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THE RELATIONSHIP BETWEEN
THE HUMAN IMMUNODEFICIENCY VIRUS
AND
THE ACQUIRED IMMUNODEFICIENCY SYNDROME

The National Institute of Allergy and
Infectious Diseases
National Institutes of Health
Bethesda, Maryland

Contents

The Definition of AIDS

The Designation AIDS is a Surveillance Tool

Quantifying the Epidemic

A Brief History of the Emergence of AIDS

Initial Theories

Retrovirus Hypothesis

Seroprevalence Surveys

HIV and Other Lentiviruses

Course of HIV Infection

Immunologic Profile of People With AIDS

Mechanisms of CD4+ T Cell Depletion

Koch's Postulates Fulfilled

Evidence From Animal and Laboratory Models

Geographic Considerations

Evidence From Blood Donor-Recipient Pairs

Impact of HIV Infection on Mortality of Hemophiliacs

Pediatric AIDS

Single Source Outbreak of Pediatric AIDS

Answering the Skeptics: the "Risk-AIDS" or "Behavioral
Hypothesis"

AIDS and Injection Drug Users

Sex and the AIDS Epidemic

Drug Use in the Pre-AIDS Era

AZT and AIDS

Disease Progression Despite Antibodies

Risks Associated With Transfusion

Exposure to Factor VIII

Distribution of AIDS Cases

AIDS in Africa

Conclusion

References
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The acquired immunodeficiency syndrome (AIDS) is characterized by
the progressive loss of the CD4+ helper/inducer subset of T
lymphocytes, leading to severe immunosuppression and
constitutional disease, neurological complications, and
opportunistic infections and neoplasms that rarely occur in
persons with intact immune function. Although the precise
mechanisms leading to the destruction of the immune system have
not been fully delineated, abundant epidemiologic, virologic and
immunologic data support the conclusion that infection with the
human immunodeficiency virus (HIV) is the underlying cause of
AIDS.

The evidence for HIV's primary role in the pathogenesis of AIDS
is reviewed elsewhere (Ho et al., 1987; Fauci, 1988, 1993a;
Greene, 1993; Levy, 1993; Weiss, 1993). In addition, many
scientists (Blattner et al., 1988a,b; Ginsberg, 1988; Evans,
1989a,b, 1992; Weiss and Jaffe, 1990; Gallo, 1991; Goudsmit,
1992; Groopman, 1992; Kurth, 1990; Ascher et al., 1993a,b;
Schechter et al., 1993a,b; Lowenstein, 1994; Nicoll and Brown,
1994; Harris, 1995) have responded to specific arguments from
individuals who assert that AIDS is not caused by HIV. The
present discussion reviews the AIDS epidemic and summarizes the
evidence supporting HIV as the cause of AIDS.

The Definition of AIDS

The term AIDS first appeared in the Morbidity and Mortality
Weekly Report (MMWR) of the Centers for Disease Control (CDC) in
1982 to describe ". . . a disease, at least moderately predictive
of a defect in cell-mediated immunity, occurring with no known
cause for diminished resistance to that disease" (CDC, 1982b).
The initial CDC list of AIDS-defining conditions, which included
Kaposi's sarcoma (KS), Pneumocystis carinii pneumonia (PCP),
Mycobacterium avium complex (MAC) and other conditions, has been
updated on several occasions, with significant revisions (CDC,
1985a, 1987a, 1992a).

For surveillance purposes, the CDC currently defines AIDS in an
adult or adolescent age 13 years or older as the presence of one
of 25 AIDS-indicator conditions, such as KS, PCP or disseminated
MAC. 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 (CDC, 1987b).
The case definition in adults and adolescents was expanded in
1993 to include HIV infection in an individual with a CD4+ T cell
count less than 200 cells per cubic millimeter (mm3) of blood
(CDC, 1992a). The current surveillance definition replaced
criteria published in 1987 that were based on clinical conditions
and evidence of HIV infection but not on CD4+ T cell
determinations (CDC, 1987a).

In many developing countries, where diagnostic facilities may be
minimal, epidemiologists employ a case definition based on the
presence of various clinical symptoms associated with immune
deficiency and the exclusion of other known causes of
immunosuppression, such as cancer or malnutrition (Ryder and
Mugewrwa, 1994a; Davachi, 1994).

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,
leading to progressively severe symptoms and, ultimately,
profound immunodeficiency and opportunistic infections and
neoplasms (Fauci, 1993a). In clinical practice, symptomatology
and measurements of immune function, notably levels of CD4+ T
lymphocytes, are used to guide the treatment of HIV-infected
persons rather than an all-or-nothing paradigm of AIDS/non-AIDS
(CDC, 1992a; Sande et al., 1993; Volberding and Graham, 1994).

Quantifying the Epidemic

Between June 1981 and Dec. 31, 1994, 441,528 cases of AIDS in the
United States, including 270,870 AIDS-related deaths, were
reported to the CDC (CDC, 1995a). AIDS is now the leading cause
of death among adults aged 25 to 44 in the United States (CDC,
1995b).

Worldwide, 1,025,073 cases of AIDS were reported to the World
Health Organization (WHO) through December 1994, an increase of
20 percent since December 1993 (WHO, 1995a). Allowing for
under-diagnosis, incomplete reporting and reporting delay, and
based on the available data on HIV infections around the world,
the WHO estimates that over 4.5 million AIDS cumulative cases had
occurred worldwide by late 1994 and that 19.5 million people
worldwide had been infected with HIV since the beginning of the
epidemic (WHO, 1995a). By the year 2000, the WHO estimates that
30 to 40 million people will have been infected with HIV and that
10 million people will have developed AIDS (WHO, 1994). The
Global AIDS Policy Coalition has developed a considerably higher
estimate--perhaps up to 110 million HIV infections and 25 million
AIDS cases by the turn of the century (Mann et al., 1992a).

A Brief History of the Emergence of AIDS

In 1981, clinical investigators in New York and California
observed among young, previously healthy, homosexual men an
unusual clustering of cases of rare diseases, notably Kaposi's
sarcoma (KS) and opportunistic infections such as Pneumocystis
carinii pneumonia (PCP), as well as cases of unexplained,
persistent lymphadenopathy (CDC, 1981a,b, 1982a; Masur et al.,
1981; Gottlieb et al., 1981; Friedman-Kien, 1981). It soon became
evident that these men had a common immunologic deficit, an
impairment in cell-mediated immunity resulting from a significant
loss of "T-helper" cells, which bear the CD4 marker (Gottlieb et
al., 1981; Masur et al., 1981; Siegal et al., 1981; Ammann et
al., 1983a).

The widespread occurrence of KS and PCP in young people with no
underlying disease or history of immunosuppressive therapy was
unprecedented. Searches of the medical literature, autopsy
records and tumor registries revealed that these diseases
previously had occurred at very low levels in the United States
(CDC, 1981b; CDC, 1982f).

KS, a very rare skin neoplasm, had affected mostly older men of
Mediterranean origin or cancer or transplant patients undergoing
immunosuppressive therapy (Gange and Jones, 1978; Safai and Good,
1981). Before the AIDS epidemic, the annual incidence of Kaposi's
sarcoma in the United States was 0.02 to 0.06 per 100,000
population (Rothman, 1962a; Oettle, 1962). In addition, a more
aggressive form of KS that generally occurred in younger
individuals was seen in certain parts of Africa (Rothman, 1962b;
Safai, 1984a). By 1984, never-married men in San Francisco were
found to be 2,000 times more likely to develop KS than during the
years 1973 to 1979 (Williams et al., 1994). As of Dec. 31, 1994,
36,693 patients with AIDS in the United States with a definitive
diagnosis of KS had been reported to the CDC (CDC, 1995b).

PCP, a lung infection caused by a pathogen to which most
individuals are exposed with no undue consequences, was extremely
rare prior to 1981 in individuals other than those receiving
immunosuppressive therapy or among the chronically malnourished,
such as certain Eastern European children following World War II
(Walzer, 1990). A 1967 survey, for example, found only 107 U.S.
cases of PCP reported in the medical literature up to that point,
virtually all among individuals with underlying immunosuppressive
conditions or who had undergone immunosuppressive therapy (Le
Clair, 1969). In that year, CDC became the sole supplier in the
United States of pentamidine isethionate, then the only
recommended PCP therapy, and began collecting data on each PCP
case diagnosed and treated in this country. After reviewing
requests for pentamidine in the period 1967 to 1970, researchers
found only one case of confirmed PCP without a known underlying
condition (Walzer et al., 1974). In the period immediately prior
to the recognition of AIDS, January 1976 to June 1980, CDC
received only one request for pentamidine isethionate to treat an
adult in the United States who had PCP and no underlying disease
(CDC, 1982f). In 1981 alone, 42 requests for pentamidine were
received to treat patients with PCP and no known underlying
disorders (CDC, 1982f). By Dec. 31, 1994, 127,626 individuals
with AIDS in the United States with definitive diagnoses of PCP
had been reported to the CDC (CDC, 1995b).

Another rare opportunistic disease, disseminated infection with
the Mycobacterium avium complex (MAC), also was seen frequently
in the first AIDS patients (Zakowski et al., 1982; Greene et al.,
1982). Prior to 1981, only 32 individuals with disseminated MAC
disease had been described in the medical literature (Masur,
1982a). By Dec. 31, 1994, the CDC had received reports of 28,954
U.S. AIDS patients with definitive diagnoses of disseminated MAC
(CDC, 1995b).

Initial Theories

The fact that homosexual men constituted the initial population
in which AIDS occurred in the United States led some to surmise
that a homosexual lifestyle was specifically related to the
disease (Goedert et al., 1982; Hurtenbach and Shearer, 1982;
Sonnabend et al., 1983; Durack, 1981; Mavligit et al., 1984).
These early suggestions that AIDS resulted from behavior specific
to the homosexual population were largely dismissed when the
syndrome was observed in distinctly different groups in the
United States: in male and female injection drug users; in
hemophiliacs and blood transfusion recipients; among female sex
partners of bisexual men, recipients of blood or blood products,
or injection drug users; and among infants born to mothers with
AIDS or with a history of injection drug use (CDC, 1982b,c,d,f,
1983a; Poon et al., 1983; Elliot et al., 1983; Masur et al.,
1982b; Davis et al., 1983; Harris et al., 1983; Rubinstein et
al., 1983; Oleske et al., 1983; Ammann et al., 1983b). In 1983,
for example, a study found that hemophiliacs with no history of
any of the proposed causes of AIDS in homosexual men had
developed the syndrome, and some of the men had apparently
transmitted the infection to their wives (deShazo et al., 1983).

