Non-HIV Immunosuppressive Factors in AIDS: A multifactorial, synergistic theory of AIDS aetiology

R.S. Root-Bernstein
Department of Physiology, Michigan State University, East Lansing, MI 48824 (USA)

Original Publication
Res. Immunol. Paris 1990. 1990, 141, 815-838

Recent evidence has begun to indicate that HIV (human immunodeficiency virus) is neither a sufficient nor a necessary cause of acquired immunedeficiency syndrome (AIDS). Lemaitre, et al. (1990) reported that tetracycline obviates HIV pathogenicity, leading Montaigner to suggest that a cofactor such as a mycoplasma infection may be necessary to trigger HIV cytocidal activity and replication. This observation may confirm earlier claims by Lo (Lo,1986; Lo et al. ,1989; Wright, 1990) that mycoplasmas may play an essential role in AIDS pathogenesis. Similar data has also been reported from Gallo's laboratory by Lusso et al., demonstrating that the rate of HIV replication and its cytocidal effects are determined by coinfection of cells with herpes viruses (Lusso et al., 1989) and other retroviruses (Lusso et al.,1990).

Indeed, Groopman has noted that cytomegalovirus (CMV), adenoviruses and hepatitis B virus (HBV) can also potentiate the cytotoxic effect of HIV in vitro, but maintains that these interactions have no proven bearing on the clinical picture of AIDS (Wright, 1990). His assessment is not, in fact, accurate. CMV superinfection of HIV-positive haemopheliacs has been shown to increase their probability of developing AIDS by almost 4-fold over CMV-negative, HIV-positive controls (Webster et al., 1989) and synergistic effects of CMV on Candida, Staphylococcus and Pseudomonas infections cause increased mortality in mice (Hamilton et al., 1976).

Similarly, human patients having multiple infections, such as combined CMV, HBV and Epstein-Barr virus (EBV), develop such more severe symptoms than typical CMV mononucleosis patients (Oill et al., 1977). Synergism between hepatitis C virus (HCV) and HIV leading to enhanced infection and mortality has been reported in mother-infant transmission of AIDS (Giovannini et al., 1990). And almost all AIDS patients who develop demyelinating dementias have combined CMV and Mycobacterial infections, which differentiates them significantly from non-demented patients (Root-Bernstein, 1990a). These data strongly suggest that HIV is not sufficient to cause AIDS; or, at the very least, that the rate at which HIV infection causes disease is determined by immunosuppressive cofactors.

Epidemiological findings support this conclusion. The distribution of HIV positivity is equal between men and women ages 17 to 19 in the United States and has been so for the past six years (Burke et al., 1990). If HIV were suffiicient to cause AIDS, then AIDS should affect men and women in their mid-twenties (heterosexuals, bisexuals and homosexuals) equally. Clearly, it does not (CDC, 1989a,b).

The necessity of HIV infection in AIDS has also been brought into question by reports of the syndrome or its preceding manifestations in HIV-negative individuals. Haemophiliacs develop immune deficiencies of equal magnitudes and involving the same T-cell subsets whether they are HIV-positive or not (Jin et al., 1989). A 1982 study of heroin addicts found that 24 % had T4/T8 ratios typical of AIDS patients as well as defects in E-rosette formation. When retested in 1985, only 12 % were HIV-positive (Donohoe et al., 1987, suggesting that profound immunosuppression preceded HIV infection rather than resulting from it. The only controlled study of blood transfusions that I have been able to locate indicates that 50 % of patients receiving HIV-tainted blood died within a year, and also that 50 % of "recipients of components from a random selection of donors not known to be infected with HIV, died in the year after transfusion" (Ward et al., 1989), again suggesting that HIV is an insignificant cause of morbìdity and mortality among both HIV-infected and HIV-negative patients. Longterm studies of HIV-negative patients were, unfortunately, not performed to validate or falsify this conclusion. More than a dozen HIV-negative homosexual men have developed Kaposi's sarcoma (KS) (Friedman-Kein,1990 ; Lowdell,1989 ; Afrasiabi,1986 ; Muret et al. ,1990).

