The Evidence that HIV Causes AIDS: An NIAID Fact Sheet

The Evidence That HIV Causes AIDS

BACKGROUND

The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981 and has since become a major worldwide pandemic. 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.

An HIV-infected person is diagnosed with AIDS when his or her immune system is seriously compromised and manifestations of HIV infection are severe. The U.S. Centers for Disease Control and Prevention (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. Most other AIDS-defining conditions are also "opportunistic infections" which rarely cause harm in healthy individuals. A diagnosis of AIDS also is given to HIV-infected individuals when their CD4+ T-cell count falls below 200 cells/cubic millimeter (mm³) of blood. Healthy adults usually have CD4+ T-cell counts of 600-1,500/mm³ of blood. In HIV-infected children younger than 13 years, the CDC definition of AIDS is similar to that in adolescents and adults, except for the addition of certain infections commonly seen in pediatric patients with HIV. (CDC [1]. MMWR 1992;41(RR-17):1; CDC [2]. MMWR 1994;43(RR-12):1).

In many developing countries, where diagnostic facilities may be minimal, healthcare workers use a World Health Organization (WHO) AIDS case definiton based on the presence of clinical signs associated with immune deficiency and the exclusion of other known causes of immunosuppression, such as cancer or malnutrition. An expanded WHO AIDS case definition, with a broader spectrum of clinical manifestations of HIV infection, is employed in settings where HIV antibody tests are available (WHO [3]. Wkly Epidemiol Rec. 1994;69:273).

As of the end of 2000, an estimated 36.1 million people worldwide - 34.7 million adults and 1.4 million children younger than 15 years - were living with HIV/AIDS. Through 2000, cumulative HIV/AIDS-associated deaths worldwide numbered approximately 21.8 million - 17.5 million adults and 4.3 million children younger than 15 years. In the United States, an estimated 800,000 to 900,000 people are living with HIV infection. As of December 31, 1999, 733,374 cases of AIDS and 430,441 AIDS-related deaths had been reported to the CDC. AIDS is the fifth leading cause of death among all adults aged 25 to 44 in the United States. Among African-Americans in the 25 to 44 age group, AIDS is the leading cause of death for men and the second leading cause of death for women (UNAIDS [4]. AIDS epidemic update: December 2000; CDC [5]. HIV/AIDS Surveillance Report 1999;11[2]:1; CDC [6]. MMWR 1999;48[RR13]:1).

This document summarizes the abundant evidence that HIV causes AIDS. Questions and answers at the end of this document address the specific claims of those who assert that HIV is not the cause of AIDS.

EVIDENCE THAT HIV CAUSES AIDS

HIV fulfills Koch's postulates as the cause of AIDS.

Among many criteria used over the years to prove the link between putative pathogenic (disease-causing) agents and disease, perhaps the most-cited are Koch's postulates, developed in the late 19th century. Koch's postulates have been variously interpreted by many scientists, and modifications have been suggested to accommodate new technologies, particularly with regard to viruses (Harden [7]. Pubbl Stn Zool Napoli [II] 1992;14:249; O'Brien, Goedert [8]. Curr Opin Immunol 1996;8:613). However, the basic tenets remain the same, and for more than a century Koch's postulates, as listed below, have served as the litmus test for determining the cause of any epidemic disease:

1. Epidemiological association: the suspected cause must be strongly associated with the disease.
2. Isolation: the suspected pathogen can be isolated - and propagated - outside the host.
3. Transmission pathogenesis: transfer of the suspected pathogen 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 culture 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. In addition, the polymerase chain (PCR) and other sophisticated molecular techniques have enabled researchers to document the presence of HIV genes in virtually all patients with AIDS, as well as in individuals in earlier stages of HIV disease.

Postulate #3 has been fulfilled in tragic incidents involving three laboratory workers with no other risk factors who have 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 another tragic incident, transmission of HIV from a Florida dentist to six patients has been documented by genetic analyses of virus isolated from both the dentist and the patients. The dentist and three of the patients developed AIDS and died, and at least one of the other patients has developed AIDS. Five of the patients had no HIV risk factors other than multiple visits to the dentist for invasive procedures (O'Brien, Goedert [8]. Curr Opin Immunol 1996;8:613; O'Brien [9], 1997; Ciesielski [10] et al. Ann Intern Med 1994;121:886).