Many public health experts concluded that the clustering of AIDS
cases (Auerbach et al., 1984; Gazzard et al., 1984) and the
occurrence of cases in diverse risk groups could be explained
only if AIDS were caused by an infectious microorganism
transmitted in the manner of hepatitis B virus (HBV): by sexual
contact, by inoculation with blood or blood products, and from
mother to newborn infant (Francis et al., 1983; Curran et al.,
1984; AMA, 1984; CDC, 1982f, 1983a,b).

Early suspects for the cause of AIDS were cytomegalovirus (CMV),
because of its association with immunosuppression, and
Epstein-Barr virus (EBV), which has an affinity for lymphocytes
(Gottlieb et al., 1981; Hymes et al., 1981; CDC, 1982f). However,
AIDS was a new phenomenon, and these viruses already had a
worldwide distribution. Comparative seroprevalence studies showed
no convincing evidence to assign these viruses or other known
agents a primary role in the syndrome (Rogers et al., 1983). Also
lacking was evidence that these viruses, when isolated from
patients with AIDS, differed significantly from strains found in
healthy individuals or from strains found in the years preceding
the emergence of AIDS (AMA, 1984).

Retrovirus Hypothesis

By 1983, several research groups had focused on retroviruses for
clues to the cause of AIDS (Gallo and Montagnier, 1987). Two
recently recognized retroviruses, HTLV-I and HTLV-II, were the
only viruses then known to preferentially infect helper T
lymphocytes, the cells depleted in people with AIDS (Gallo and
Reitz, 1982; Popovic et al., 1984). The pattern of HTLV
transmission was similar to that seen among AIDS patients: HTLV
was transmitted by sexual contact, from mother to child or by
exposure to infected blood (Essex, 1982; Gallo and Reitz, 1982).
In addition, HTLV-I was known to cause mild immunosuppression,
and a related retrovirus, the lymphotropic feline leukemia virus
(FeLV), caused lethal immunosuppression in cats (Essex et al.,
1975).

In May 1983, the first report providing experimental evidence for
an association between a retrovirus and AIDS was published
(Barre-Sinoussi et al., 1983). After finding antibodies
cross-reactive with HTLV-I in a homosexual patient with
lymphadenopathy, a group led by Dr. Luc Montagnier isolated a
previously unrecognized virus containing reverse transcriptase
that was cytopathic for cord-blood lymphocytes (Barre-Sinoussi et
al., 1983). This virus later became known as
lymphadenopathy-associated virus (LAV). The French group
subsequently reported that LAV was tropic for T-helper cells, in
which it grew to substantial titers and caused cell death
(Klatzmann et al., 1984a; Montagnier et al., 1984).

In 1984, a considerable amount of new data added to the evidence
for a retroviral etiology for AIDS. Researchers at the National
Institutes of Health reported the isolation of a cytopathic
T-lymphotropic virus from 48 different people, including 18 of 21
with pre-AIDS, three of four clinically normal mothers of
children with AIDS, 26 of 72 children and adults with AIDS, and
one (who later developed AIDS) of 22 healthy homosexuals (Gallo
et al., 1984). The virus, named HTLV-III, could not be found in
115 healthy heterosexual subjects.

Antibodies reactive with HTLV-III antigens were found in serum
samples of 88 percent of 48 patients with AIDS, 79 percent of 14
homosexuals with pre-AIDS, and fewer than 1 percent of hundreds
of healthy heterosexuals (Sarngadharan et al., 1984).

Shortly thereafter, the researchers found that 100 percent (34 of
34) of AIDS patients tested were positive for HTLV-III antibodies
in a study in which none of 14 controls had antibodies (Safai et
al., 1984b).

In a study in the United Kingdom reported later that year,
investigators found that 30 of 31 AIDS patients tested were
seropositive for HTLV-III antibodies, as were 110 of 124
individuals with persistent generalized lymphadenopathy
(Cheingsong-Popov et al., 1984). None of more than 1,000 blood
donors selected randomly had antibodies to HTLV-III in this
study.

During the same time period, HTLV-III was isolated from the semen
of patients with AIDS (Zagury et al., 1984, Ho et al., 1984),
findings consistent with the epidemiologic data demonstrating
AIDS transmission via sexual contact.

Researchers in San Francisco subsequently reported the isolation
of a retrovirus they named the AIDS-associated retrovirus (ARV)
from AIDS patients in different risk groups, as well as from
asymptomatic people from AIDS risk groups (Levy et al., 1984).
The researchers isolated ARV from 27 of 55 patients with AIDS or
lymphadenopathy syndrome; they detected antibodies to ARV in 90
percent of 113 individuals with the same conditions. Like
HTLV-III and LAV, ARV grew substantially in peripheral blood
mononuclear cells and killed CD4+ T cells. The same group
subsequently isolated ARV from genital secretions of women with
antibodies to the virus, data consistent with the observation
that men could contract AIDS following contact with a woman
infected with the virus (Wofsy et al., 1986).

During the same period, HTLV-III and ARV were isolated from the
brains of children and adults with AIDS-associated
encephalopathy, which suggested a role for these viruses in the
central nervous system disorders seen in many patients with AIDS
(Levy et al., 1985; Ho et al., 1985).

By 1985, analyses of the nucleotide sequences of HTLV-III, LAV
and ARV demonstrated that the three viruses belonged to the same
retroviral family and were strikingly similar (Wain-Hobson et
al., 1985; Ratner et al., 1985; Sanchez-Pescador et al., 1985).
In 1986, the International Committee of Viral Taxonomy renamed
the viruses the human immunodeficiency virus (HIV) (Coffin et
al., 1986).

Seroprevalence Surveys

Serologic tests for antibodies to HIV, developed in 1984
(Sarngadharan et al., 1984; Popovic et al., 1984; reviewed in
Brookmeyer and Gail, 1994), have enabled researchers to conduct
hundreds of seroprevalence surveys throughout the world. Using
these tests, investigators have repeatedly demonstrated that the
occurrence of AIDS-like illnesses in different populations has
closely followed the appearance of HIV antibodies (U.S. Bureau of
the Census, 1994). For example, retrospective examination of sera
collected in the late 1970s in association with hepatitis B
studies in New York, San Francisco and Los Angeles suggests that
HIV entered the U.S. population sometime in the late 1970s (Jaffe
et al., 1985a). In 1978, 4.5 percent of men in the San Francisco
cohort had antibodies to HIV (Jaffe et al., 1985a). The first
cases of AIDS in homosexual men in San Francisco were reported in
1981, and by 1984, more than two-thirds of the San Francisco
cohort had HIV antibodies and almost one-third had developed
AIDS-related conditions (Jaffe et al., 1985a). By the end of
1992, approximately 70 percent of 539 men in the San Francisco
cohort with a well-documented date of HIV seroconversion before
1983 had developed an AIDS-defining condition or had a CD4+ T
cell count of less than 200/mm3; another 11 percent had CD4+ T
cell counts between 200 and 500/mm3 (Buchbinder et al., 1994).

Retrospective tests of the U.S. blood supply have shown that, in
1978, at least one batch of Factor VIII was contaminated with HIV
(Evatt et al., 1985; Aronson, 1993). Factor VIII was given to
some 2,300 males in the United States that year. In July 1982,
the first cases of AIDS in hemophiliacs were reported (CDC,
1982c). Through Dec. 31, 1994, 3,863 individuals in the United
States with hemophilia or other coagulation disorders had been
diagnosed with AIDS (CDC, 1995a).

Elsewhere in the world, a similar chronological association
between HIV and AIDS has been noted. The appearance of HIV in the
blood supply has preceded or coincided with the occurrence of
AIDS cases in every country and region where cases of AIDS have
been reported (Institute of Medicine, 1986; Chin and Mann, 1988;
Curran et al., 1988; Piot et al., 1988; Mann, 1992; Mann et al.,
1992; U.S. Bureau of the Census, 1994). For example, a review of
serosurveys associated with dengue fever in the Caribbean found
that the earliest evidence of HIV infection in Haiti appeared in
samples from 1979 (Pape et al., 1983, 1993); the first cases of
AIDS in Haiti and in Haitians in the United States were reported
in the early 1980s (CDC, 1982e; Pape et al., 1983, 1993).
In Africa between 1981 and 1983, clinical epidemics of chronic,
life-threatening enteropathic diseases ("slim disease"),
cryptococcal meningitis, progressive KS and esophageal
candidiasis were recognized in Rwanda, Tanzania, Uganda, Zaire
and Zambia, and in 1983 the first AIDS cases among Africans were
reported (Quinn et al., 1986; Essex, 1994). The earliest blood
sample from Africa from which HIV has been recovered is from a
possible AIDS patient in Zaire, tested in connection with a 1976
Ebola virus outbreak (Getchell et al., 1987; Myers et al., 1992).

Serologic data have suggested the presence of HIV infection as
early as 1959 in Zaire (Nahmias et al., 1986). Other
investigators have found evidence of HIV proviral DNA in tissues
of a sailor who died in Manchester, England, in 1959 (Corbitt et
al., 1990). In the latter case, this finding may have represented
a contamination with a virus isolated at a much later date (Zhu
and Ho, 1995).

HIV did not become epidemic until 20 to 30 years later, perhaps
because of the migration of poor and young sexually active
individuals from rural areas to urban centers in developing
countries, with subsequent return migration and, internationally,
due to civil wars, tourism, business travel and the drug trade
(Quinn, 1994).

HIV and Other Lentiviruses

As a retrovirus, HIV is an RNA virus that codes for the enzyme
reverse transcriptase, which transcribes the viral genomic RNA
into a DNA copy that ultimately integrates into the host cell
genome (Fauci, 1988). Within the retrovirus family, HIV is
classified as a lentivirus, having genetic and morphologic
similarities to animal lentiviruses such as those infecting cats
(feline immunodeficiency virus), sheep (visna virus), goats
(caprine arthritis-encephalitis virus), and non-human primates
(simian immunodeficiency virus) (Stowring et al., 1979; Gonda et
al., 1985; Haase, 1986; Temin, 1988, 1989). Like HIV in humans,
these animal viruses primarily infect cells of the immune system,
including T lymphocytes and macrophages (Haase, 1986, 1990; Levy,
1993).

Lentiviruses often cause immunodeficiency in their hosts in
addition to slow, progressive wasting disorders,
neurodegeneration and death (Haase, 1986, 1990). SIV, for
example, infects several subspecies of macaque monkeys, causing
diarrhea, wasting, CD4+ T cell depletion, opportunistic
infections and death (Desrosiers, 1990; Fultz, 1993). HIV is
closely related to SIV, as evidenced by viral protein
cross-reactivity and genetic sequence similarities (Franchini et
al., 1987; Hirsch et al., 1989; Desrosiers, 1990; Myers, 1992).

