Evidence that HIV causes AIDS
Acquired immunodeficiency syndrome (AIDS) was first recognized in 1981 and has since become a major worldwide epidemic. AIDS is caused by the human immunodeficiency virus (HIV). By leading to the destruction and/or functional impairment of cells of the immune system, notably CD4+ T cells, HIV progressively destroys the body's ability to fight infections and certain cancers.
This document summarizes the abundant evidence that HIV causes AIDS. Questions and answers further on in this document address the specific claims of those who assert that HIV is not the cause of AIDS.
The below information was taken from the NIAID Fact Sheet
"The Evidence That HIV Causes AIDS"
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Definition of AIDS
The Centers for Disease Control (CDC) currently defines AIDS in an adult or adolescent age 13 years or older as the presence of one of 26 conditions indicative of severe immunosuppression associated with HIV infection, such as Pneumocystis carinii pneumonia (PCP), a condition extraordinarily rare in people without HIV infection. These conditions are commonly referred to as 'opportunistic infections'. Most other AIDS-defining conditions are also 'opportunistic infections' which rarely cause harm in healthy individuals. A diagnosis of AIDS is also given to HIV-infected individuals with a CD4+ T cell count less than 200 cells per cubic millimeter (mm3) of blood. In children younger than 13 years, the definition of AIDS is similar to that in adolescents and adults, except that lymphoid interstitial pneumonitis and recurrent bacterial infections are included in the list of AIDS-defining conditions.
The designation "AIDS" is a surveillance tool. Surveillance definitions of AIDS have proven useful epidemiologically to track and quantify the recent epidemic of HIV-mediated immunosuppression and its manifestations. However, AIDS represents only the end stage of a continuous, progressive pathogenic process, beginning with primary infection with HIV, continuing with a chronic phase that is usually asymptomatic, and leading to progressively severe symptoms and, ultimately, profound immunodeficiency and opportunistic infections and cancers.
Evidence That HIV Causes AIDS
Before the appearance of HIV, AIDS-related diseases such as PCP, Kaposi's Sarcoma (KS) and Mycobacterium avium complex (MAC) were rare in developed countries; today, they are common in HIV-infected individuals.
Prior to the appearance of HIV, AIDS-related conditions such as PCP, KS and disseminated infection with MAC were extraordinarily rare in the United States. In a 1967 survey, only 107 cases of PCP in this country had been described in the medical literature, virtually all among individuals with underlying immunosuppressive conditions. Before the AIDS epidemic, the annual incidence of Kaposi's sarcoma in the United States was 0.2 to 0.6 per million population, and only 32 individuals with disseminated MAC disease had been described in the medical literature.
By the end of 1999, CDC had received reports of 166,368 HIV-infected patients in the United States with definitive diagnoses of PCP, 46,684 with definite diagnoses of KS, and 41,873 with definitive diagnoses of disseminated MAC.
AIDS and HIV infection are invariably linked in time, place and population group.
Historically, the occurrence of AIDS in human populations has closely followed the appearance of HIV. In the United States, the first cases of AIDS were reported in 1981 among homosexual men in New York and California and retrospective examination of frozen blood samples from a cohort of gay men showed the presence of HIV antibodies as early as 1978 but not before then. Subsequently, in every country and city where AIDS has appeared, evidence of HIV infection has preceded AIDS by just a few years.
Many studies agree that only a single factor, HIV, predicts whether a person will develop AIDS.
Other viral infections, bacterial infections, sexual behavior patterns and drug abuse patterns do not predict who develops AIDS. Individuals from diverse backgrounds, including heterosexual men and women, homosexual men and women, hemophiliacs, sexual partners of hemophiliacs and transfusion recipients, injection-drug users and infants have all developed AIDS, with the only common denominator being their infection with HIV.
Numerous serosurveys show that AIDS is common in populations where many individuals have HIV antibodies. Conversely, in populations with low seroprevalence of HIV antibodies, AIDS is extremely rare.
Foe example, in the southern African country of Zimbabwe (population 11.4 million), more than 25 percent of adults ages 15 to 49 are estimated to be HIV-positive, based on numerous studies. As of November 1999, 74, 000 cases of AIDS were reported to the World Health Organization (WHO). In contrast, Madagascar, an island country off the southeast coast of Africa (population 15.1 million) with a very low seroprevalence rate, reported only 37 cases of AIDS to WHO through November 1999.
