Pharmac. & Ther. Vol. 55: 201-277, 1992


Department of Molecular and Cell Biology, 229 Stanley Hall, University of California at Berkeley, Berkeley, CA 94720, U.S.A.

2. Definition of AIDS

2.1. AIDS: 2 Epidemics, Sub-Epidemics and 25 Epidemic-Specific Diseases

AIDS includes 25 previously known diseases and two clinically and epidemiologically very different AIDS epidemics, one in America and Europe, the other in Africa (Table 1) (Centers for Disease Control, 1987; Institute of Medicine, 1988; World Health Organization, 1992a). The American/European epidemic falls into four sub-epidemics: the male homosexual, the intravenous drug user, the hemophilia and the transfusion recipient epidemics (Table 1).

2.1.1. The Epidemics by Case Numbers, Gender and Age

The American/European AIDS epidemics of homosexuals and intravenous drug users are new, starting with drug-using homosexual AIDS patients in Los Angeles and New York in 1981 (Centers for Disease Control, 1981; Gottlieb et al., 1981; Jaffe et al., 1983a). By December 1991, 206,392 AIDS cases had been recorded in the U.S. and 65,979 in Europe (Table 1) (World Health Organization, 1992a; Centers for Disease Control, 1992b). The U.S. has reported about 30,000-40,000 new cases annually since 1987, and Europe reports about 12,000-16,000 cases annually (World Health Organization, 1992a; Centers for Disease Control, 1992b).

Remarkably for a presumably infectious disease, 90% of all American and 86% of all European AIDS patients are males. Nearly all American (98%) and European (96%) AIDS patients are over 20 years old; the remaining 2% and 4%, respectively, are mostly infants (Table 1) (World Health Organization, 1992a; Centers for Disease Control, 1992b). There is very little AIDS among teenagers, as only 789 American teenagers have developed AIDS over the last 10 years, including 160 in 1991 and 170 in 1990 (Centers for Disease Control, 1992b).

Since 1985, 129,066 AIDS cases have been recorded in Africa (World Health Organization, 1992b), mainly from the people of Central Africa (Blattner, 1991). Unlike the American and European cases, the African cases are distributed equally between the sexes (Quinn et al., 1986; Blattner et al., 1988; Institute of Medicine, 1988; Piot et al., 1988; Goodgame, 1990) and range "in age from 8 to 85 years" (Widy-Wirski et al., 1988).

An AIDS crisis that was reported to "loom" in Thailand as of 1990 (Anderson, 1990; Smith, 1990) and that was predicted to "explode" now (Mann and the Global AIDS Policy Coalition, 1992) has generated only 123 AIDS patients from 1984 until June 1991 (Weniger et al., 1991).

2.1.2. AIDS Diseases

The majority of American (62%) and European (75%) AIDS patients have microbial diseases or opportunistic infections that result from a previously acquired immunodeficiency (World Health Organization, 1992a; Centers for Disease Control, 1992b). In America these include Pneumocystis pneumonia (50%), candidiasis (17%) and mycobacterial infections such as tuberculosis (11%), toxoplasmosis (5%), cytomegalovirus (8%) and herpes virus disease (4%) (Table 1) (Centers for Disease Control, 1992b). Pneumocystis pneumonia is often described and perceived as an AIDS-specific pneumonia. However, Pneumocystis carinii is a ubiquitous fungal parasite that is present in all humans and may become active upon immune deficiency like many others (Freeman, 1979; Pifer, 1984; Williford Pifer et al., 1988; Root-Bernstein, 1990a). Since bacterial opportunists of immune deficiency, like tuberculosis bacillus or pneumococcus, are readily defeated with antibiotics, fungal and viral pneumonias predominate in countries where antibiotics are readily available. This is particularly true for risk groups that use antibiotics chronically as AIDS prophylaxis (Callen, 1990; Bardach, 1992). Indeed, young rats treated for several weeks simultaneously with antibiotics and immunosuppressive cortisone all developed Pneumocystis pneumonia spontaneously (Weller, 1955).