One feature that distinguishes lentiviruses from other
retroviruses is the remarkable complexity of their viral genomes.
Most retroviruses that are capable of replication contain only
three genes--env, gag and pol (Varmus, 1988). HIV contains not
only these essential genes but also the complex regulatory genes
tat, rev, nef, and auxiliary genes vif, vpr and vpu (Greene,
1991). The actions of these additional genes probably contribute
to the profound pathogenicity that differentiates HIV from many
other retroviruses.
CD4+ T cells, the cells depleted in AIDS patients, are primary
targets of HIV because of the affinity of the gp120 glycoprotein
component of the viral envelope for the CD4 molecule (Dalgleish
et al., 1984; Klatzmann et al., 1984b; McDougal et al., 1985a,
1986). These so-called T-helper cells coordinate a number of
critical immunologic functions. The loss of these cells results
in the progressive impairment of the immune system and is
associated with a deteriorating clinical course (Pantaleo et al.,
1993a). In advanced HIV disease, abnormalities of virtually every
component of the immune system are evident (Fauci, 1993a;
Pantaleo et al., 1993a).

Course of HIV Infection

Primary HIV infection is associated with a burst of HIV viremia
and often a concomitant abrupt decline of CD4+ T cells in the
peripheral blood (Cooper et al., 1985; Daar et al., 1991; Tindall
and Cooper, 1991; Clark et al., 1991; Pantaleo et al., 1993a,
1994). The decrease in circulating CD4+ T cells during primary
infection is probably due both to HIV-mediated cell killing and
to re-trafficking of cells to the lymphoid tissues and other
organs (Fauci, 1993a).

The median period of time between infection with HIV and the
onset of clinically apparent disease is approximately 10 years in
western countries, according to prospective studies of homosexual
men in which dates of seroconversion are known (Lemp et al.,
1990; Pantaleo et al., 1993a; Hessol et al., 1994). Similar
estimates of asymptomatic periods have been made for HIV-infected
blood-transfusion recipients, injection drug users and adult
hemophiliacs (reviewed in Alcabes et al., 1993a).

HIV disease, however, is not uniformly expressed in all
individuals. A small proportion of persons infected with the
virus develop AIDS and die within months following primary
infection, while approximately 5 percent of HIV-infected
individuals exhibit no signs of disease progression even after 12
or more years (Pantaleo et al., 1995a; Cao et al., 1995). Host
factors such as age or genetic differences among individuals, the
level of virulence of the individual strain of virus, as well as
influences such as co-infection with other microbes may determine
the rate and severity of HIV disease expression in different
people (Fauci, 1993a; Pantaleo et al., 1993a). Such variables
have been termed "clinical illness promotion factors" or
co-factors and appear to influence the onset of clinical disease
among those infected with any pathogen (Evans, 1982). Most 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 (Robinson, 1990). Co-factors probably
also determine why some smokers develop lung cancer, while others
do not.

As disease progresses, increasing amounts of infectious virus,
viral antigens and HIV-specific nucleic acids in the body
correlate with a worsening clinical course (Allain et al., 1987;
Nicholson et al., 1989; Ho et al., 1989; Schnittman et al., 1989,
1990a, 1991; Mathez et al., 1990; Genesca et al., 1990; Hufert et
al., 1991; Saag et al., 1991; Aoki-Sei et al., 1992; Yerly et
al., 1992; Bagnarelli et al., 1992; Ferre et al., 1992; Michael
et al., 1992; Pantaleo et al., 1993b; Gupta et al., 1993; Connor
et al., 1993; Saksela et al., 1994; Dickover et al., 1994; Daar
et al., 1995; Furtado et al., 1995).

Cross-sectional studies in adults and children have shown that
levels of infectious HIV or proviral DNA in the blood are
substantially higher in patients with AIDS than in asymptomatic
patients (Ho et al., 1989; Coombs et al., 1989; Saag et al.,
1991; Srugo et al., 1991; Michael et al., 1992; Aoki-Sei et al.,
1992). In both blood and lymph tissues from HIV-infected
individuals, researchers at the National Institutes of Health
found viral burden and replication to be substantially higher in
patients with AIDS than in early-stage patients (Pantaleo et al.,
1993b). This group also found deterioration of the architecture
and microenvironment of the lymphoid tissue to a greater extent
in late-stage patients than in asymptomatic individuals. The
dissolution of the follicular dendritic cell network of the lymph
node germinal center and the progressive loss of
antigen-presenting capacity are likely critical factors that
contribute to the immune deficiency seen in individuals with AIDS
(Pantaleo et al., 1993b).

More recently, the same group studied 15 long-term
non-progressors, defined as individuals infected for more than
seven years (usually more than 10 years) who received no
antiretroviral therapy and showed no decline in CD4+ T cells.
They found that viral burden and viral replication in the
peripheral blood and in lymph nodes, measured by DNA and RNA PCR,
respectively, were at least 10 times lower than in 18
HIV-infected individuals whose disease progression was more
typical. In addition, the lymph node architecture in long-term
non-progressors remained intact (Pantaleo et al., 1995a).

Longitudinal studies also have quantified viral burden and
replication in the blood and their relationship to disease
progression (Schnittman et al., 1990a; Connor et al., 1993;
Saksela et al., 1994; Daar et al., 1995; Furtado et al., 1995).
In a study of asymptomatic HIV-infected individuals who
ultimately developed rapidly progressive disease, the number of
CD4+ T cells in which HIV DNA could be found increased over time,
whereas this did not occur in patients with stable disease
(Schnittman et al., 1990a). Using serial blood samples from
HIV-infected individuals who had a precipitous drop in CD4+ T
cells followed by a rapid progression to AIDS, other groups found
a significant increase in the levels of HIV DNA concurrent with
or prior to CD4+ T cell decline (Connor et al., 1993; Daar et
al., 1995). Increased expression of HIV mRNA in peripheral blood
mononuclear cells has also been shown to precede clinically
defined progression of disease (Saksela et al., 1994).

In the longitudinal Multicenter AIDS Cohort Study (MACS),
homosexual and bisexual men for whom the time of seroconversion
had been documented had increasing levels of both plasma HIV RNA
and intracellular RNA as disease progressed and had CD4+ T cell
numbers that declined (Gupta et al., 1993; Mellors et al., 1995).
Men who remained asymptomatic with stable CD4+ T cell numbers
maintained extremely low levels of viral RNA. These findings
suggest that plasma HIV RNA levels are a strong, CD4-independent
predictor of rapid progression to AIDS. Another longitudinal
study found that increasing plasma RNA levels were highly
predictive of the development of zidovudine (AZT) resistance and
death in patients on long-term therapy with that drug (Vahey et
al., 1994).

Other evidence suggests that changes in viral load due to changes
in therapy can predict clinical benefit in patients. It was
recently found that the amount of HIV RNA in the peripheral blood
decreased in patients who switched to didanosine (ddI) after
taking AZT and increased in patients who continued to take AZT
(NTIS, 1994; Welles et al., 1995). Decreases in HIV RNA were
associated with fewer progressions to new, previously undiagnosed
AIDS-defining diseases or death. This study provided the first
evidence that a therapy-induced reduction of HIV viral load is
associated with clinical outcome. Similarly, studies of blood
samples collected serially from HIV-infected patients found that
a decrease in HIV RNA copy number in the first months following
treatment with AZT strongly correlated with improved clinical
outcome (O'Brien et al., 1994; Jurriaans et al., 1995).

The emergence of HIV variants that are more cytopathic and
replicate in a wider range of susceptible cells in vitro has also
been shown to correlate with disease progression in HIV-infected
individuals (Fenyo et al., 1988; Tersmette et al., 1988, 1989a,b;
Richman and Bozzette, 1994; Connor et al., 1993, Connor and Ho,
1994a,b). Similar results have been seen in vivo with macaques
infected with molecularly cloned SIV (Kodama et al., 1993). It
has also been reported that HIV isolates from patients who
progress to AIDS have a higher rate of replication compared with
HIV isolates from individuals who remain asymptomatic (Fenyo et
al., 1988; Tersmette et al., 1989a), and that rapidly replicating
variants of HIV emerge during the asymptomatic stage of infection
prior to disease progression (Tersmette et al., 1989b; Connor and
Ho, 1994b).

Immunologic Profile of People With AIDS

It is well established that a number of viral, rickettsial,
fungal, protozoal and bacterial infections can cause transient T
cell decreases (Chandra, 1983). Immune deficiencies due to
tumors, autoimmune diseases, rare congenital disorders,
chemotherapy and other factors have been shown to render certain
individuals susceptible to opportunistic infections (Ammann,
1991). As mentioned above, chronic malnutrition following World
War II resulted in PCP in Eastern European children (Walzer,
1990). Transplant recipients treated with immunosuppressive drugs
such as cyclosporin and glucocorticoids often suffer recurrent
diseases due to pathogens such as varicella zoster virus and
cytomegalovirus that also cause disease in HIV-infected
individuals (Chandra, 1983; Ammann, 1991).

However, the specific immunologic profile that typifies AIDS--a
progressive reduction of CD4+ T cells resulting in persistent
CD4+ T lymphocytopenia and profound deficits in cellular
immunity--is extraordinarily rare in the absence of HIV infection
or other known causes of immunosuppression. This was recently
demonstrated in several surveys that sought to determine the
frequency of idiopathic CD4+ T-cell lymphocytopenia (ICL), which
is characterized by CD4+ T cell counts lower than 300 cells per
cubic millimeter (mm3) of blood in the absence of HIV antibodies
or conditions or therapies associated with depressed levels of
CD4+ T cells (reviewed in Fauci, 1993b; Laurence, 1993).

In a CDC survey, only 47 (.02 percent) of 230,179 individuals
diagnosed with AIDS were both HIV-seronegative and had
persistently low CD4+ T cell counts (<300/mm3) in the absence of
conditions or therapies associated with immunosuppression (Smith
et al., 1993).

In the MACS, 22,643 CD4+ 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 (Vermund
et al., 1993a). A similar review of another cohort of homosexual
and bisexual men found no case of persistently lowered CD4+ T
cell counts among 756 HIV-seronegative men who had no other cause
of immunosuppression (Smith et al., 1993). Analogous results were
reported from the San Francisco Men's Health Study, a
population-based cohort recruited in 1984. Among 206
HIV-seronegative heterosexual and 526 HIV-seronegative homosexual
or bisexual men, only one had consistently low CD4+ T cell counts
(Sheppard et al., 1993). This individual also had low CD8+ T cell
counts, suggesting that he had general lymphopenia rather than a
selective loss of CD4+ T cells. No AIDS-defining clinical
condition was observed among these HIV-seronegative men.