In cohort studies, severe immunosuppression and AIDS-defining illnesses occur exclusively in individuals who are HIV-infected.
Conversely, matched controls, individuals with similar lifestyles but without HIV infection, virtually never suffer these symptoms.
For example, in one cohort in Vancouver, investigators followed 715 homosexual men for a median of 8.6 years. Every case of AIDS in this cohort occurred in individuals who were positive for HIV antibodies. No AIDS-defining illnesses occurred in men who remained negative for HIV antibodies, despite the fact that these men had appreciable patterns of illicit drug use and receptive anal intercourse.
In some studies conducted, it has been shown that death rates are markedly higher among HIV-seropositive individuals than among HIV-seronegative individuals.
Excess mortality among HIV-seropositive people also has been repeatedly observed in studies in developed countries, perhaps most dramatically among hemophiliacs. For example, 6,278 hemophiliacs where studied in the United Kingdom during the period 1977-91. Among 2,448 with severe hemophilia, the annual death rate was stable at 8 per 1,000 during 1977-84. While deaths rates remained stable at 8 per 1,000 from 1985-92 among HIV-negative persons with severe hemophilia, deaths rose steeply among those who had become HIV-positive following HIV-tainted transfusions during 1979-1986, reaching 81 per 1,000.
The specific immunologic profile that typifies AIDS—a persistently low CD4+ T cell count—is extraordinarily rare in the absence of HIV infection or other known cause of immunosuppression.
For example, in the MACS study, 22,643 CD4+ T-cell counts were carried out, related to 2,713 HIV-negative men. There was only one individual with a CD4 + T-cell count persistently lower than 300 cells/mm3. This individual was taking other drugs that would have had an affect on his CD4 count.
Nearly everone with AIDS has antibodies to HIV.
A survey of 230,179 AIDS patients in the United States revealed only 299 HIV-seronegative individuals. An evaluation of 172 of these 299 patients found 131 actually to be seropositive; an additional 34 died before their serostatus could be confirmed.
HIV can be detected in virtually everyone with AIDS.
Recently developed sensitive testing methods, including the polymerase chain reaction (PCR) and improved culture techniques, have enabled researchers to find HIV in patients with AIDS with few exceptions. HIV has been repeatedly isolated from the blood, semen and vaginal secretions of patients with AIDS, findings consistent with the epidemiologic data demonstrating AIDS transmission via sexual activity and contact with infected blood.
The HIV-infected twin develops AIDS while the uninfected twin does not.
Researchers have documented cases of HIV-infected mothers who have given birth to twins, one of whom is HIV-infected and the other not. The HIV-infected children developed AIDS, while the other children remained clinically and immunologically normal.
Studies of transfusion-acquired AIDS cases have repeatedly led to the discovery of HIV in the patient as well as in the blood donor.
Numerous studies have shown an almost perfect correlation between the occurrence of AIDS in a blood recipient and donor, and evidence of similar HIV strains in both the recipient and the donor.
HIV causes the death of CD4+ T lymphocytes in vitro and in vivo.
CD4+ T cells are the cells depleted in people with AIDS. Although the loss of CD4+ T cells is not the only immune defect seen in people with AIDS, the observation that HIV also infects and damages these cells in vitro establishes an obvious link between HIV and AIDS.
Among HIV-infected patients who receive anti-HIV therapy, those whose viral loads are driven to low levels are much less likely to develop AIDS or die than patients who do not respond to therapy. Such an effect would not be seen if HIV did not have a central role in causing AIDS.
Clinical trials in both HIV-infected children and adults have demonstrated a link between a good virologic response to therapy i.e. a reduced risk of developing AIDS or dying.
This effect has also been seen in routine clinical practice. For example, in an analysis of 2,674 HIV-infected patients who started highly active antiretroviral therapy (HAART) in 1995-1998, 6.6 percent of patients who achieved and maintained undetectable viral loads developed AIDS or died within 30 months, compared with 20.1 percent of patients who never achieved undetectable concentrations.
HIV fulfills Koch's postulates as the cause of AIDS
Koch's postulates of disease causation stipulate: 1) the suspected cause must be strongly associated with the disease, 2) the suspected agent can be isolated and propagated outside the host, and 3) that the transfer of the agent to an uninfected host, man or animal, produces the disease in that host.
