA-C, molecules that are similar to HLA-G in that they specialize in pathogen recognition and immune system activation. The third SNP is located in a gene called HCP5 (HLA complex P5), an inactive retrovirus first incorporated into the human genome millions of years ago that shares similarities in DNA sequence with HIV and is thought to interfere with viral replication.

Diagnosis, treatment, and prevention

      Tests for the disease check for antibodies to HIV, which appear from four weeks to six months after exposure. The most common test for HIV is the enzyme-linked immunosorbent assay (ELISA). If the result is positive, the test is repeated on the same blood sample. Another positive result is confirmed using a more specific test such as the Western blot. A problem with ELISA is that it produces false positive results in people who have been exposed to parasitic diseases such as malaria; this is particularly troublesome in Africa, where both AIDS and malaria are rampant. polymerase chain reaction (PCR) tests, which screen for viral RNA and therefore allow detection of the virus after very recent exposure, and Single Use Diagnostic Screening (SUDS) are other options. Because these tests are very expensive, they are often out of reach for the majority of the population at risk for the disease. Pharmaceutical companies are developing new tests that are less expensive and that do not need refrigeration, allowing for a greater testing of the at-risk population around the world.

      There is no cure or effective vaccine for HIV infection. Efforts at prevention have focused primarily on changes in sexual behaviour such as the practice of abstinence and the use of condoms (condom). Attempts to reduce intravenous drug use and to discourage the sharing of needles have also led to a reduction in infection rates in some areas. HIV infection is treated with three classes of antiretroviral medications. Protease inhibitors, which inhibit the action of an HIV enzyme called protease, include ritonavir, saquinivir, indinavir, amprenivir, nelfinavir, and lopinavir. Nucleoside reverse transcriptase (RT) inhibitors (e.g., abacavir [ABC], zidovudine [ AZT], zalcitabine [ddC], didanosine [ddI], stavudine [d4T], and lamivudine [3TC]) and non-nucleoside RT inhibitors (e.g., efavirenz, delavirdine, and nevirapine) both inhibit the action of reverse transcriptase. Each drug has unique side effects, and, in addition, treatment with combinations of these drugs leads to additional side effects including a fat-redistribution condition called lipodystrophy.

      Because HIV rapidly becomes resistant to any single antiretroviral drug, combination treatment is necessary for effective suppression of the virus. Highly active antiretroviral therapy (HAART), a combination of three or more RT and protease inhibitors, has resulted in a marked drop in the mortality rate from HIV infection in the United States and other industrialized states since its introduction in 1996. Because of its high cost, HAART is generally not available in regions of the world hit hardest by the AIDS epidemic. Although HAART does not appear to eradicate HIV, it largely halts viral replication, thereby allowing the immune system to reconstitute itself. Levels of free virus in the blood become undetectable; however, the virus is still present in reservoirs, the best-known of which is a latent reservoir in a subset of helper T cells called resting memory T cells. The virus can persist in a latent state in these cells, which have a long life span due to their role in allowing the immune system to respond readily to previously encountered infections. These latently infected cells represent a major barrier to curing the infection. Patients successfully treated with HAART no longer suffer from the AIDS-associated conditions mentioned above, although severe side effects may accompany the treatment. Patients must continue to take all of the drugs without missing doses in the prescribed combination or risk developing a drug-resistant virus; viral replication resumes if HAART is discontinued.

      Antiretroviral therapy is typically initiated once CD4 levels have fallen to 200 cells per microlitre of blood, which generally coincides with the establishment of symptomatic disease. In most patients, initiating treatment at this point provides maximal therapeutic effectiveness, in that it minimizes the severity of drug toxicities and thus the risk for discontinuance of treatment and development of drug resistance. However, studies have indicated that in patients with morbidity-increasing factors, such as coinfection with a hepatitis virus or unusually rapid CD4 decline or high viral load, initiating treatment earlier, when CD4 levels have declined to 350 cells per microlitre, can improve survival and delay the onset of AIDS-related diseases significantly. Other studies have indicated that beginning antiretroviral treatment in infants immediately following diagnosis, rather than waiting until symptoms appear, can reduce infant mortality and disease progression dramatically. Such studies have resulted in the consideration of treatment recommendations that are more dynamic today than in the past, thereby improving treatment outcomes for certain subsets of patients with HIV.

      The identification of gene variations in HLA-B, HLA-C, HLA-G, and HCP5 has opened avenues of drug and vaccine development that had not been previously explored for HIV infection. Scientists anticipate that therapies aimed at these genes will serve as ways to boost immune response.

Robert Siliciano

Social, legal, and cultural aspects

 As with any epidemic for which there is no cure, tragedy shadows the disease's advance. From wreaking havoc on certain populations (such as the gay community in San Francisco in the 1980s) to infecting more than one-third of adults in sub-Saharan African countries such as Botswana, Swaziland, and Zimbabwe at the turn of the 21st century, AIDS has had a devastating social impact. Its collateral cultural effect has been no less far-reaching, sparking new research in medicine and complex legal debates, as well as intense competition among scientists, pharmaceutical companies, and research institutions. Since the mid-1980s, the International AIDS Society has held regular conferences at which new research and medical advances were discussed.