Studies of blood donors, recipients of blood and blood products,
and household and sexual contacts of transfusion recipients also
suggest that persistently low CD4+ T cell counts are extremely
rare in the absence of HIV infection (Aledort et al., 1993; Busch
et al., 1994). Longitudinal studies of injection-drug users have
demonstrated that unexplained CD4+ T lymphocytopenia is almost
never seen among HIV-seronegative individuals in this population,
despite a high risk of exposure to hepatitis B, cytomegalovirus
and other blood-borne pathogens (Des Jarlais et al., 1993; Weiss
et al., 1992).

Mechanisms of CD4+ T Cell Depletion

HIV infects and kills CD4+ T lymphocytes in vitro, although
scientists have developed immortalized T-cell lines in order to
propagate HIV in the laboratory (Popovic et al., 1984; Zagury et
al., 1986; Garry, 1989; Clark et al., 1991). Several mechanisms
of CD4+ T cell killing have been observed in lentivirus systems
in vitro and may explain the progressive loss of these cells in
HIV-infected individuals (reviewed in Garry, 1989; Fauci, 1993a;
Pantaleo et al., 1993a). These mechanisms include disruption of
the cell membrane as HIV buds from the surface (Leonard et al.,
1988) or the intracellular accumulation of heterodisperse RNAs
and unintegrated DNA (Pauza et al., 1990; Koga et al., 1988).
Evidence also suggests that intracellular complexing of CD4 and
viral envelope products can result in cell killing (Hoxie et al.,
1986).

In addition to these direct mechanisms of CD4+ T cell depletion,
indirect mechanisms may result in the death of uninfected CD4+ T
cells (reviewed in Fauci, 1993a; Pantaleo et al., 1993a).
Uninfected cells often fuse with infected cells, resulting in
giant cells called syncytia that have been associated with the
cytopathic effect of HIV in vitro (Sodroski et al., 1986; Lifson
et al., 1986). Uninfected cells also may be killed when free
gp120, the envelope protein of HIV, binds to their surfaces,
marking them for destruction by antibody-dependent cellular
cytotoxicity responses (Lyerly et al., 1987). Other autoimmune
phenomena may also contribute to CD4+ T cell death since HIV
envelope proteins share some degree of homology with certain
major histocompatibility complex type II (MHC-II) molecules
(Golding et al., 1989; Koenig et al., 1988).

A number of investigators have suggested that superantigens,
either encoded by HIV or derived from unrelated agents, may
trigger massive stimulation and expansion of CD4+ T cells,
ultimately leading to depletion or anergy of these cells
(Janeway, 1991; Hugin et al., 1991). The untimely induction of a
form of programmed cell death called apoptosis has been proposed
as an additional mechanism for CD4+ T cell loss in HIV infection
(Ameisen and Capron, 1991; Terai et al., 1991; Laurent-Crawford
et al., 1991). Recent reports indicate that apoptosis occurs to a
greater extent in HIV-infected individuals than in non-infected
persons, both in the peripheral blood and lymph nodes (Finkel et
al., 1995; Pantaleo and Fauci, 1995b; Muro-Cacho et al., 1995).

It has also been observed that HIV infects precursors of CD4+ T
cells in the bone marrow and thymus and damages the
microenvironment of these organs necessary for the optimal
sustenance and maturation of progenitor cells (Schnittman et al.,
1990b; Stanley et al., 1992). These findings may help explain the
lack of regeneration of the CD4+ T cell pool in patients with
AIDS (Fauci, 1993a).

Recent studies have demonstrated a substantial viral burden and
active viral replication in both the peripheral blood and
lymphoid tissues even early in HIV infection (Fox et al., 1989;
Coombs et al., 1989; Ho et al., 1989; Michael et al., 1992;
Bagnarelli et al., 1992; Pantaleo et al., 1993b; Embretson et
al., 1993; Piatak et al., 1993). One group has reported that 25
percent of CD4+ T cells in the lymph nodes of HIV-infected
individuals harbor HIV DNA early in the course of disease
(Embretson et al., 1993). Other data suggest that HIV infection
is sustained by a dynamic process involving continuous rounds of
new viral infection and the destruction and replacement of over 1
billion CD4+ T cells per day (Wei et al., 1995; Ho et al., 1995).

Taken together, these studies strongly suggest that HIV has a
central role in the pathogenesis of AIDS, either directly or
indirectly by triggering a series of pathogenic events that
contribute to progressive immunosuppression.

Koch's Postulates Fulfilled

Recent developments in HIV research provide some of the strongest
evidence for the causative role of HIV in AIDS and fulfill the
classical postulates for disease causation developed by Henle and
Koch in the 19th century (Koch's postulates reviewed in Evans,
1976, 1989a; Harden, 1992). Koch's postulates have been variously
interpreted by many scientists over the years. One scientist who
asserts that HIV does not cause AIDS has set forth the following
interpretation of the postulates for proving the causal
relationship between a microorganism and a specific disease
(Duesberg, 1987):

1) The microorganism must be found in all cases of the
disease.

2) It must be isolated from the host and grown in pure
culture.

3) It must reproduce the original disease when introduced into
a susceptible host.

4) It must be found in the experimental host so infected.

Recent developments in HIV/AIDS research have shown that HIV
fulfills these criteria as the cause of AIDS.

1) The development of DNA PCR has enabled researchers to document
the presence of cell-associated proviral HIV in virtually all
patients with AIDS, as well as in individuals in earlier stages
of HIV disease (Kwok et al., 1987; Wages et al., 1991; Bagasra et
al., 1992; Bruisten et al., 1992; Petru et al., 1992; Hammer et
al., 1993). RNA PCR has been used to detect cell-free and/or
cell-associated viral RNA in patients at all stages of HIV
disease (Ottmann et al., 1991; Schnittman et al., 1991; Aoki-Sei,
1992; Michael et al., 1992; Piatak et al., 1993).

2) Improvements in co-culture techniques have allowed the
isolation of HIV in virtually all AIDS patients, as well as in
almost all seropositive individuals with both early- and
late-stage disease (Coombs et al., 1989; Schnittman et al., 1989;
Ho et al., 1989; Jackson et al., 1990).

1-4) All four postulates have been fulfilled in three laboratory
workers with no other risk factors who have developed AIDS or
severe immunosuppression after accidental exposure to
concentrated HIVIIIB in the laboratory (Blattner et al., 1993;
Reitz et al., 1994; Cohen, 1994c). Two patients were infected in
1985 and one in 1991. All three have shown marked CD4+ T cell
depletion, and two have CD4+ T cell counts that have dropped
below 200/mm3 of blood. One of these latter individuals developed
PCP, an AIDS indicator disease, 68 months after showing evidence
of infection and did not receive antiretroviral drugs until 83
months after the infection. In all three cases, HIVIIIB was
isolated from the infected individual, sequenced, and shown to be
the original infecting strain of virus.

In addition, as of Dec. 31, 1994, CDC had received reports of 42
health care workers in the United States with documented,
occupationally acquired HIV infection, of whom 17 have developed
AIDS in the absence of other risk factors (CDC, 1995a). These
individuals all had evidence of HIV seroconversion following a
discrete percutaneous or mucocutaneous exposure to blood, body
fluids or other clinical laboratory specimens containing HIV.

The development of AIDS following known HIV seroconversion also
has been repeatedly observed in pediatric and adult blood
transfusion cases (Ward et al., 1989; Ashton et al., 1994), in
mother-to-child transmission (European Collaborative Study, 1991,
1992; Turner et al., 1993; Blanche et al., 1994), and in studies
of hemophilia, injection drug use, and sexual transmission in
which the time of seroconversion can be documented using serial
blood samples (Goedert et al., 1989; Rezza et al., 1989; Biggar,
1990; Alcabes et al., 1993a,b; Giesecke et al., 1990; Buchbinder
et al., 1994; Sabin et al., 1993).

In many such cases, infection is followed by an acute retroviral
syndrome, which further strengthens the chronological association
between HIV and AIDS (Pedersen et al., 1989, 1993; Schechter et
al., 1990; Tindall and Cooper, 1991; Keet et al., 1993; Sinicco
et al., 1993; Bachmeyer et al., 1993; Lindback et al., 1994).

Evidence From Animal and Laboratory Models

A recent study demonstrated that an HIV variant that causes AIDS
in humans--HIV-2--also causes a similar syndrome when injected
into baboons (Barnett et al., 1994). Over the course of two
years, HIV-2-infected animals exhibited a significant decline in
immune function, as well as lymphocytic interstitial pneumonia
(which often afflicts children with AIDS), the development of
lesions similar to those seen in Kaposi's sarcoma, and severe
weight loss akin to the wasting syndrome that occurs in human
AIDS patients. Other studies suggest that pigtailed macaques also
develop AIDS-associated diseases subsequent to HIV-2 infection
(Morton et al., 1994).

Asian monkeys infected with clones of the simian immunodeficiency
virus (SIV), a lentivirus closely related to HIV, also develop
AIDS-like syndromes (reviewed in Desrosiers, 1990; Fultz, 1993).
In macaque species, various cloned SIV isolates induce syndromes
that parallel HIV infection and AIDS in humans, including early
lymphadenopathy and the occurrence of opportunistic infections
such as pulmonary Pneumocystis carinii infection,
cytomegalovirus, cryptosporidium, candida and disseminated MAC
(Letvin et al., 1985; Kestler et al., 1990; Dewhurst et al.,
1990; Kodama et al., 1993).

In cell culture experiments, molecular clones of HIV are tropic
for the same cells as clinical HIV isolates and laboratory
strains of the virus and show the same pattern of cell killing
(Hays et al., 1992), providing further evidence that HIV is
responsible for the immune defects of AIDS. Moreover, in severe
combined immunodeficiency (SCID) mice with human thymus/liver
implants, molecular clones of HIV produce the same patterns of
cell killing and pathogenesis as seen with clinical isolates
(Bonyhadi et al., 1993; Aldrovandi et al., 1993).

Geographic Considerations

Convincing evidence that HIV causes AIDS also comes from the
geographic correlation between rates of HIV antibody positivity
and incidence of disease. Numerous studies have shown that AIDS
is common only in populations with a high seroprevalence of HIV
antibodies. Conversely, in populations in which HIV antibody
seroprevalence is low, AIDS is extremely rare (U.S. Bureau of the
Census, 1994).