In addition, through December 1999, the CDC had received reports of 56 health care workers in the United States with documented, occupationally acquired HIV infection, of whom 25 have developed AIDS in the absence of other risk factors. The development of AIDS following known HIV seroconversion also has been repeatedly observed in pediatric and adult blood transfusion cases, in mother-to-child transmission, and in studies of hemophilia, injection-drug use and sexual transmission in which seroconversion can be documented using serial blood samples (CDC [5]. HIV AIDS Surveillance Report 1999;11[2]:1; AIDS Knowledge Base, 1999). For example, in a 10-year study in the Netherlands, researchers followed 11 children who had become infected with HIV as neonates by small aliquots of plasma from a single HIV-infected donor. During the 10-year period, eight of the children died of AIDS. Of the remaining three children, all showed a progressive decline in cellular immunity, and two of the three had symptoms probably related to HIV infection (van den Berg [11] et al. Acta Paediatr 1994;83:17).

Koch's postulates also have been fulfilled in animal models of human AIDS. Chimpanzees experimentally infected with HIV have developed severe immunosuppression and AIDS. In severe combined immunodeficiency (SCID) mice given a human immune system, HIV produces similar patterns of cell killing and pathogenesis as seen in people. HIV-2, a less virulent variant of HIV which causes AIDS in people, also causes an AIDS-like syndrome in baboons. More than a dozen strains of simian immunodeficiency virus (SIV), a close cousin of HIV, cause AIDS in Asian macaques. In addition, chimeric viruses known as SHIVs, which contain an SIV backbone with various HIV genes in place of the corresponding SIV genes, cause AIDS in macaques. Further strengthening the association of these viruses with AIDS, researchers have shown that SIV/SHIVs isolated from animals with AIDS cause AIDS when transmitted to uninfected animals (O'Neil [12] et al. J Infect Dis 2000;182:1051; Aldrovandi [13] et al. Nature 1993;363:732; Liska [14] et al. AIDS Res Hum Retroviruses 1999;15:445; Locher [15] et al. Arch Pathol Lab Med 1998;22:523; Hirsch [16] et al. Virus Res 1994;32:183; Joag [17] et al. J Virol 1996;70:3189).

AIDS and HIV infection are invariably linked in time, place and population group.

Historically, the occurence of AIDS in human populations around the world 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 U.S. cohort of gay men showed the presence of HIV antibodies as early as 1978, but not before then. Subsequently, in every region, country and city where AIDS has appeared, evidence of HIV infection has preceded AIDS by just a few years (CDC [18]. MMWR 1981;30:250; CDC [19]. MMWR 1981;30:305; Jaffe [20] et al. Ann Intern Med 1985;103:210; U.S. Census Bureau [21]; UNAIDS [22]).

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 (NIAID [23], 1995).

In cohort studies, severe immunosuppression and AIDS-defining illnesses occur almost exclusively in individuals who are HIV-infected.

For example, analysis of data from more than 8,000 participants in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) demonstrated that participants who were HIV-seropositive were 1,100 times more likely to develop an AIDS-associated illness than those who were HIV-seronegative. These overwhelming odds provide a clarity of association that is unusual in medical research (MACS and WIHS Principal Investigators [24], 2000).

In a Canadian cohort, investigators followed 715 homosexual men for a median of 8.6 years. Every case of AIDS in this cohort occurred in individuals who were HIV-seropositive. No AIDS-defining illnesses occurred in men who remained negative for HIV antibodies, despite the fact that these individuals had appreciable patterns of illicit drug use and receptive anal intercourse (Schechter [25] et al. Lancet 1993;341:658).

Before the appearance of HIV, AIDS-related diseases such as PCP, KS and 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 Pneumocystis carinii pneumonia (PCP), Kaposi's sarcoma (KS) and disseminated infection with the Mycobacterium avium complex (MAC) were extraordinarily rare in the United States. In a 1967 survey, only 107 cases of PCP in the United States 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 only 0.2 to 0.6 cases per million population, and only 32 individuals with disseminated MAC disease had been described in the medical literature (Safai [26]. Ann NY Acad Sci 1984;437:373; Le Clair [27]. Am Rev Respir Dis 1969;99:542; Masur [28]. JAMA 1982;248:3013).