And several cases of chronic oral or oesophageal candidiasis and immune thromobocytopenia accompanied by low CD4+ T-cell counts in HIV-negative patients without known causes of immunosuppression have also been reported (Parkhurst and Peakman, 1989; Gatenby, 1989; Daus et al., 1989). It is impossible to determine how prevalent HIV-negative AIDS cases are at present since existing data are inadequate. Five percent of AIDS patients tested for HIV do not demonstrate the presence of antibody or virus and only about 50 % of all AIDS patients in the United States have ever been tested for HIV antibody (CDC, 1989). Since the surveillance definition of AIDS does not require an HIV-positive antibody test, but only the presence of an opportunistic infection in the absence of certain defimed causes of immunosuppression (CDC, 1987), it is possible that a considerable number of HIV-negative AIDS cases exist and that many physicians assume HIV infection without adequate evidence. The existence of even a handful of such cases is, in any event, sufficient logically to doubt the necessity of HIV as a cause of AIDS.

It is therefore essential that the non-HIV immunosuppressive agents be reevaluated as possible cofactors for HIV or, in some combination, as possible causes of AIDS in the absence of HIV. We must, in other words, consider a multifactorial, synergistic aetiology for AIDS.

I have recently completed a literature review of non-HIV immunosuppressive factors associated with AIDS (Root-Bernstein, 1990b). I found that every AIDS patient has some subset of established immunosuppressive agents at work that include, but are not limited to: immunological contact with semen components (Mathur et al., 1981; Mavligit et al., 1984) ; recreational drugs such as the nitrites (Lotzova et al., 1984 ; Brambilla, 1985) ; addictive drugs such as the opiates and cocaine (Brown et al., 1974; Weber and Pert, 1989); multiple, concurrent infections with viruses, bacteria, amoeba, protozoa and/or fungi (Rouse and Horohov, 1986; Mella, 1967; Smith, 1985; Hartung et al., 1979); malnutrition dueto any of several causes including malabsorption syndrome associated with "gay bowel syndrome" (Yardley and Hendrix, 1980) ; the indirect results of drug addiction, anorexia and poverty (Chandra, 1983 ; Dowd and Heatley, 1984; Pifer et al., 1987); anaesthetics (Tsuda and Kahan, 1983); chronic antibiotic use (Munster et al., 1977; Pifer et al., 1987); blood transfusions (Salveteirra et al., 1980; Fischer et al., 1980; Thomas et al., 1983); and blood factor treatment (Bedall et al., 1985; Pollack et al., 1985; McPherson et al., 1986).

While none of these agents are sufficiently immunosuppressive in and of themselves (with the possible exceptions: massive blood transfusion, prolonged i.v. drug use and severe malnutrition) to account for the profound problems associated with AIDS, a combination of several of them acting synergistically would certainly be sufficient. Notably CMV infections (Oill et al., 1977; Carney et al., 1981), EBV infections (Weigle et al., 1983), mycobacterial infections (Beck et al., 1985; Shiratsuchi and Tsuyuguchi, 1984), blood transfusions (Kaplan et al., 1984), a combination of surgery with anaesthetics (Hole and Dakke, 1984), opiates (Donohoe et al., 1986; 1987) and malnutrition (Chandra et al., 1982) have each been demonstrated in the absence of HIV infection to cause the abnormal T4/T8 lymphocyte ratio and the diminished natural killer cell activity typical of AIDS patients. Since each of these agents occurs with high frequency (and often in various combinations with the others) in AIDS patients, the exclusive attribution of AIDS-related T-cell subset abnormalities to HIV is inaccurate. On the contrary, it is necessary to recognize that every AIDS patient has multiple, concurrent causes of immunosuppression in addition to, and sometimes in the absence of, HIV-infection (Root-Bernstein, 1990b).