Malawi, a country in southern Africa with 8.2 million
inhabitants, reported 34,167 cases of AIDS to the WHO as of
December 1994 (WHO, 1995a). This is the highest case rate in the
region. The rate of HIV seroprevalence in Malawi is also high, as
evidenced by serosurveys of pregnant women and blood donors (U.S.
Bureau of the Census, 1994). In one survey, approximately 23
percent of more than 6,600 pregnant women in urban areas were
HIV-positive (Dallabetta et al., 1993). Approximately 20 percent
of 547 blood donors in a 1990 survey were HIV-positive (Kool et
al., 1990).

In contrast, Madagascar, an island country off the southeast
coast of Africa with a population of 11.3 million, reported only
nine cases of AIDS to the WHO through December 1994 (WHO, 1995a).
HIV seroprevalence is extremely low in this country; in recent
surveys of 1,629 blood donors and 1,111 pregnant women, no
evidence of HIV infection was found (Rasamindrakotroka et al.,
1991). Yet, other sexually transmitted diseases are common in
Madagascar; a 1989 seroepidemiologic study for syphilis found
that 19.5 percent of 12,457 persons tested were infected (Latif,
1994; Harms et al., 1994). It is likely that due to the relative
geographic isolation of this island nation, HIV was introduced
late into its population. However, the high rate of other STDs
such as syphilis would predict that HIV will spread in this
country in the future.

Similar patterns have been noted in Asia. Thailand reported
13,246 cases of AIDS to the WHO through December 1994, up from
only 14 cases through 1988 (WHO, 1995a). This rise has paralleled
the spread of HIV infection in Thailand. Through 1987, fewer than
.05 percent of 200,000 Thais from all risk groups were
HIV-seropositive (Weniger et al., 1991). By 1993, 3.7 percent of
55,000 inductees into the Royal Thai Army tested positive for HIV
antibodies, up from 0.5 percent of men recruited in 1989 (U.S.
Bureau of the Census Database, December 1994). Seropositivity
among brothel prostitutes in Thailand rose from 3.5 percent in
June 1989 to 27.1 percent in June 1993 (Hanenberg et al., 1994).
By mid-1993, an estimated 740,00 people were infected with HIV in
Thailand (Brown and Sittitrai, 1994). By the year 2000,
researchers estimate that there may be 1.4 million cumulative HIV
infections and 480,000 AIDS cases in that country (Cohen, 1994b).

By comparison, South Korea reported only 25 cases of AIDS to the
WHO through Dec. 1994 (WHO, 1995a). In serosurveys in that
country conducted in 1993, HIV seroprevalence was .008 percent
among female prostitutes and .00007 percent among blood donors
(Shin et al., 1994).

Evidence From Blood Donor-Recipient Pairs

By the end of 1994, 7,223 cumulative cases of AIDS in the United
States resulting from blood transfusions or the receipt of blood
components or tissue had been reported to the CDC (CDC, 1995a).
Virtually all of these cases can be traced to transfusions before
the screening of the blood supply for HIV commenced in 1985
(Jones et al., 1992; Selik et al., 1993).

Compelling evidence supporting a cause-and-effect relationship
between HIV and AIDS has come from studies of transfusion
recipients with AIDS who have received blood from at least one
donor with HIV infection. In the earliest such study (before the
discovery of HIV), seven patients with transfusion-acquired AIDS
were shown to have received a total of 99 units of blood
components. At least one donor to each patient was identified who
had AIDS-like symptoms or immunosuppression (Curran et al.,
1984).

With the identification of HIV and the development of serologic
assays for the virus in 1984, it became possible to trace
infected donors (Sarngadharan et al., 1984). The first reports of
donor-recipient pairs appeared later that year (Feorino et al.,
1984; Groopman et al., 1984). In one instance, HIV was isolated
from both donor and recipient, and both had developed AIDS
(Feorino et al., 1984); in the other, the recipient was HIV
antibody-positive and had developed AIDS, and the donor had
culturable virus in his blood and was in a group considered to be
at high risk for AIDS (Groopman et al., 1984). Molecular analysis
of HIV isolates from these donor-recipient pairs found that the
viruses were slightly different but much more similar than would
be expected by chance alone (Feorino et al., 1984; Groopman et
al., 1984).

In a subsequent study of patients with transfusion-acquired AIDS,
28 of 28 individuals had antibodies to HIV, and each had received
blood from an HIV-infected donor (Jaffe et al., 1985b). Similar
results were reported from a set of 18 patients with
transfusion-acquired AIDS, each of whom had received blood from
an HIV-infected donor (McDougal et al., 1985b). Fifteen of the 18
donors in this study had low CD4+/CD8+ T cell ratios, an immune
defect seen in pre-AIDS and AIDS patients.

Another group studied seropositive recipients of blood from 112
donors in whom AIDS later developed and from 31 donors later
found to be positive for HIV antibody. Of 101 seropositive
recipients followed for a median of 55 months after infection, 43
developed AIDS (Ward et al., 1989).

More recently, Australian investigators identified 25 individuals
with transfusion-acquired HIV whose infection could be traced to
eight individuals who donated blood between 1980 and 1985, and
subsequently developed AIDS. By 1992, nine of the 25 HIV-infected
blood recipients had developed AIDS, with progression to AIDS and
death more rapid among the recipients who received blood from the
faster-progressing donors (Ashton et al., 1994).

Impact of HIV Infection on Mortality of Hemophiliacs

As noted above, HIV has been detected in stored blood samples
taken from hemophiliac patients in the United States as early as
1978 (Aronson, 1993). By 1984, 55 to 78 percent of U.S.
hemophilic patients were HIV-infected (Lederman et al., 1985;
Andes et al., 1989). A more recent survey found 46 percent of
9,496 clotting-factor recipients to be HIV-infected, only 9 of
whom had a definitive date of seroconversion subsequent to April
1987 (Fricke et al., 1992). By Dec. 31, 1994, 3,863 individuals
in the United States with hemophilia or coagulation disorders had
been diagnosed with AIDS (CDC, 1995a).

The impact of HIV on the life expectancy of hemophiliacs has been
dramatic. In a retrospective study of mortality among 701
hemophilic patients in the United States, median life expectancy
for males with hemophilia increased from 40.9 years at the
beginning of the century (1900-1920) to a high of 68 years after
the introduction of factor therapy (1971 to 1980). In the era of
AIDS (1981 to 1990), life expectancy declined to 49 years (Jones
and Ratnoff, 1991).

Another analysis found that the death rate for individuals with
hemophilia A in the United States rose three-fold between the
periods 1979-1981 and 1987-1989. Median age at death decreased
from 57 years in 1979-1981 to 40 years in 1987-1989 (Chorba et
al., 1994).

In the United Kingdom, 6,278 males diagnosed with hemophilia were
living during the period 1977-91. During 1979-86, 1,227 were
infected with HIV during transfusion therapy. Among 2,448
individuals with severe hemophilia, the annual death rate was
stable at 8 per 1,000 during 1977-84; during 1985-92 death rates
remained at 8 per 1,000 among HIV-seronegative persons with
severe hemophilia but rose steeply in those who were
seropositive, reaching 81 per 1,000 in 1991-92. Among 3,830 with
mild or moderate hemophilia, the pattern was similar, with an
initial death rate of 4 per 1,000 in 1977-84, rising to 85 per
1,000 in 1991-92 among seropositive individuals (Darby et al.,
1995).

In a British cohort of hemophiliacs infected with HIV between
1979 and 1985 and followed prospectively, 50 of 111 patients had
died by the end of 1994, 43 after a diagnosis of AIDS. Only eight
of the 61 living patients had CD4+ T cell counts above 500/mm3
(Lee et al., 1995).

Pediatric AIDS

Newborn infants have no behavioral risk factors, yet 6,209
children in the United States have developed AIDS through Dec.
31, 1994 (CDC, 1995a).

Studies have consistently shown that of infants born to
HIV-infected mothers, only the 15-40 percent of infants who
become HIV-infected before or during birth go on to develop
immunosuppression and AIDS, while babies who are not HIV-infected
do not develop AIDS (Katz, 1989; d'Arminio et al., 1990; Prober
and Gershon, 1991; European Collaborative Study, 1991; Lambert et
al., 1990; Lindgren et al. 1991; Andiman et al., 1990; Johnson et
al., 1989; Rogers et al., 1989; Hutto et al., 1991). Moreover, in
those infants who do acquire HIV and develop AIDS, the rate of
disease progression varies directly with the severity of the
disease in the mother at the time of delivery (European
Collaborative Study, 1992; Blanche et al., 1994).
Almost all infants born to seropositive mothers have detectable
HIV antibody, which may persist for as long as 15 months. In most
cases, the presence of this antibody does not represent actual
infection with HIV, but is antibody from the HIV-infected mother
that diffuses across the placenta. In a French study of 22
infants born to HIV-infected mothers, seven babies had antibodies
to HIV after one year and all developed AIDS. In these seven
infants, the presence of HIV antibodies marked actual infection
with HIV, not merely antibodies acquired from the mother. The
other 15 children showed a complete loss of maternally acquired
HIV antibodies, were not actually infected, and remained healthy.
Of the babies who developed AIDS, virus was found in four of four
infants tested. HIV was not found in the 15 children who remained
healthy (Douard et al., 1989; Gallo, 1991).

In the European Collaborative Study, children born to
HIV-seropositive mothers are followed from birth in 10 European
centers. A majority of the mothers have a history of injection
drug use. A recent report showed that none of the 343 children
who had lost maternally transferred HIV antibodies (i.e. they
were truly HIV-negative) had developed AIDS or persistent immune
deficiency. In contrast, among 64 children who were truly
HIV-infected (i.e. they remained HIV antibody positive), 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, 1991).

In a multicenter study in Bangkok, Thailand, 105 children born to
HIV-infected mothers were recently evaluated at 6 months of age
(Chearskul et al., 1994). Of 27 infants determined to be
HIV-infected by polymerase chain reaction, 24 developed
HIV-related symptoms, including six who developed CDC-defined
AIDS and four who died with conditions clinically consistent with
AIDS. Among 77 exposed but uninfected infants, no deaths
occurred.

In a study of 481 infants in Haiti, the survival rate at 18
months was 41 percent for HIV-infected infants, 84 percent among
uninfected infants born to seropositive women, and 95 percent
among infants born to seronegative women (Boulos et al., 1994).

Investigators have also reported cases of HIV-infected mothers
with twins discordant for HIV-infection in which the HIV-infected
child developed AIDS, while the other child remained clinically
and immunologically normal (Park et al., 1987; Menez-Bautista et
al., 1986; Thomas et al., 1990; Young et al., 1990; Barlow and
Mok, 1993; Guerrero Vazquez et al., 1993).