Table 1. AIDS Statistics*

Epidemics                    American                    European                African

AIDS total 1985-1991 206,000 66,000 129,000 AIDS annual since 1990 30-40,000 12-16,000 ~20,000 HIV carriers since 1985 1 million 500,000 6 million Annual AIDS per HIV carrier 3-4% 3% about 0.3% AIDS by sex 90% male 86% male 50% male AIDS by age, over 20 years 98% 96% ? AIDS by risk group male homosexual 62% 48% intravenous drugs 32% 33% transfusions 2% 3% hemophiliacs 1% 3% general population 3% 13% 100% AIDS by Disease: Microbial 50% Pneumocystis pneumonia 75% opportunistic infections 17% candidiasis 11% mycobacterial disease fever including 3% tuberculosis diarrhea 5% toxoplasmosis tuberculosis 8% cytomegalovirus slim disease 4% herpes virus Microbial total 62% 75% about 90% (sum > 62% due to overlap) Non-Microbial 19% wasting 5% wasting 10% Kaposi's 12% Kaposi's 6% dementia 5% dementia 3% lymphoma 3% lymphoma Non-microbial total 38% 25%

* Data from references cited in Section 2. There are small (± 1%) discrepancies between some numbers cited here and the most recent surveys cited in the text, because some calculations are based on previous surveys.

Contrary to its name, AIDS of many American (38%) and European (25%) patients does not result from immunodeficiency and microbes (Section 3.5.8). Instead, these patients suffer dementia (6%/5%), wasting disease (19%/5%), Kaposi's sarcoma (10%/12%) and lymphoma (3%/3%) (Table 1) (World Health Organization, 1992a; Centers for Disease Control, 1992b).

The African epidemic includes diseases that have been long established in Africa, such as fever, diarrhea, tuberculosis and "slim disease" (Table l) (Colebunders et al., 1987; Konotey-Ahulu, 1987; Pallangyo et al., 1987; Berkley et al., 1989; Evans, 1989a; Goodgame, 1990; De Cock et al., 1991; Gilks, 1991). Only about 1% are Kaposi's sarcomas (Widy-Wirski et al., 1988). The African AIDS definition is based primarily on these Africa-specific diseases (Widy-Wirski et al., 1988) "because of limited facilities for diagnosing HIV infection" (De Cock et al., 1991).

2.1.3. AIDS Risk Groups and Risk-group Specific AIDS Diseases

Almost all American (97%) and European (87%) AIDS patients come from abnormal health risk groups whose health had been severely compromised prior to the onset of AIDS: 62% of American (47% of European) AIDS patients are male homosexuals who have frequently used oral aphrodisiac drugs (Section 4), 32% (33%) are intravenous drug users, 2% (3%) are critically ill recipients of transfusions and 1% (3%) are hemophiliacs (Institute of Medicine, 1988; Brenner et al., 1990; Centers for Disease Control, 1992b; World Health Organization, 1992a). About 38% of the American teenage AIDS cases are hemophiliacs and recipients of transfusions, 25% are intravenous drug users or sexual partners of intravenous drug users and 25% are male homosexuals (Centers for Disease Control, 1992b). Approximately 70% of the American babies with AIDS are born to drug-addicted mothers ("crack babies") and 13% are born with congenital deficiencies like hemophilia (Centers for Disease Control, 1992b). Only 3% of the American and 13% of the European AIDS patients are from "undetermined exposure categories," i.e. from the general population (Table 1) (World Health Organization, 1992a; Centers for Disease Control, 1992b). Some of the differences between European and American statistics may reflect differences in national AIDS standards between different European countries and the U.S. and differences in reporting between the World Health Organization (WHO) and the American Centers for Disease Control (CDC) (World Health Organization, 1992a). By contrast to the American and European AIDS epidemics, African AIDS does not claim its victims from sexual, behavioral or clinical risk groups.

The AIDS epidemics of different risk groups present highly characteristic, country-specific and sub-epidemic-specific AIDS diseases (Table 1 and Table 2):

1. About 90% of the AIDS diseases from Africa are old African diseases that are very different from those of the American/European epidemic (Section 2.1.2, Table 1). The African diseases do not include Pneumocystis pneumonia and candidiasis (Goodgame, 1990), although Pneumocystis and Candida are ubiquitous microbes in all humans including Africans (Freeman, 1979; Pifer, 1984).