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 definitive diagnoses of KS, and 41,873 with definitive diagnoses of disseminated MAC (personal communication).

In developing countries, patterns of both rare and endemic diseases have changed dramatically as HIV has spread, with a far greater toll now being exacted among the young and middle-aged, including well-educated members of the middle class.

In developing countries, the emergence of the HIV epidemic has dramatically changed patterns of disease in affected communities. As in developed countries, previously rare, "opportunistic" diseases such as PCP and certain forms of meningitis have become more commonplace. In addition, as HIV seroprevalence rates have risen, there have been significant increases in the burden of endemic conditions such as tuberculosis (TB), particularly among young people. For example, as HIV seroprevalence increased sharply in Blantyre, Malawi from 1986 to 1995, tuberculosis admissions at the city's main hospital rose more than 400 percent, with the largest increase in cases among children and young adults. In the rural Hlabisa District of South Africa, admissions to tuberculosis wards increased 360 percent from 1992 to 1998, concomitant with a steep rise in HIV seroprevalence. High rates of mortality due to endemic conditions such as TB, diarrheal diseases and wasting syndromes, formerly confined to the elderly and malnourished, are now common among HIV-infected young and middle-aged people in many developing countries (UNAIDS [22], 2000; Harries [29] et al. Int J Tuberc Lung Dis 1997;1:346; Floyd [30] et al. JAMA 1999;282:1087).

In studies conducted in both developing and developed countries, death rates are markedly higher among HIV-seropositive individuals than among HIV-seronegative individuals.

For example, Nunn [31] and colleagues (BMJ 1997;315:767) assessed the impact of HIV infection over five years in a rural population in the Masaka District of Uganda. Among 8,833 individuals of all ages who had an unambiguous result on testing for HIV-antibodies (either 2 or 3 different test kits were used for blood samples from each individual), HIV-seropositive people were 16 times more likely to die over five years than HIV-seronegative people (see table [32]). Among individuals ages 25 to 34, HIV-seropositive people were 27 times more likely to die than HIV-seronegative people.

In another study in Uganda, 19,983 adults in the rural Rakai District were followed for 10 to 30 months (Sewankambo et al. AIDS 2000;14:2391). In this cohort, HIV-seropositive people were 20 times more likely to die than HIV-seronegative people during 31,432 person-years of observation.

Similar findings have emerged from other studies (Boerma [33] et al. AIDS 1998;12(suppl 1):S3); for example,

• in Tanzania, HIV-seropositive people were 12.9 time more likely to die over two years than HIV-seronegative people (Borgdorff [34] et al. Genitourin Med 1995;71:212)
• in Malawi, mortality over three years among children who survived the first year of life was 9.5 times higher among HIV-seropositive children than among HIV-seronegative children (Taha [35] et al. Pediatr Infect Dis J 1999;18:689)
• in Rwanda, mortality was 21 times higher for HIV-seropositive children than for HIV-seronegative children after five years (Spira [36] et al. Pediatrics 1999;14:e56). Among the mothers of these children, mortality was 9 times higher among HIV-seropositive women than among HIV-seronegative women in four years of follow-up (Leroy [37] et al. J Acquir Immune Defic Syndr Hum Retrovirol 1995;9:415).
• 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 (Ackah [38] et al. Lancet 1995; 345:607).
• in the former Zaire (now the Democratic Republic of Congo), HIV-infected infants were 11 times more likely to die from diarrhea than uninfected infants (Thea [39] et al. NEJM 1993;329:1696).
• in South Africa, the death rate for children hospitalized with severe lower respiratory tract infections was 6.5 times higher for HIV-infected infants than for uninfected children (Madhi [40] et al. Clin Infect Dis 2000;31:170).

Kilmarx [41] and colleagues (Lancet 2000; 356:770) recently reported data on HIV infection and mortality in a cohort of female commercial sex workers in Chiang Rai, Thailand. Among 500 women enrolled in the study between 1991 and 1994, the mortality rate through October 1998 among women who were HIV-infected at enrollment (59 deaths among 160 HIV-infected women) was 52.7 times higher than among women who remained uninfected with HIV (2 deaths among 306 uninfected women). The mortality rate among women who became infected during the study (7 deaths among 34 seroconverting women) was 22.5 higher than among persistently uninfected women. Among the HIV-infected women, only 3 of whom received antiretroviral medications, all reported causes of death were associated with immunosuppression, whereas the reported causes of death of the two uninfected women were postpartum amniotic embolism and gunshot wound.