      In order to raise public awareness, advocates promote the wearing of a loop of red ribbon to indicate their concern. Activist groups lobby governments for funding for education, research, and treatment, and support groups provide a wide range of services including medical, nursing, and hospice care, housing, psychological counseling, meals, and legal services. Those who have died of AIDS have been memorialized in the more than 44,000 panels of the AIDS Memorial Quilt, which has been displayed worldwide both to raise funds and to emphasize the human dimension of the tragedy. The United Nations designated December 1 as World AIDS Day.

      Regarding access to the latest medical treatments for AIDS, the determining factors tend often to be geographic and economic. Simply put, developing nations often lack the means and funding to support the advanced treatments available in industrialized countries. On the other hand, in many developed countries specialized health care has caused the disease to be perceived as treatable or even manageable. This perception has fostered a lax attitude toward HIV prevention (such as safe sex practices or sterile needle distribution programs), which in turn has led to new increases in HIV infection rates.

      Because of the magnitude of the disease in Africa, and in sub-Saharan Africa in particular, the governments of this region have tried to fight the disease in a variety of ways. Some countries have made arrangements with multinational pharmaceutical companies to make HIV drugs available in Africa at lower costs. Other countries, such as South Africa, have begun manufacturing these drugs themselves instead of importing them. Plants indigenous to Africa are also being scrutinized for their usefulness in developing various HIV treatments.

      In the absence of financial resources to pay for new drug therapies, many African countries have found education to be the best defense against the disease. In Uganda, for example, songs about the disease, nationally distributed posters, and public awareness campaigns starting as early as kindergarten have all helped to stem the spread of AIDS. Prostitutes in Senegal are licensed and regularly tested for HIV, and the clergy, including Islamic religious leaders, work to inform the public about the disease. Other parts of Africa, however, have seen little progress. For example, the practice of sexually violating very young girls has developed among some HIV-positive African men because of the misguided belief that such acts will somehow cure them of the disease. In the opinion of many, only better education can battle the damaging stereotypes, misinformation, and disturbing practices associated with AIDS.

      Laws concerning HIV and AIDS typically fall into four broad categories: mandatory reporting, mandatory testing, laws against transmission, and immigration. The mandatory reporting of newly discovered HIV infections is meant to encourage early treatment. Many countries, including Canada, Switzerland, Denmark, and Germany, have enacted mandatory screening laws for HIV. Some countries, such as Estonia, require mandatory testing of prison populations (in response to explosive rates of infection among the incarcerated). Most of the United States requires some form of testing for convicted sex offenders. Other legal and international issues concern the criminalization of knowing or unknowing transmission (more prevalent in the United States and Canada) and the rights of HIV-positive individuals to immigrate to or even enter foreign countries.

      In the United States some communities have fought the opening of AIDS clinics or the right of HIV-positive children to attend public schools. Several countries—notably Thailand, India, and Brazil—have challenged international drug patent laws, arguing that the societal need for up-to-date treatments supersedes the rights of pharmaceutical companies. At the start of the 21st century many Western countries were also battling the reluctance of some governments to direct public awareness campaigns at high-risk groups such as homosexuals, prostitutes, and drug users out of fear of appearing to condone their lifestyles.

      For the world of art and popular culture, HIV/AIDS has been double-edged. On the one hand, AIDS removed from the artistic heritage many talented photographers, singers, actors, dancers, and writers in the world. On the other hand, as with the tragedy of war and even the horror of the Holocaust, AIDS has spurred moving works of art as well as inspiring stories of perseverance. From Paul Monette (Monette, Paul)'s Love Alone, to John Corigliano's Symphony No. 1, to the courage with which American tennis star Arthur Ashe (Ashe, Arthur) publicly lived his final days after acquiring AIDS from a blood transfusion—these, as much as the staggering rates of infection, constitute the legacy of AIDS.

Keith Dorwick

Additional Reading

General interest and in-depth works

Basic information on the political, demographic, and scientific aspects of HIV/AIDS is provided by Alan Whiteside, HIV/AIDS: A Very Short Introduction (2008). Comprehensive coverage of the virus and disease is provided by Hung Fan, Ross F. Conner, and Luis P. Villarreal, AIDS: Science and Society, 5th ed. (2007). The impacts of social and economic issues in Africa on epidemiological and biomedical research of AIDS are discussed in Ezekiel Kalipeni et al. (eds.), HIV and AIDS in Africa: Beyond Epidemiology (2003).

Documentaries

An informative documentary covering progress in both the sociopolitical and the scientific realms of HIV/AIDS is The Age of AIDS (2006), a PBS Home Video written and produced by Renata Simone, William Cran, and Greg Barker and narrated by Will Lyman. A critically acclaimed documentary about the AIDS pandemic and its impact on people worldwide is A Closer Walk (2006), a Worldwide Documentaries film, produced and directed by Robert Bilheimer and narrated by Glenn Close and Will Smith.Kara Rogers

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