2. The American/European epidemic falls into several sub-epidemics based on sub-epidemic-specific diseases:

a) American homosexuals have Kaposi's sarcoma 20 times more often than all other American AIDS patients (Selik et al., 1987; Beral et al., 1990).

b) Intravenous drug users have a proclivity for tuberculosis (Sections 4.5 and 4.6).

c) "Crack" (cocaine) smokers exhibit pneumonia and tuberculosis (Sections 3.4.5 and 4.6).

d) Ninety-nine percent of all hemophiliacs with AIDS have opportunistic infections, of which about 70% are fungal and viral pneumonias, but less than 1% have Kaposi's sarcoma (Evatt et al., 1984; Centers for Disease Control, 1986; Selik et al., 1987; Koerper, 1989).

e) Nearly all recipients of transfusions have pneumonia (Curran et al., 1984; Selik et al., 1987).

f) HIV-positive wives of hemophiliacs exhibit only pneumonia and a few other AIDS-defining opportunistic infections (Section

g) American babies exclusively have bacterial diseases (18%) and a high rate of dementia (14%) compared to adults (6%) (Table 1) (Centers for Disease Control, 1992b).

h) Users of the cytotoxic DNA chain terminator AZT, prescribed to inhibit HIV, develop anemia, leukopenia and nausea (Section 4.6.2).

3. The Thai mini-epidemic of 123 is made up of intravenous drug users (20%), heterosexual male and female "sex workers" (50%) and male homosexuals (30%) (Weniger et al., 1991). Among the Thais 24% have tuberculosis, 22% have pneumonia and other opportunistic infections common in Thailand and 10% have had septicemia, which is indicative of intravenous drug consumption (Weniger et al., 1991).

2.2. The HIV-AIDS Hypothesis, or the Definition of AIDS

Based on epidemiological data collected between 1981 and 1983, AIDS researchers from the CDC (Centers for Disease Control, 1986) "found in gay culture-particularly in its perceived "extreme" and "non-normative" aspects (that is "promiscuity" and recreational drugs)-the crucial clue to the cause of the new syndrome" (Oppenheimer, 1992). Accordingly the CDC had initially favored a "lifestyle" hypothesis for AIDS.

However, by 1983 immunodeficiency was also recorded in hemophiliacs, some women and intravenous drug users. Therefore, the CDC adopted the "hepatitis B analogy" (Oppenheimer, 1992) and re-interpreted AIDS as a new viral disease, transmitted sexually and parenterally by blood products and needles shared for the injection of intravenous drugs (Francis et al., 1983; Jaffe et al., 1983b; Centers for Disease Control, 1986; Oppenheimer, 1992). In April 1984 the American Secretary of Health and Human Services and the virus researcher Robert Gallo announced at a press conference that the new AIDS virus was found. The announcement was made, and a test for antibody against the virus-termed the "AIDS test"-was registered for a patent, before even one American study had been published on this virus (Connor, 1987; Adams, 1989; Crewdson, 1989; Culliton, 1990; Rubinstein, 1990). Since then most medical scientists have believed that AIDS is infectious, spread by the transmission of HIV.

According to the virus-AIDS hypothesis the 25 different AIDS diseases and the very different AIDS epidemics and sub-epidemics are all held together by a single common cause, HIV. There are two strains of HIV that are 50% related, HIV-1 and HIV-2. But as yet only one American-born AIDS patient has been infected by HIV-2 (O'Brien et al., 1992). Since nearly all HIV-positive AIDS cases recorded to date are infected by HIV-1, this strain will be referred to as HIV in this article. The HIV-AIDS hypothesis proposes: (a) that HIV is a sexually, parenterally and perinatally transmitted virus, (b) that it causes immunodeficiency by killing T-cells, but on average only 10 years after infection in adults and two years after infection in infants-a period that is described as the "latent period of HIV" because the virus is assumed to become reactivated in AIDS-and (c) that all AIDS diseases are consequences of this immunodeficiency (Coffin et al., 1986; Institute of Medicine, 1986, 1988; Gallo, 1987; Blattner et al., 1988; Gallo and Montagnier, 1988; Lemp et al., 1990; Weiss and Jaffe, 1990; Blattner, 1991; Goudsmit, 1992).