Excess mortality among HIV-seropositive people also has been repeatedly observed in studies in developed countries, perhaps most dramatically among hemophiliacs. For example, Darby [42] et al. (Nature 1995;377:79) studied 6,278 hemophiliacs living in the United Kingdom during the period 1977-91. Among 2,448 individuals with severe hemophilia, the annual death rate was stable at 8 per 1,000 during 1977-84. While death rates remained stable at 8 per 1,000 from 1985-1992 among HIV-seronegative persons with severe hemophilia, deaths rose steeply among those who had become HIV-seropositive following HIV-tainted transfusions during 1979-1986, reaching 81 per 1,000 in 1991-92. Among 3,830 individuals with mild or moderate hemophilia, the pattern was similar, with an initial death rate of 4 per 1,000 in 1977-84 that remained stable among HIV-seronegative individuals but rose to 85 per 1,000 in 1991-92 among seropositive individuals.

Similar data have emerged from the Multicenter Hemophilia Cohort Study. Among 1,028 hemophiliacs followed for a median of 10.3 years, HIV-infected individuals (n=321) were 11 times more likely to die than HIV-negative subjects (n=707), with the dose of Factor VIII having no effect on survival in either group (Goedert [43]. Lancet 1995;346:1425).

In the Multicenter AIDS Cohort Study (MACS), a 16-year study of 5,622 homosexual and bisexual men, 1,668 of 2,761 HIV-seropositive men have died (60 percent), 1,547 after a diagnosis of AIDS. In contrast, among 2,861 HIV-seronegative participants, only 66 men (2.3 percent) have died (A. Munoz, MACS, personal communication).

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 (Hammer [44] et al. J Clin Microbiol 1993;31:2557; Jackson [45] et al. J Clin Microbiol 1990;28:16).

Numerous studies of HIV-infected people have shown that high levels of infectious HIV, viral antigens, and HIV nucleic acids (DNA and RNA) in the body predict immune system deterioration and an increased risk for developing AIDS. Conversely, patients with low levels of virus have a much lower risk of developing AIDS.

For example, in an anlysis of 1,604 HIV-infected men in the Multicenter AIDS Cohort Study (MACS), the risk of a patient developing AIDS with six years was strongly associated with levels of HIV RNA in the plasma as measured by a sensitive test known as the branched-DNA signal-amplification assay (bDNA):

(Source: Mellors [46] et al. Ann Intern Med 1997;126:946)

Similar associations between increasing HIV RNA levels and a greater risk of disease progression have been observed in HIV-infected children in both developed and developing countries (Palumbo [47] et al. JAMA 1998;279:756; Taha [48] et al. AIDS 2000;14:453).

In the very small proportion of untreated HIV-infected individuals whose disease progresses very slowly, the amount of HIV in the blood and lymph nodes is significantly lower than in HIV-infected people whose disease progression is more typical (Pantaleo [49] et al. NEJM 1995;332:209; Cao [50] et al. NEJM 1995;332:201; Barker [51] et al. Blood 1998;92:3105).

The availability of potent combinations of drugs that specifically block HIV replication has dramatically improved the prognosis for HIV-infected individuals. Such an effect would not be seen if HIV did not have a central role in causing AIDS.

Clinical trials have shown that potent three-drug combinations of anti-HIV drugs, known as highly active antiretroviral therapy (HAART), can significantly reduce the incidence of AIDS and death among HIV-infected individuals as compared to previously available HIV treatment regimens (Hammer [52] et al. NEJM 1997;337:725; Cameron [53] et al. Lancet 1998;351:543).