Single Source Outbreak of Pediatric AIDS

Other researchers have used molecular epidemiology to find a
single source of HIV for an outbreak of pediatric AIDS cases in
Russia. In that country between 1988 and 1990, over 250 children
were infected with HIV after exposure to non-sterile needles. By
June 1994, 43 of these children had died of AIDS (Irova et al.,
1993). In a recent report on 22 of these children from two
hospitals, 12 had developed AIDS. Molecular analysis of HIV
isolates from all 22 children showed the isolates to be very
closely related, confirming epidemiological data that these two
outbreaks resulted from a single source: an infant born to an
HIV-infected mother whose husband was infected in central Africa
(Bobkov et al., 1994).

Answering the Skeptics:
the "Risk-AIDS" or "Behavioral" Hypothesis

Skeptics of the role of HIV in AIDS have espoused a "risk-AIDS"
or a "drug-AIDS" hypothesis (Duesberg, 1987-1994), asserting at
different times that factors such as promiscuous homosexual
activity; repeated venereal infections and antibiotic treatments;
the use of recreational drugs such as nitrite inhalants, cocaine
and heroin; immunosuppressive medical procedures; and treatment
with the drug AZT are responsible for the epidemic of AIDS.

Such arguments have been repeatedly contradicted. Compelling
evidence against the risk-AIDS hypothesis has come from cohort
studies of high-risk groups in which all individuals with
AIDS-related conditions are HIV-antibody positive, while matched,
HIV-antibody negative controls do not develop AIDS or
immunosuppression, despite engaging in high-risk behaviors.

In a prospectively studied cohort in Vancouver (Schechter et al.,
1993a), 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 HIV-negative men
despite the fact that these men reported appreciable levels of
nitrite use, other recreational drug use, and frequent receptive
anal intercourse. The average rate of CD4+ T cell decline was 50
cells/mm3 per year in the HIV-positive men, while the
HIV-negative men showed no decline. Significantly, the decline of
CD4+ T cell counts in HIV-positive men and the stability of CD4+
T cell counts in HIV-negative men were apparent whether or not
nitrite inhalants were used. There were 101 AIDS-related deaths
among the HIV-seropositive men, including six unrelated to HIV
infection. In the seronegative group, only two deaths occurred:
one heart attack and one suicide. In this study, lifetime
prevalences of risk behaviors were similar in the 136
HIV-seropositive men who developed AIDS and in the 226
HIV-seropositive men who did not develop AIDS: use of nitrite
inhalants, 88 percent in both groups; use of other illicit drugs,
75 percent and 80 percent, respectively; more than 25 percent of
sexual encounters involving receptive anal intercourse, 78
percent and 82 percent, respectively. Among HIV-seronegative men
(none of whom developed AIDS), the lifetime prevalences of these
behaviors were somewhat lower, but substantial: 56 percent, 74
percent and 58 percent, respectively.

Similar results were reported from the San Francisco Men's Health
Study, a cohort of single men recruited in San Francisco in 1984
without regard to sexual preference, lifestyle or serostatus
(Ascher et al., 1993a). During 96 months of follow-up, 215 cases
of AIDS had occurred among 445 HIV-antibody positive homosexual
men, 174 of whom had died. Among 367 antibody-negative homosexual
men and 214 antibody-negative heterosexual men, no AIDS cases and
eight deaths unrelated to AIDS-defining conditions were observed.
The authors found no overall effect of drug consumption,
including nitrites, on the development of Kaposi's sarcoma or
other AIDS-defining conditions, nor an effect of the extent of
the participants' drug use on these conditions. A consistent loss
of CD4+ T cells was limited to HIV-positive subjects, among whom
there was no discernible difference in CD4+ T cell counts related
to drug-taking behavior. Among HIV-seronegative men, moderate or
heavy drug users had higher CD4+ T cell counts than non-users.

Observational studies of HIV-infected individuals have found that
drug use does not accelerate progression to AIDS (Kaslow et al.,
1989; Coates et al., 1990; Lifson et al., 1990; Robertson et al.,
1990). In a Dutch cohort of HIV-seropositive homosexual men, no
significant differences in sexual behavior or use of cannabis,
alcohol, tobacco, nitrite inhalants, LSD or amphetamines were
found between men who remained asymptomatic for long periods and
those who progressed to AIDS (Keet et al., 1994). Another study,
of five cohorts of homosexual men for whom dates of
seroconversion were well-documented, found no association between
HIV disease progression and history of sexually transmitted
diseases, number of sexual partners, use of AZT, alcohol, tobacco
or recreational drugs (Veugelers et al., 1994).

Similarly, in the San Francisco City Clinic Cohort, recruited in
the late 1970s and early 1980s in conjunction with hepatitis B
studies, no consistent differences in exposure to recreational
drugs or sexually transmitted diseases were seen between
HIV-infected men who progressed to AIDS and those who remained
healthy (Buchbinder et al., 1994).

Because many children with AIDS are born to mothers who abuse
recreational drugs (Novick and Rubinstein, 1987; European
Collaborative Study, 1991), it has been postulated that the
mothers' drug consumption is responsible for children developing
AIDS (Duesberg, 1987-1994). This theory is contradicted by
numerous reports of infants with AIDS born to women infected with
HIV through heterosexual contact or transfusions who do not use
drugs (CDC, 1995a). As noted above, the only factor that predicts
whether a child will develop AIDS is whether he or she is
infected with HIV, not maternal drug use.

AIDS and Injection Drug Users

Central to the "risk-AIDS" hypothesis is the notion that chronic
injection drug use causes AIDS (Duesberg, 1992), a view that is
contradicted by numerous studies.

Although some evidence suggests injection drug use can cause
certain immunologic abnormalities, such as reduction in natural
killer (NK) cell activity (reviewed in Kreek, 1990), the specific
immune deficit that leads to AIDS--a progressive reduction of
CD4+ T cells resulting in persistent CD4+ T lymphocytopenia--is
rare in HIV-seronegative injection drug users in the absence of
other immunosuppressive conditions (Des Jarlais et al., 1993;
Weiss et al., 1992).

In a survey of 229 HIV-seronegative injection drug users in New
York City, mean CD4+ T cell counts of the group were consistently
over 1000/mm3 (Des Jarlais et al., 1993). Only two individuals
had two CD4+ T cell measurements of fewer than 300/mm3, one of
whom died with cardiac disease and non-Hodgkin's lymphoma listed
as the cause of death. In a study of 180 HIV-seronegative
injection drug users in New Jersey, the participants' average
CD4+ T cell count was 1169/mm3 (Weiss et al., 1992). Two of these
individuals, both with generalized lymphocytopenia, had CD4+ T
cell counts less than 300/mm3.

In the MACS, median CD4+ T cell counts of 63 HIV-seronegative
injection drug users rose from 1061/mm3 to 1124/mm3 in a 15 to 21
month follow-up period (Margolick et al., 1992). In a
cross-sectional study, 11 HIV-seronegative, long-term heroin
addicts had mean CD4+ T cell counts of 1500/mm3, while 11 healthy
controls had CD4+ T cell counts of 820 cells/mm3 (Novick et al.,
1989).

Recent data also refute the notion that a certain lifetime dosage
of injection drugs is sufficient to cause AIDS in
HIV-seronegative individuals. In a Dutch study, investigators
compared 86 HIV-seronegative individuals who had been injecting
drugs for a mean of 7.6 years with 70 HIV-seropositive people who
had injected drugs for a mean of 9.1 years. Upon enrollment in
1989, CD4+ T cell counts were 914/mm3 in the HIV-seronegative
group, and 395/mm3 in the seropositive group. By 1994, there were
25 deaths attributable to AIDS-defining conditions in the
seropositive group; among HIV-seronegative individuals, eight
deaths occurred, none due to AIDS-defining diseases (Cohen,
1994a).

Excess mortality among HIV-infected injection drug users as
compared to HIV-seronegative users has also been observed by
other investigators. In a prospective Italian study of 2,431
injection drug users enrolled in drug treatment programs from
1985 to 1991, HIV-seropositive individuals were 4.5 times more
likely to die than HIV-seronegative subjects (Zaccarelli et al.,
1994). No deaths due to AIDS-defining conditions were seen among
1,661 HIV-seronegative individuals, 41 of whom died of other
conditions, predominantly overdose, liver disease and accidents.
Among 770 individuals who were HIV-seropositive at study entry or
who seroconverted during the study period, 89 died of
AIDS-related conditions and 52 of other conditions.

In HIV-seropositive individuals, a number of investigators have
found no statistical association between injection drug use and
decline of CD4+ T cell counts (Galli et al., 1989, 1991;
Schoenbaum et al., 1989; Margolick et al., 1992, 1994; Montella
et al., 1992; Alcabes et al., 1993b, 1994; Galai et al., 1995),
nor a difference in disease progression between active versus
former users of injection drugs (Weber et al., 1990; Galli et
al., 1991; Montella et al., 1992; Italian Seroconversion Study,
1992).

Taken together, these studies suggest that any negative effects
of injection drugs on CD4+ T cell levels are limited and may
explain why many investigators have found that HIV-seropositive
injection drug users have rates of disease progression that are
similar to other HIV-infected individuals (Rezza et al., 1990;
Montella et al., 1992; Galli et al., 1989; Selwyn et al., 1992;
Munoz et al., 1992; Italian Seroconversion Study, 1992; MAP
Workshop, 1993; Pezzotti et al., 1992; Margolick et al., 1992,
1994; Alcabes, 1993b, 1994; Galai et al., 1995).

Sex and the AIDS Epidemic

It has been asserted ". . . in America, only promiscuity aided by
aphrodisiac and psychoactive drugs, practiced mostly by 20 to 40
year-old male homosexuals and some heterosexuals, seems to
correlate with AIDS diseases" (Duesberg, 1991). Even a cursory
review of history provides evidence to the contrary: such
behaviors have existed for decades --in some cases centuries--and
have increased only in a relative sense in recent years, if at
all, whereas AIDS clearly is a new phenomenon.

If promiscuity were a cause of AIDS, one would have expected
cases to have occurred among prostitutes (male or female) prior
to 1978. Reports of such cases are lacking, even though
prostitution has been present in most if not all cultures
throughout history.

In this country, trends in gonorrheal infections suggest that
extramarital sexual activity was extensive in the pre-AIDS era.
Cases of gonorrhea in the United States peaked at approximately 1
million in 1978; between 250,000 and 530,000 cases were reported
each year in the 1960s, approximately 250,000 cases each year in
the 1950s, and between 175,000 and 380,000 cases annually in the
1940s (CDC, 1987c, 1993b). Despite the frequency of sexually
transmitted diseases, only a handful of documented cases of AIDS
in the United States prior to 1978 have been reported.