Recognition of the importance of non-HIV immunosuppressive agents as aetiological agents in AIDS requires concomitant recognition that infection by HIV is not the only factor that distinguishes AIDS risk groups from non-risk groups. I have therefore predicted that in HIV-positive individuals development to full-blown AIDS will depend upon the number and intensity of non-HIV immunosuppressive agents also at work in that individual, and therefore that the rate of disease progression may vary from extremely fast (a few months) for those repeatedly exposed to intense, multiple immunosuppressive factors, to infinitely long (a lifetime) for those who incur none of the listed immunosuppressive agents. It is also probable that AIDS can be induced in HIV-negative individuals by a concordance of several of these non-HIV immunosuppressive agents or, alternatively, prevented in HIV-positive individuals by eliminating these factors or controlling their effects (Root-Bernstein, 1990b).

The recognition of immunosuppression by non-HIV factors in AIDS also requires rethinking of and researching into much of what we have taken for granted about AIDS. If some combination of such factors is sufficient to cause AIDS in the absence of HIV, then several conclusions follow. One is that AIDS should not be a new syndrome, since most of the immunosuppressive agents listed above are not, themselves, new. That prediction is, in fact, correct. Several dozen cases of Pneumocystis pneumonia, CMV infections and other opportunistic diseases in Western European and North American patients matching the CDC surveillance definition of AIDS have been reported by Huminer and his colleagues (1987; 1988) ; Katner and Pankey (1987) found 28 cases of KS between 1902 and 1978 satisfying the definition of AIDS; and I have recently reported the existence of several hundred further cases of KS dating back as far as Kaposi's first paper of 1872 that also satisfy the CDC surveillance definition of AIDS (Root-Bernstein, 1990c).

These are just the tip of an apparently unsuspected iceberg. Hundreds of cases of other opportunistic infections satisfying the CDC criteria also lie buried in the literature. Three diseases, progressive multifocal leukoencephalopathy (PML), disseminated cryptococcosis and disseminated CMV infection will sene to illustrate a phenomenon true of all the opportunistic diseases associated with AIDS.

Among the diseases indicative of AIDS in an otherwise healthy induvidual with no known cause of immunosuppression is PML (CDC, 1987). PML was first described in 1958 (Astrom et al., 1958). By 1970, some 50 cases of PML had been described (Fermaglich et al., 1970), of which five were previously healthy individuals (Astrom et al., 1958; Smith, 1959; Richardson, I961; Silverman and Rubinstein, 1965; Fermaglich et al., 1970), and two others were indìviduals whose predisposing diseases - hypersplenism (Weinstein et al., 1963) and tuberculosis (Hadington and Umiker, 1962) - are not usually associated with immune suppression. All 7 of these previously healthy cases were male. By 1976, about 50 more cases of PML had been reported (Matthews et al., 1976), of which at least 5 (Bolton and Rozdilsky, 1971; Weiner et al., 1972; Faris and Martinez, 1972; Knight et al.,1976; Rockwell et al., 1976) and possibly one more (Matthews et al., 1976) were AIDS-like, characterized by deficiencies in cellular immunity due to unknown causes. In one case, even cellular immunosuppression could not be demonstrated (Rockwell et al., 1976), which is a phenomenon that also typifies long-term survivors among HIV-negative homosexuals with KS (Friedman-Kein et al., 1990).

These data suggest that about 10 % of all PML cases would have qualified as AIDS cases prior to 1981. Unfortunately, no data appear to exist on he incidence of PML prior to this decade, so the number of possible AIDS-like cases cannot be determined. Interestingly, the incidence of PML does not appear to have increased with the recognition of AIDS. Between 1980 and the end of 1984 only 4 cases of AIDS-associated PML were reported (Moskowitz et al., 1984) - one per year on average - which is the same incidence as in the previous 15 years.