Use of these 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, among both adults and children (Figure 1 [54]; CDC [5]. HIV AIDS Surveillance Report 1999;11[2]:1; Palella [55] et al. NEJM 1998;338:853; Mocroft [56] et al. Lancet 1998;352:1725; Mocroft [57] et al. Lancet 2000;356:291; Vittinghoff [58] et al. J Infect Dis 1999;179:717; Detels [59] et al. JAMA 1998;280:1497; de Martino [60] et al. JAMA 2000;284:190; CASCADE Collaboration [61]. Lancet 2000;355:1158; Hogg [62] et al. CMAJ 1999;160:659; Schwarcz [63] et al. Am J Epidemiol 2000;152:178; Kaplan [64] et al. Clin Infect Dis 2000;30:S5; McNaghten [65] et al. AIDS 1999;13:1687;).

For example, in a prospective study of more than 7,300 HIV-infected patients in 52 European outpatient clinics, the incidence of new AIDS-defining illnesses declined from 30.7 per 100 patient-years of observation in 1994 (before the availability of HAART) to 2.5 per 100 patient years in 1998, when the majority of patients received HAART (Mocroft [57] et al. Lancet 2000;356:291).

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. much less virus in the body) and a reduced risk of developing AIDS or dying (Montaner [66] et al. AIDS 1998;12:F23; Palumbo [47] et al. JAMA 1998;279:756; O'Brien [67] et al. NEJM 1996;334:426; Katzenstein [68] et al. NEJM 1996;335:1091; Marschner [69] et al. J Infect Dis 1998;177:40; Hammer [52] et al. NEJM 1997;337:725; Cameron [53] et al. Lancet 1998;351:543).

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 (<400 copies/mL of blood) developed AIDS or died within 30 months, compared with 20.1 percent of patients who never achieved undetectable concentrations (Ledergerber [70] et al. Lancet 1999;353:863).

Nearly everyone 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 (Smith [71] et al. N Engl J Med 1993;328:373).

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.

For 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 antibody-positive, based on numerous studies. As of November 1999, more than 74,000 cases of AIDS in Zimbabwe had been 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 HIV seroprevalence rate, reported only 37 cases of AIDS to WHO through November 1999. Yet, other sexually transmitted diseases, notably syphilis, are common in Madagascar, suggesting that conditions are ripe for the spread of HIV and AIDS if the virus becomes entrenched in that country (U.S. Census Bureau [21]; UNAIDS [22], 2000; WHO [72]. Wkly Epidemiol Rec 1999;74:1; Behets [73] et al. Lancet 1996;347:831).

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 NIAID-supported Multicenter AIDS Cohort Study (MACS), 22,643 CD4+ T-cell determinations in 2,713 HIV-seronegative homosexual and bisexual men revealed only one individual with a CD4+ T-cell count persistently lower than 300 cells/mm³ of blood, and this individual was receiving immunosuppressive therapy. Similar results have been reported from other studies (Vermund [74] et al. NEJM 1993;328:442; NIAID [75], 1995).

Newborn infants have no behavioral risk factors for AIDS, yet many children born to HIV-infected mothers have developed AIDS and died.

Only newborns who become HIV-infected before or during birth, during breastfeeding, or (rarely) following exposure to HIV-tainted blood or blood products after birth, go on to develop the profound immunosuppression that leads to AIDS. Babies who are not HIV-infected do not develop AIDS. In the United States, 8,718 cases of AIDS among children younger than age 13 had been reported to the CDC as of December 31, 1999. Cumulative U.S. AIDS deaths among individuals younger than age 15 numbered 5,044 through December 31, 1999. Globally, UNAIDS estimates that 480,000 child deaths due to AIDS occurred in 1999 alone (CDC [5]. HIV/AIDS Surveillance Report 1999;11[2]:1; UNAIDS [22]. AIDS epidemic update: June 2000).

Because many HIV-infected mothers abuse recreational drugs, some have argued that maternal drug use itself causes pediatric AIDS. However, studies have consistently shown that babies who are not HIV-infected do not develop AIDS, regardless of their mothers' drug use (European Collaborative Study [76]. Lancet 1991;337:253; European Collaborative Study [77]. Pediatr Infect Dis J 1997;16:1151; Abrams [78] et al. Pediatrics 1995;96:451).