Because of this belief, 25 previously known, and in part entirely unrelated diseases have been redefined as AIDS, provided they occur in the presence of HIV. HIV is in practice only detectable indirectly via antiviral antibodies, because of its chronic inactivity even in AIDS patients (Section 3.3). These antibodies are identified with disrupted HIV, a procedure that is termed the "AIDS test" (Institute of Medicine, 1986; Rubinstein, 1990). Virus isolation is a very inefficient and expensive procedure, designed to activate dormant virus from leukocytes. It depends on the activation of a single, latent HIV from about 5 million leukocytes from an antibody-positive person. For this purpose the cells must be propagated in vitro away from the virus-suppressing immune system of the host. Virus may then be detected weeks later in the culture medium (Weiss et al., 1988; Duesberg, 1989c).

Antibodies against HIV were originally claimed to be present in most (88%) AIDS patients (Sarngadharan et al., 1984), but have since been confirmed in no more than about 50% of the American AIDS patients (Institute of Medicine, 1988; Selik et al., 1990). The rest are presumptively diagnosed based on disease criteria outlined by the CDC (Centers for Disease Control, 1987; Institute of Medicine, 1988). Because of confidentiality laws more tests are probably done than are reported to the CDC.

Since the "AIDS test" became available in 1985, over 20 million tests have been performed annually in the U.S. alone on blood donors, servicemen and applicants to the Army, AIDS patients and many others, and millions more are performed in Europe, Russia, Africa and other countries (Section 3.6). On the basis of such widespread testing, clearly the most comprehensive in the history of virology, about 1 million, or 0.4% of mostly healthy Americans (Curran et al., 1985; Institute of Medicine, 1988; Duesberg, 1991a; Vermund, 1991; Centers for Disease Control, 1992a), 0.5 million, or 0.2% of Western Europeans (Mann et al., 1988; Blattner, 1991; World Health Organization, 1992a), 6 million, or 10% of mostly healthy Central Africans (Curran et al., 1985; Institute of Medicine, 1988; Piot et al., 1988; Goodgame, 1990; Blattner, 1991; Anderson and May, 1992) and 300,000 or 0.5% of healthy Thais (Weniger et al., 1991) are estimated to carry antibodies to HIV (Table 1). According to the CDC the incidence of HIV-2 is "relatively high" in Western Africa with a record of 9% in one community, but "exceedingly low" in the U.S. where not even one infection was detected among 31,630 blood donors (O'Brien et al., 1992).

2.3. Alternative Infectious Theories of AIDS

In view of the heterogeneity of the AIDS diseases and the difficulties in reducing them to a common, active microbe, several investigators have proposed that AIDS is caused by a multiplicity of infectious agents such as viruses and microbes, or combinations of HIV with other microbes (Sonnabend et al., 1983; Konotey-Ahulu, 1987, 1989; Stewart, 1989; Cotton, 1990; Goldsmith, 1990; Lemaitre et al., 1990; Root-Bernstein, 1990a,c; Balter, 1991; Lo et al., 1991).

However, the proponents of infectious AIDS who reject HIV as the sole cause or see it as one of several causes of AIDS have failed to establish a consistent alternative to or cofactor for HIV. Instead, they typically blame AIDS on viruses and microbes that are widespread and either harmless or not life-threatening to a normal immune system, such as Pneumocystis, cytomegalovirus, herpes virus, hepatitis virus, tuberculosis bacillus, Candida, mycoplasma, treponema, gonococci, toxoplasma and cryptosporidiae (Section 3.5.7) (Freeman, 1979; Mims and White, 1984; Pifer, 1984; Evans, 1989c; Mills and Masur, 1990; Bardach, 1992). Since such microbes are more commonly active in AIDS patients than in others, they argue that either chronic or repeated infections by such microbes would generate fatal AIDS (Sonnabend et al., 1983; Stewart, 1989; Mills and Masur, 1990; Root-Bernstein, 1990a,c).

Yet all of these microbes also infect people with normal immune systems either chronically or repeatedly without causing AIDS (Freeman, 1979; Mims and White, 1984; Evans, 1989c; Mills and Masur, 1990). It follows that pathogenicity by these microbes in AIDS patients is a consequence of immunodeficiency acquired by other causes (Duesberg, 1990c, 1991a). This is why most of these infections are termed opportunistic.