With regard to postulate 1), numerous studies from around the world show that virtually all AIDS patients are HIV-seropositive: that is they carry antibodies that indicate HIV-infection. With regard to postulate 2), modern techniques have allowed the isolation of HIV in virtually all AIDS patients, as well as in almost all HIV seropositive individuals with both early-and late-stage disease. Postulate 3) has been fulfilled in incidents involving three laboratory workers with no other risk factors who developed AIDS or severe immunosuppression after accidental exposure to concentrated, cloned HIV in the laboratory. In all three cases, HIV was isolated from the infected individual, sequenced and shown to be the infecting strain of virus.
In addition, through December 1999, the CDC had received reports of 56 health care workers in the United States with documented, occupationally acquired infection, of whom 25 have developed AIDS in the absence of other risk factors. The development of AIDS following known HIV seroconversion has also been repeatedly observed in pediatric and adult blood transfusion cases, in mother-to-child transmission, and in studies of hemophilia, injecting drug use and sexual transmission in which seroconversion can be documented using serial blood samples.
Answering the skeptics, responses to arguments that HIV does not cause AIDS
Myth: HIV antibody testing is unreliable
Fact: Diagnosis of infection using antibody testing is one of the best-established concepts in medicine. HIV antibody tests exceed the performance of most other infectious disease tests in both sensitivity (the ability of the screening test to give a positive finding when the person tested truly has the disease) and specificity (the ability of the test to give a negative finding when the subjects tested are free of the disease under study). Current HIV antibody tests have sensitivity and specificity in excess of 98% and are therefore extremely reliable.
Progress in testing methodology has also enabled detection of viral genetic material, antigens and the virus itself in body fluids and cells. While not widely used for routine testing due to high cost and requirements in laboratory equipment, these direct testing techniques have confirmed the validity of the antibody tests.
Myth: There is no AIDS in Africa. AIDS is nothing more than a new name for old diseases.
Fact: The diseases that have come to be associated with AIDS in Africa — such as wasting syndrome, diarrheal diseases and Tuberculosis (TB) — have long been severe burdens there. However, high rates of mortality from these diseases, formerly confined to the elderly and malnourished, are now common among HIV-infected young and middle-aged people.
For example, in a study in Cote d'Ivoire, HIV-seropositive individuals with pulmonary tuberculosis (TB) were 17 times more likely to die within six months than HIV-seronegative individuals with pulmonary TB. In Malawi, mortality over three years among children who had received recommended childhood immunizations and who survived the first year of life was 9.5 times higher among HIV-seropositive children than among HIV-seronegative children. The leading causes of death were wasting syndrome and respiratory conditions. Elsewhere in Africa, findings are similar.
Myth: HIV cannot be the cause of AIDS because researchers are unable to explain precisely how HIV destroys the immune system.
Fact: A great deal is known about the pathogenesis of HIV disease, even though important details remain to be elucidated. However, a complete understanding of the pathogenesis of a disease is not a prerequisite to knowing its cause. Most infectious agents have been associated with the disease they cause long before their pathogenic mechanisms have been discovered. Because research in pathogenesis is difficult when precise animal models are unavailable, the disease-causing mechanisms in many diseases, including tuberculosis and hepatitis B are poorly understood. The critics' reasoning would lead to the conclusion that M. tuberculosis is not the cause of tuberculosis or that hepatitis B virus is not a cause of liver disease.
Myth: AZT and other antiretroviral drugs, not HIV, cause AIDS.
Fact: The vast majority of people with AIDS never received antiretroviral drugs, including those in developed countries prior to the licensure of AZT in 1987, and people in developing countries today where very few individuals have access to these medications. As with medications for any serious diseases, antiretroviral drugs can have toxic side effects. However, there is no evidence that antiretroviral drugs cause the severe immunosuppression that typifies AIDS, and abundant evidence that antiretroviral therapy, when used according to the established guidelines, can improve the length and quality of life of HIV-infected individuals.
In the 1980s, clinical trials enrolling patients with AIDS found that AZT given as single-drug therapy conferred a modest (and short-lived) survival advantage compared to placebo. Among HIV-infected patients who had not yet developed AIDS, placebo-controlled trials found that AZT given as single-drug therapy delayed, for a year or two, the onset of AIDS-related illness. Significantly, long-term follow-up of these trails did not show a prolonged benefit of AZT, but also never indicated that the drug increased disease progression or mortality. The lack of excess AIDS cases and death in the AZT arms of these placebo-controlled trials effectively counters the argument that AZT causes AIDS.