For example, a majority of the HIV-infected, pregnant women enrolled in the European Collaborative Study are current or former injection drug users. In this ongoing study, mothers and their babies are followed from birth in 10 centers in Europe. In a paper in Lancet, study investigators reported that none of 343 HIV-seronegative children born to HIV-seropositive mothers had developed AIDS or persistent immune deficiency. In contrast, among 64 seropositive children, 30 percent presented with AIDS within 6 months of age or with oral candidiasis followed rapidly by the onset of AIDS. By their first birthday, 17 percent died of HIV-related diseases (European Collaborative Study [76]. Lancet 1991;337:253).

In a study in New York, investigators followed 84 HIV-infected and 248 HIV-uninfected infants, all born to HIV-seropositive mothers. The mothers of the two groups of infants were equally likely to be injection drug users (47 percent vs. 50 percent), and had similar rates of alcohol, tobacco, cocaine, heroin and methadone use. Of the 84 HIV-infected children, 22 died during a median follow-up period of 27.6 months, including 20 infants who died before their second birthday. Twenty-one of these deaths were classified as AIDS-related. Among the 248 uninfected children, only one death (due to child abuse) was reported during a median follow-up period of 26.1 months (Abrams [78] et al. Pediatrics 1995;96:451).

The HIV-infected twin develops AIDS while the uninfected twin does not.

Because twins share an in utero environment and genetic relationships, similarities and differences between them can provide important insight into infectious diseases, including AIDS (Goedert [79]. Acta Paediatr Supp 1997;421:56). 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 (Park [80] et al. J Clin Microbiol 1987;25:1119; Menez-Bautista [81] et al. Am J Dis Child 1986;140:678; Thomas [82] et al. Pediatrics 1990;86:774; Young [83] et al. Pediatr Infect Dis J 1990;9:454; Barlow and Mok [84]. Arch Dis Child 1993;68:507; Guerrero Vazquez [85] et al. An Esp Pediatr 1993;39:445).

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 homologous HIV strains in both the recipient and the donor (NIAID [86], 1995).

HIV is similar in genetic structure and morphology to other lentiviruses that often cause immunodeficiency in their animal hosts in addition to slow, progressive wasting disorders, neurodegeneration and death.

Like HIV in humans, animal viruses such as feline immunodeficiency virus (FIV) in cats, visna virus in sheep and simian immunodeficiency virus (SIV) in monkeys primarily infect cells of the immune system such as T cells and macrophages. For example, visna virus infects macrophages and causes a slowly progressive neurologic disease (Haase [87]. Nature 1986;322:130).

HIV causes the death and dysfunction of CD4+ T lymphocytes in vitro and in vivo.

CD4+ T cell dysfunction and depletion are hallmarks of HIV disease. The recognition that HIV infects and destroys CD4+ T cells in vitro strongly suggests a direct link between HIV infection, CD4+ T cell depletion, and development of AIDS. A variety of mechanisms, both directly and indirectly related to HIV infection of CD4+ T cells, are likely responsible for the defects in CD4+ T cell function observed in HIV-infected people. Not only can HIV enter and kill CD4+ T cells directly, but several HIV gene products may interfere with the function of uninfected cells (NIAID [88], 1995; Pantaleo [89] et al. NEJM 1993;328:327).

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 (WHO [72], 1998; Sloand [90] et al. JAMA 1991;266:2861).

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 (Jackson [45] et al. J Clin Microbiol 1990;28:16; Busch [91] et al. NEJM 1991;325:1; Silvester [92] et al. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:411; Urassa [93] et al. J Clin Virol 1999;14:25; Nkengasong [94] et al. AIDS 1999;13:109; Samdal [95] et al. Clin Diagn Virol 1996;7:55.

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 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, including well-educated members of the middle class (UNAIDS [22], 2000).

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 (Ackah [38] et al. Lancet 1995; 345:607). 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 and respiratory conditions (Taha [35] et al. Pediatr Infect Dis J 1999;18:689). 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 (Evans [96]. Yale J Biol Med 1982;55:193).

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 (UNAIDS [22], 2000).

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 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 illnesses. Significantly, long-term follow-up of these trials 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 (NIAID [97], 1995).