Historians, archaeologists and sociologists have documented
extensive homosexual activity dating from the ancient Greeks to
the well-established homosexual subculture in the United States
in the 20th century (Weinberg and Williams, 1974; Gilbert,
1980-81; Saghir and Robins, 1973; Reinisch et al., 1990; Doll et
al., 1990; Katz, 1992; Friedman and Downey, 1994). Depictions of
anal intercourse, both male and female, can be found in the art
and literature of numerous cultures on all inhabited continents
(Reinisch et al., 1990). In the 1940s, Kinsey et al. reported
that 37 percent of all American males surveyed had at least some
overt homosexual experience to the point of orgasm between
adolescence and old age and that 10 percent of men were
exclusively or predominantly homosexual between the ages of 16
and 55 (Kinsey et al., 1948). More recent surveys have found that
2 to 5 percent of men are homosexual or bisexual (reviewed in
Friedman and Downey, 1994; Seidman and Rieder, 1994; Laumann,
1994).

Many homosexuals had multiple sexual partners in the pre-AIDS
era: a 1969 survey found that more than 40 percent of white
homosexual males and one-third of black homosexual males had at
least 500 partners in their lifetime, and an additional
one-fourth reported between 100 and 500 partners (Bell and
Weinberg, 1978). A majority of these men reported that more than
half their partners had been strangers before the sexual
encounters (Bell and Weinberg, 1978). Further evidence of
extensive homosexual behavior in the years preceding the AIDS
epidemic comes from reports of numerous cases of rectal
gonorrheal and anal herpes simplex virus infections among men
(Jefferiss, 1956; Scott and Stone, 1966; Pariser and Marino,
1970; Owen and Hill, 1972; British Cooperative Clinical Group,
1973; Jacobs, 1976; Judson et al., 1977; Merino and Richards,
1977; McMillan and Young, 1978).

Drug Use in the Pre-AIDS Era

A temporal association between the onset of extensive use of
recreational drugs and the AIDS epidemic is also lacking. The
widespread use of opiates in the United States has existed since
the middle of the 19th century (Courtwright, 1982); as many as
313,000 Americans were addicted to opium and morphine prior to
1914. Heroin use spread throughout the country in the 1920s and
1930s (Courtwright, 1982), and the total number of active heroin
users peaked at about 626,000 in 1971 (Greene et al., 1975;
Friedland, 1989). Opiates were initially administered by oral or
inhalation routes, but by the 1920s addicts began to inject
heroin directly into their veins (Courtwright, 1982). In 1940,
intravenous use of opiates was seen in 80 percent of men admitted
to a large addiction research center in Kentucky (Friedland,
1989).

While cocaine use increased markedly during the 1970s (Kozel and
Adams, 1986), the use of the drug, frequently with morphine, is
well-documented in the United States since the late 19th century
(Dale, 1903; Ashley, 1975; Spotts and Shontz, 1980). For example,
a survey in 1902 reported that only 3 to 8 percent of the cocaine
sold in New York, Boston and other cities went into the practice
of medicine or dentistry (Spotts and Shontz). After a period of
relative obscurity, cocaine became increasingly popular in the
late 1950s and 1960s. Over 70 percent of 1,100 addicts at the
addiction research center in Kentucky in 1968 and 1969 reported
use or abuse of cocaine (Chambers, 1974).

The recreational use of nitrite inhalants ("poppers") also
predates the AIDS epidemic. Reports of the widespread use of
these drugs by young men in the 1960s were the impetus for the
reinstatement by the Food and Drug Administration of the
prescription requirement for amyl nitrite in 1968 (Israelstam et
al., 1978; Haverkos and Dougherty, 1988). Since the early years
of the AIDS epidemic, the use of nitrite inhalants has declined
dramatically among homosexual men, yet the number of AIDS cases
continues to increase (Ostrow et al., 1990, 1993; Lau et al.,
1992).

In the general population, the number of individuals aged 25 to
44 years reporting current use of marijuana, cocaine, inhalants,
hallucinogens and cigarettes declined between 1974 and 1992,
while the AIDS epidemic worsened (Substance Abuse and Mental
Health Services Administration, 1994).

AZT and AIDS

Although some individuals maintain that treatment with zidovudine
(AZT) has compounded the AIDS epidemic (Duesberg, 1992),
published reports of both placebo-controlled clinical trials and
observational studies provide data to the contrary.

In patients with symptomatic HIV disease, for whom a beneficial
effect is measured in months, AZT appears to slow disease
progression and prolong life, according to double-blind,
placebo-controlled clinical studies (reviewed in Sande et al.,
1993; McLeod and Hammer, 1992; Volberding and Graham, 1994). A
clinical trial known as BW 002 compared AZT with placebo in 282
patients with AIDS or advanced signs or symptoms of HIV disease.
In this study, which led to the approval of AZT by the FDA, only
one of 145 patients treated with AZT died compared with 19 of 137
placebo recipients in a six month period. Opportunistic
infections occurred in 24 AZT recipients and 45 placebo
recipients. In addition to reducing mortality, AZT was shown to
have reduced the frequency and severity of AIDS-associated
opportunistic infections, improved body weight, prevented
deterioration in Karnofsky performance score, and increased
counts of CD4+ T lymphocytes in the peripheral blood (Fischl et
al., 1987; Richman et al., 1987). Continued follow-up in 229 of
these patients showed that the survival benefit of AZT extended
to at least 21 months after the initiation of therapy; survival
in the original treatment group was 57.6 percent at that time,
whereas survival among members of the original placebo group was
51.5 percent at nine months (Richman and Andrews, 1988; Fischl et al., 1989).

In another placebo-controlled study known as ACTG 016, which
enrolled 711 symptomatic HIV-infected patients with CD4+ T cell
counts between 200 and 500 cells/mm3, those taking AZT were less
likely to experience disease progression than those on placebo
during a median study period of 11 months (Fischl et al., 1990).
In this study, no difference in disease progression was noted
among participants who began the trial with CD4+ T cell counts
greater than 500/mm3.

A Veteran's Administration study of 338 individuals with early
symptoms of HIV disease and CD4+ T cell counts between 200 and
500 cells/mm3 found that immediate therapy significantly delayed
disease progression compared with deferred therapy, but did not
lengthen (or shorten) survival after an average study period of
more than two years (Hamilton et al., 1992).

Among asymptomatic HIV-infected individuals, several
placebo-controlled clinical trials suggest that AZT can delay
disease progression for 12 to 24 months but ultimately does not
increase survival. Significantly, long-term follow-up of persons
participating in these trials, although not showing prolonged
benefit of AZT, has never indicated that the drug increases
disease progression or mortality (reviewed in McLeod and Hammer,
1992; Sande et al., 1993; Volberding and Graham, 1994). The lack
of excess AIDS cases and death in the AZT arms of these large
trials effectively rebuts the argument that AZT causes AIDS.

During a 4.5 year follow-up period (mean 2.6 years) of a trial
known as ACTG 019, no differences were seen in overall survival
between AZT and placebo groups among 1,565 asymptomatic patients
entering the study with fewer than 500 CD4+ T cells/mm3
(Volberding et al., 1994). In that study, AZT was superior to
placebo in delaying progression to AIDS or advanced ARC for
approximately one year, and a more prolonged benefit was seen
among a subset of patients.

The Concorde study in Europe enrolled 1,749 asymptomatic patients
with CD4+ T cell counts less than 500/mm3. In that study, no
statistically significant differences in progression to advanced
disease were observed after three years between individuals
taking AZT immediately and those who deferred AZT therapy or did
not take the drug (Concorde Coordinating Committee, 1994).
However, the rate of progression to death, AIDS or severe ARC was
slower among the "immediate" AZT group during the first year of
therapy. Although the Concorde study did not show a significant
benefit over time with the early use of AZT, it clearly
demonstrated that AZT was not harmful to the patients in the
"immediate" AZT group as compared to the "deferred" AZT group.

A European-Australian study (EACG 020) of 993 patients with CD4+
T cell counts greater than 400/mm3 showed no differences between
AZT and placebo arms of the trial during a median study period of
94 weeks, although AZT did delay progression to certain clinical
and immunological endpoints for up to three years (Cooper et al.,
1993). Both this study and the Concorde study reported little
severe AZT-related hematologic toxicity at doses of 1,000 mg/day,
which is twice the recommended daily dose in the United States.

Uncontrolled studies have found increased survival and/or reduced
frequency of opportunistic infections in patients with HIV
disease and AIDS who were treated with AZT or other
anti-retrovirals (Creagh-Kirk et al., 1988; Moore et al.,
1991a,b; Ragni et al., 1992; Schinaia et al., 1991; Koblin et
al., 1992; Graham et al., 1991, 1992, 1993; Longini, 1993; Vella
et al., 1992, 1994; Saah et al., 1994; Bacellar et al., 1994). In
the Multicenter AIDS Cohort Study, for example, HIV-infected
individuals treated with AZT had significantly reduced mortality
and progression to AIDS for follow-up intervals of six, 12, 18
and 24 months compared to those not taking AZT, even after
adjusting for health status, CD4+ T cell counts and PCP
prophylaxis (Graham et al., 1991, 1992).

In addition, several cohort studies show that life expectancy of
individuals with AIDS has increased since the use of AZT became
common in 1986-87. Among 362 homosexual men in hepatitis B
vaccine trial cohorts in New York City, San Francisco and
Amsterdam, the time from seroconversion to death, a period not
influenced by variations in diagnosing AIDS, has lengthened
slightly in recent years (Hessol et al., 1994). In a Dutch study
of 975 males and females with HIV infection, median survival with
AIDS increased from nine months in 1982-1985, to 26 months in
1990 (Bindels et al., 1994). Even taking into consideration the
benefits of improved PCP prophylaxis and treatment, if AZT were
contributing to or causing disease, one would expect a decrease
in survival figures, rather than an increase that parallels the
use of AZT.

In an analysis from the San Francisco Men's Health Study, the
investigators note that 169 (73 percent) of 233 AIDS patients had
been treated with AZT at one time or another. However, 90 (53
percent of the 169) were diagnosed with clinical AIDS before
beginning AZT treatment, and another 51 (30 percent of the 169)
had CD4+ T cell counts lower than 200/mm3 before initiation of
AZT treatment (Ascher et al., 1995). The authors conclude, "These
data are not consistent with the hypothesis of a causal role for
AZT in AIDS."