Subsequent clinical trials found that patients receiving two-drug combinations had up to 50 percent increases in time to progression to AIDS and in survival when compared to people receiving single-drug therapy. In more recent years, three-drug combination therapies have produced another 50 percent to 80 percent improvements in progression to AIDS and in survival when compared to two-drug regimens in clinical trials. Use of potent anti-HIV combination therapies has contributed to dramatic reductions in the incidence of AIDS and AIDS-related deaths in populations where these drugs are widely available, an effect which clearly would not be seen if antiretroviral drugs caused AIDS.
Myth: Behavioral factors such as recreational drug use and multiple sexual partners account for AIDS.
Fact: The proposed behavioral causes of AIDS, such as multiple sexual partners and long-term recreational drug use, have existed for many years. The epidemic of AIDS, characterized by the occurrence of formerly rare opportunistic infections such as Pneumocystis carinii pneumonia (PCP) did not occur in the United States until a previously unknown human retrovirus—HIV—spread through certain communities.
Compelling evidence against the hypothesis that behavioral factors cause AIDS comes from recent studies that have followed cohorts of homosexual men for long periods of time and found that only HIV-seropositive men develop AIDS. For example, in a prospectively studied cohort in Vancouver, 715 homosexual men were followed for a median of 8.6 years. Among 365 HIV-positive individuals, 136 developed AIDS. No AIDS-defining illnesses occurred among 350 seronegative men despite the fact that these men reported appreciable use of inhalable nitrites ("poppers") and other recreational drugs, and frequent receptive anal intercourse. Other studies show that among homosexual men and injection drug users, the specific immune deficit that leads to AIDS—a progressive and sustained loss of CD4+ T cells—is extremely rare in the absence of other immunosuppressive conditions. In the Multicenter AIDS Cohort Study, more than 22,000 T-cell determinations in 2,713 HIV-seronegative homosexual men revealed only one individual with a CD4+ T cell count persistently lower than 300 cells/mm3, and this individual was receiving immunosuppressive therapy.
In a survey of 229 HIV-seronegative injection drug users in New York City, mean CD4+ T cell counts of the group were consistently more than 1000 cells/mm3. Only two individuals had two CD4+ T cell measurements of less than 300/mm3, one of whom died with cardiac disease and non-Hodgkin's lymphoma listed as the cause of death. In another study, HIV-seronegative, long-term heroin addicts had mean CD4+ T cell counts of 1500/mm3, while eleven healthy controls had CD4+ counts of 820 cells/mm3.
Myth: AIDS among transfusion recipients is due to underlying diseases that necessitated the transfusion, rather than to HIV.
Fact: This notion is contradicted by a report by the Transfusion Safety Study Group (TSSG), which compared HIV-negative and HIV-positive blood recipients who had been given transfusions for similar diseases. Approximately 3 years after the transfusion, the mean CD4+ T cell count in 64 HIV-negative recipients was 850/mm3, while 111 HIV-seropositive individuals had average CD4+ T cell count of 375/mm3. By 1993, there were 37 cases of AIDS in the HIV-infected group, but not a single AIDS-defining illness in the HIV-seronegative transfusion recipients.
Myth: High usage of clotting factor, not HIV, leads to CD4+ T-cell reduction and AIDS in hemophiliacs.
Fact: This view is contradicted by several large studies. For example, among HIV-seronegative patients with hemophilia A enrolled in the Transfusion Safety Study, no significant differences in CD4+ T cell counts were noted between 79 patients with no or minimal factor treatment and 52 with the largest amount of lifetime treatments . Patients in both groups had CD4+ T cell counts within the normal range. In another report from the Transfusion Safety Study, no instances of AIDS-defining illnesses were seen among 402 HIV-seronegative hemophiliacs who had received factor therapy.
Myth: The distribution of AIDS cases casts doubt on HIV as the cause. Viruses are not gender-specific, yet only a small proportion of AIDS cases are among women.
Fact: The distribution of AIDS cases, whether in the United States or elsewhere in the world, invariably mirrors the prevalence of HIV in a population. In the United States, HIV first appeared in populations of homosexual men and injection drug users, a majority of whom are male. Because HIV is spread primarily through sex or by the exchange of HIV-contaminated needles during injection drug use, it is not surprising that a majority of U.S. AIDS cases have occurred in men.