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 (HHS, 2004 [98]). 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 (Figure 1 [54]; CDC [5]. HIV AIDS Surveillance Report 1999;11[2]:1; Palella [55] et al. NEJM 1998;338:853; Mocroft [56] et al. Lancet 1998;352:1725; Mocroft [57] et al. Lancet 2000;356:291; Vittinghoff [58] et al. J Infect Dis 1999;179:717; Detels [59] et al. JAMA 1998;280:1497; de Martino [60] et al. JAMA 2000;284:190; CASCADE Collaboration [61]. Lancet 2000;355:1158; Hogg [62] et al. CMAJ 1999;160:659; Schwarcz [63] et al. Am J Epidemiol 2000;152:178; Kaplan [64] et al. Clin Infect Dis 2000;30:S5; McNaghten [65] et al. AIDS 1999;13:1687).

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 (NIAID, 1995a [99]; NIAID, 1995b [100]).

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 (Schechter [25] et al. Lancet 1993;341:658).

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. For example, 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 of blood, and this individual was receiving immunosuppressive therapy (Vermund [74] et al. NEJM 1993;328:442).

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 of blood. Only two individuals had two CD4+ T-cell measurements of less than 300/mm³ of blood, one of whom died with cardiac disease and non-Hodgkin's lymphoma listed as the cause of death (Des Jarlais [101] et al. J Acquir Immune Defic Syndr 1993;6:820).

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 of blood, while 111 HIV-seropositive individuals had average CD4+ T-cell counts of 375/mm³ of blood. 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 (Donegan [102] et al. Ann Intern Med 1990;113:733; Cohen [103]. Science 1994;266:1645).

MYTH: High usage of clotting factor concentrate, not HIV, leads to CD4+ T-cell depletion and AIDS in hemophiliacs.

FACT: This view is contradicted by many 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 (Hasset [104] et al. Blood 1993;82:1351). 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 (Aledort [105] et al. NEJM 1993;328:1128).

In a cohort in the United Kingdom, researchers matched 17 HIV-seropositive hemophiliacs with 17 HIV-seronegative hemophiliacs with regard to clotting factor concentrate usage over a ten-year period. During this time, 16 AIDS-defining clinical events occurred in 9 patients, all of whom were HIV-seropositive. No AIDS-defining illnesses occurred among the HIV-negative patients. In each pair, the mean CD4+ T cell count during follow-up was, on average, 500 cells/mm³ lower in the HIV-seropositive patient (Sabin [106] et al. BMJ 1996;312:207).

Among HIV-infected hemophiliacs, Transfusion Safety Study investigators found that neither the purity nor the amount of Factor VIII therapy had a deleterious effect on CD4+ T cell counts (Gjerset [107] et al., Blood 1994;84:1666). Similarly, the Multicenter Hemophilia Cohort Study found no association between the cumulative dose of plasma concentrate and incidence of AIDS among HIV-infected hemophiliacs (Goedert [108] et al. NEJM 1989;321:1141.).

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 (U.S. Census Bureau [21], 1999; UNAIDS [22], 2000).

Increasingly, however, women in the United States 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 United States. Approximately 23 percent of U.S. adult/adolescent AIDS cases reported to the CDC in 1998 were among women. In 1998, AIDS was the fifth leading cause of death among women aged 25 to 44 in the United States, and the third leading cause of death among African-American women in that age group (NIAID Fact Sheet: HIV/AIDS Statistics [109]).

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 (U.S. Census Bureau [21], 1999; UNAIDS [22], 2000).

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 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 (NIAID [110], 1995).

Also, HIV is well recognized as being able to mutate to avoid the ongoing immune response of the host (Levy [111]. Microbiol Rev 1993;57:183).

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 (PCR) 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 (Richman [112] J Clin Invest 2000;105:565).

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 in industrialized countries, 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 (Alcabes [113] et al. Epidemiol Rev 1993;15:303).

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 (Evans [96]. Yale J Biol Med 1982;55:193; Levy [111]. Microbiol Rev 1993;57:183; Fauci [114]. Nature 1996;384:529).

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 (NIAID [75], 1995; UNAIDS [22], 2000).

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 Mycobacterium avium complex (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 (USPHS/IDSA, 2001 [115]).

More information on this issue is available on the NIAID Focus On the HIV-AIDS Connection [116] web page.

NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov [117].

Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

This article was created in 1994, last updated on February 27, 2003,
and posted to this Web site on September 26, 2005.