Disease Progression Despite Antibodies

It has been argued that HIV cannot cause AIDS because the body
develops HIV-specific antibodies following primary infection
(Duesberg, 1992). This reasoning ignores numerous examples of
viruses other than HIV that can be pathogenic after evidence of
immunity appears (Oldstone, 1989). Primary poliovirus infection
is a classic example of a disease in which high titers of
neutralizing antibodies develop in all infected individuals, yet
a small percentage of individuals develop subsequent paralysis
(Kurth, 1990). Measles virus may persist for years in brain
cells, eventually causing a chronic neurological disease despite
the presence of antibodies (Gershon, 1990). Viruses such as
cytomegalovirus, herpes simplex and varicella zoster may be
activated after years of latency even in the presence of abundant
antibodies (Weiss and Jaffe, 1990). Lentiviruses with long and
variable latency periods, such as visna virus in sheep, cause
central nervous system damage even after the specific production
of neutralizing antibodies (Haase, 1990). Furthermore, it is now
well-documented that HIV can mutate rapidly to circumvent
immunologic control of its replication.

Risks Associated With Transfusion

It has been argued that AIDS among transfusion recipients is due
to underlying diseases that necessitated the transfusion, rather
than to HIV (Duesberg, 1991). This theory is contradicted by a
report by the Transfusion Safety Study Group, which compared
HIV-negative and HIV-positive blood recipients who had been given
transfusions for similar diseases. Approximately three 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 counts of 375/mm3 (Donegan et
al., 1990). 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 (Cohen, 1994d).

People have received blood transfusions for decades; however, as
discussed above, AIDS-like symptoms were extraordinarily rare
before the appearance of HIV. Recent surveys have shown that
AIDS-like symptoms remain very rare among transfusion recipients
who are HIV-seronegative and their sexual contacts. In one study
of transfusion safety, no AIDS-defining illnesses were seen among
807 HIV-negative recipients of blood or blood products, or 947
long-term sexual or household contacts of these individuals
(Aledort et al., 1993).

In addition, through 1994, the CDC had received reports of 628
cases of AIDS in individuals whose primary risk factor was sex
with an HIV-infected transfusion recipient (CDC, 1995a), a
finding not explainable by the "risk-AIDS" hypothesis.

Exposure to Factor VIII

It has also been argued that cumulative exposure to foreign
proteins in Factor VIII concentrates leads to CD4+ T cell
depletion and AIDS in hemophiliacs (Duesberg, 1992). This view is
contradicted by several large studies. 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
53 patients with the largest amount of lifetime treatments
(cumulative totals in the latter group ranged from 100,000 to
2,000,000 U in two years) (Hassett et al., 1993). Although the
CD4+ T cell counts seen in the low- and high- groups (756/mm3 and
718/mm3, respectively) were 20 to 25 percent lower than controls,
such levels are still within the normal range.

In a report from the Multicenter Hemophilia Cohort Study, the
mean CD4+ T cell counts among 161 HIV-seronegative hemophiliacs
was 784/mm3; among 715 HIV-seropositive hemophiliacs, the mean
CD4+ T cell count was 253/mm3 (Lederman et al., 1995).

In another study, no instances of AIDS-defining illnesses were
seen among 402 HIV-seronegative hemophiliacs treated with factor
therapy or in 83 hemophiliacs who received no treatment
subsequent to 1979 (Aledort et al., 1993; Mosely et al., 1993).

In a retrospective study of patients with severe hemophilia A,
the rate of CD4+ T cell loss was 31.4 every six months for 41
HIV-seropositive individuals without AIDS and 49.7 every six
months for 14 HIV-seropositive individuals with AIDS. In
contrast, among 28 HIV-seronegative individuals, CD4+ T cell
counts increased at a rate of 13.1 cells/six months (Becherer et
al., 1990).

In a study of children and adolescents with hemophilia, the
median CD4+ T cell count of 126 HIV-seronegative individuals was
895/mm3 at study entry; no individuals had CD4+ T cell counts
below 200/mm3. In contrast, 26 percent of seropositive children
had CD4+ T cell counts of less than 200/mm3; the mean CD4+ T cell
count for seropositive children was 423/mm3 (Jason et al., 1994).

Although some reports have suggested that high-purity Factor VIII
concentrates are associated with a slower rate of CD4+ T cell
decline in HIV-infected hemophiliacs than products of low and
intermediate purity (Hilgartner et al., 1993; Goldsmith et al.,
1991; de Biasi et al., 1991), other studies have shown no such
benefit (Mannucci et al., 1992; Gjerset et al., 1994). In a study
of 525 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 et al., 1994). Similarly, the Multicenter
Hemophilia Cohort Study found no association between the
cumulative dose of plasma concentrate and incidence of AIDS among
242 HIV-infected hemophiliacs and thus "no support for cofactor
hypotheses involving either antigen stimulation or inoculum size"
(Goedert et al., 1989).

In addition to the evidence from the cohort studies cited above,
it should be noted that 10 to 20 percent of wives and sex
partners of male HIV-positive hemophiliacs in the United States
are also HIV-infected (Pitchenik et al., 1984; Kreiss et al.,
1985; Peterman et al., 1988; Smiley et al., 1988; Dietrich and
Boone, 1990; Lusher et al., 1991). Through December 1994, the CDC
had received reports of 266 cases of AIDS in those who had sex
with a person with hemophilia (CDC, 1995a). These data cannot be
explained by a non-infectious theory of AIDS etiology.

Distribution of AIDS Cases

Certain skeptics maintain that the distribution of AIDS cases
casts doubt on HIV as the cause of the syndrome. They claim
infectious microbes are not gender-specific, yet relatively few
people with AIDS are women (Duesberg, 1992).

In 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 (U.S. Bureau of the Census,
1994). In the United States, HIV first appeared in populations of
homosexual men and injection drug users, a majority of whom are
male (Curran et al., 1988). 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 are becoming HIV-infected, usually
through the exchange of HIV-contaminated needles or sex with an
HIV-infected male (Vermund, 1993b; CDC, 1995a). As the number of
HIV-infected women has risen, so too have the number of female
AIDS cases. In the United States, the proportion of AIDS cases
among women has increased from 7 percent in 1985 to 18 percent in
1994. AIDS is now the fourth leading cause of death among women
aged 25 to 44 in the United States (CDC, 1994).

In Africa, HIV was first recognized in sexually active
heterosexuals, and in some parts of Africa AIDS cases have
occurred as frequently in women as in men (Quinn et al., 1986;
Mann, 1992a). In Zambia, for example, the 29,734 AIDS cases
reported to the WHO through October 20, 1993, were equally
divided among males and females (WHO, 1995a,b).

AIDS in Africa

One vocal skeptic of the role of HIV in AIDS argues that, in
Africa, AIDS is nothing more than a new name for old diseases
(Duesberg, 1991). It is true that the diseases that have come to
be associated with AIDS in Africa--wasting, 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 (Essex, 1994). In a recent study of more
than 9,000 individuals in rural Uganda, people testing positive
for HIV antibodies were 60 times as likely to die during the
subsequent two-year observation period as were otherwise similar
persons who tested negative (Mulder et al., 1994b). Large
differences in mortality were also seen between HIV-seropositive
and HIV-seronegative individuals in another large Ugandan cohort
(Sewankambo et al., 1994).

Elsewhere in Africa findings are similar. One study of 1,400
Rwandan women tested for HIV during pregnancy found that HIV
infected women were 20 times more likely to die in the two years
following pregnancy than their HIV-negative counterparts (Lindan
et al., 1992). In another study in Rwanda, 215 HIV-seropositive
women and 216 HIV-seronegative women were followed prospectively
for up to four years, during which time 21 women developed AIDS
(WHO definition), all of them in the HIV-seropositive group. The
mortality rate among the HIV-seropositive women was nine times
higher than seen among the HIV-seronegative women (Leroy et al.,
1995)

In Zaire, investigators found that families in which the mother
was HIV-1 seropositive experienced a five- to 10-fold higher
maternal, paternal and early childhood mortality rate than
families in which the mother was HIV-seronegative (Ryder et al.,
1994b). In another study in Zaire, infants with HIV infection
were shown to have an 11-fold increased risk of death from
diarrhea compared with uninfected children (Thea et al., 1993).
In patients with pulmonary tuberculosis in Cote d'Ivoire,
HIV-seropositive individuals were 17 times more likely to die
than HIV-seronegative individuals (Ackah et al., 1995).

The extraordinary death rates among HIV-infected individuals
confirm that the virus is an important cause of premature
mortality in Africa (Dondero and Curran, 1994).

CONCLUSION

HIV and AIDS have been repeatedly linked in time, place and
population group; the appearance of HIV in the blood supply has
preceded or coincided with the occurrence of AIDS cases in every
country and region where AIDS has been noted. Among individuals
without HIV, AIDS-like symptoms are extraordinarily rare, even in
populations with many AIDS cases. Individuals as different as
homosexual men, elderly transfusion recipients, heterosexual
women, drug-using heterosexual men and infants have all developed
AIDS with only one common denominator: infection with HIV.
Laboratory workers accidentally exposed to highly concentrated
HIV and health care workers exposed to HIV-infected blood have
developed immunosuppression and AIDS with no other risk factor
for immune dysfunction. Scientists have now used PCR to find HIV
in virtually every patient with AIDS and to show that HIV is
present in large and increasing amounts even in the pre-AIDS
stages of HIV disease. Researchers also have demonstrated a
correlation between the amount of HIV in the body and progression
of the aberrant immunologic processes seen in people with AIDS.

Despite this plethora of evidence, the notion that HIV does not
cause AIDS continues to find a wide audience in the popular
press, with potential negative impact on HIV-infected individuals
and on public health efforts to control the epidemic.
HIV-infected individuals may be convinced to forego anti-HIV
treatments that can forestall the onset of the serious infections
and malignancies of AIDS (Edelman et al., 1991). Pregnant
HIV-infected women may dismiss the option of taking AZT, which
can reduce the likelihood of transmission of HIV from mother to
infant (Connor et al., 1994; Boyer et al., 1994).

People may be dissuaded from being tested for HIV, thereby
missing the opportunity, early in the course of disease, for
counselling as well as for treatment with drugs to prevent
AIDS-related infections such as PCP. Such prophylactic measures
prolong survival and improve the quality of life of HIV-infected
individuals (CDC, 1992b).

Most troubling is the prospect that individuals will discount the
threat of HIV and continue to engage in risky sexual behavior and
needle sharing. If public health messages on AIDS prevention are
diluted by the misconception that HIV is not responsible for
AIDS, otherwise preventable cases of HIV infection and AIDS may
occur, adding to the global tragedy of the epidemic.

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