Increasingly, however, women in this country are becoming HIV-infected, usually through the exchange of HIV-contaminated needles or sex with an HIV-infected male. The CDC estimates that 30 percent of new HIV infections in the United States in 1998 were in women. As the number of HIV-infected women has risen, so too has the number of female AIDS patients in the U.S. In 1998, approximately 23% of adult/adolescent AIDS cases in the United States were among women. In the same year, AIDS was the fifth leading cause of death among women aged 25 to 44 in the U.S.
In Africa, HIV was first recognized in sexually active heterosexuals, and AIDS cases in Africa have occurred at least as frequently in women as in men. Overall, the worldwide distribution of HIV infection and AIDS between men and women is approximately 1 to 1.
Myth: HIV cannot be the cause of AIDS because the body develops a vigorous antibody response to the virus.
Fact: This reasoning ignores numerous examples of viruses other than HIV that can be pathogenic after evidence of immunity appears. Measles virus may persist for years in brain cells, eventually causing a chronic neurologic disease despite the presence of antibodies. Viruses such as cytomegalovirus, herpes simplex and varicella zoster (shingles) may be activated after years of latency even in the presence of abundant antibodies. In animals, viral relatives of HIV with long and variable latency periods, such as visna virus in sheep, cause central nervous system damage even after the production of antibodies.
Also, HIV is well recognized as being able to mutate to avoid the ongoing immune response of the host.
Myth: Only a small number of CD4+ T cells are infected by HIV, not enough to damage the immune system.
Fact: New techniques such as the polymerase chain reaction have enabled scientists to demonstrate that a much larger proportion of CD4+ T cells are infected than previously realized, particularly in lymphoid tissues. Macrophages and other cell types are also infected with HIV and serve as reservoirs for the virus. Although the fraction of CD4+ T cells that is infected with HIV at any given time is never extremely high (only a small subset of activated cells serve as ideal targets of infection), several groups have shown that rapid cycles of death of infected cells and infection of new target cells occur throughout the course of disease.
Myth: HIV is not the cause of AIDS because many individuals with HIV have not developed AIDS.
Fact: HIV disease has a prolonged and variable course. The median period of time between infection with HIV and the onset of clinically apparent disease is approximately 10 years, according to prospective studies of homosexual men in which dates of seroconversion are known. Similar estimates of asymptomatic periods have been made for HIV-infected blood-transfusion recipients, injection drug users and adult hemophiliacs.
As with many diseases, a number of factors can influence the course of HIV disease. Factors such as age or genetic differences between individuals, the level of virulence of the individual strain of virus, as well as exogenous influences such as co-infection with other microbes may determine the rate and severity of HIV disease expression. Similarly, some people infected with hepatitis B, for example, show no symptoms or only jaundice and clear their infection, while others suffer disease ranging from chronic liver inflammation to cirrhosis and hepatocellular carcinoma. Co-factors probably also determine why some smokers develop lung cancer, while others do not.
Myth: Some people have many symptoms associated with AIDS but do not have HIV infection.
Fact: Most AIDS symptoms result from the development of opportunistic infections and cancers associated with severe immunosuppression secondary to HIV.
However, immunosuppression has many other potential causes. Individuals who take glucocorticoids and/or immunosuppressive drugs to prevent transplant rejection or for autoimmune diseases can have increased susceptibility to unusual infections, as do individuals with certain genetic conditions, severe malnutrition and certain kinds of cancers. There is no evidence suggesting that the numbers of such cases have risen, while abundant epidemiologic evidence shows a staggering rise in cases of immunosuppression among individuals who share one characteristic: HIV infection.
Myth: The spectrum of AIDS-related infections seen in different populations proves that AIDS is actually many diseases not caused by HIV.
Fact: The diseases associated with AIDS, such as PCP and MAC are not caused by HIV but rather result from the immunosuppression caused by HIV disease. As the immune system of an HIV-infected individual weakens, he or she becomes susceptible to the particular viral, fungal and bacterial infections common in the community. For example, HIV-infected people in certain midwestern and mid-Atlantic regions are much more likely than people in New York City to develop histoplasmosis, which is caused by a fungus. A person in Africa is exposed to different pathogens than is an individual in an American city. Children may be exposed to different infectious agents than adults.