Extrapulmonary or disseminated cryptococcosis is another disease indicative of AIDS. Cryptococci were first isolated about a century ago, and the first patient to be identified with a disseminated form of the disease was diagnosed in 1894 (reviewed in Fitzpatrick and Poser, 1960). The first clinical case of cryptococcal meningitis was described in 1914 (Verse, 1914), and thereafter cryptococcal infections were found in virtually every organ in the body. Some of these cases are quite interesting in the retrospective light of AIDS: an 18-year-old male with prostatism caused by cryptococcus infection (Tillotson and Lerner, 1965); dozens of cases of cryptococcal hepatitis (e.g., Proknow et al., 1965; Sabesin et al., 1963); and a very large proportion of cryptococcal meningitis cases in which no predisposing disease was present. By 1955, some 300 cases of cryptococcal meningitis, mainly among men (ca. 80 %), had been reported in the medical literature (Rubin and Fucolovw, 1958). Published cases represent a small fraction of actual cases, however, since 151 fatal cases were reported to the National Office of Vital Statistics (United States) between 1949 and 1953 alone (Fitzpatrick and Poser, 1960). Approximately 80 % of these patients had central nervous system complications, and 10 % disseminated lesions involving skin and bone (Fitzpatrick and Poser, 1960). Between a quarter and a half of all patients with cryptococcal infections through the 1970s were also without underlying disease yet suffered from measurable defects in cell-mediated immunity (Diamond and Bennett, 1973; Graybill and Alford, 1974; Schimpf and Bennett, 1975; Butler et a1., 1964; Spickard et al., 1963; Diamond and Bennett, 1974). The number of disseminated cryptococcal infections in the absence of underlying disease or immunosuppressive treatment can only be approximated. Voluntary reporting attributed 788 deaths to cryptococcal meningitis between 1952 and 1963 in the US, or 66 per year (CDC, 1965). Cryptococcal meningitis cases, however, represent only about half of all disseminated cryptococcal infections (Duperval et al., 1977), so that the total number of disseminated cryptococcosis cases probably exceeded 120 per year during this period. If a quarter of these cases had no predisposing disease (see above), then it is probable that about 30 of these cases would have qualified as AIDS cases each year until 1963. All published reports agree that the incidence of cryptococcosis then increased at least ten-fold during the 1960s and '70s (Littman and Walter, 1968; Duperval et al.,1977), which would have created a large, apparently unrecognized base-line of well over 100 disseminated cases per year in otherwise healthy individuals prior to the recognition of AIDS. Notably, the geographical incidence of disseminated cryptococcal cases paralleled the subsequent geographical incidence of AIDS, centreing in New York City (Littman and Walter, 1968).

Several factors may have prevented the widespread recognition of these cases. Disseminated cryptococcosis presents significant diagnostic difficulties. In 1980, Bernad et al. (1980) reported that the classical India ink preparation method for identifying cryptococci was only 50 % accurate at most, and that even serological methods were far from optimal. Thus, they found six cases of cryptococcal meningitis (and one of herpes simplex encephalitis) that had been misdiagnosed at Massachusetts General Hospital between 1971 and I979. Notably, 3 of these patients, including the herpes simplex case, were men aged 20, 30 and 56 years old who presented without an associated medical condition and without prior immunosuppressive treatment. Each of these cases satisfies CDC requirements for a diagnosis of AIDS.

Similar tricky diagnostic problems spot the literature on cryptococcus including notable cases such as a young Frenchman with KS that was initially misdiagnosed as splenolymphatic lymphoma; his case was complicated by toxoplasmosis and a terminal crytpococcal infection that was diagnosed only at autopsy (Mongin et al., 979). Such cases suggest that many AIDS cases were similarly misdiagnosed or never diagnosed prior to 1981, and that part of the "epidemic" of the past decade has resulted from better diagnostic techniques, identification of risk groups, and increased awareness among physicians themselves of the opportunistic infections associated with AIDS. We tend to forget that knowledge, like disease, can also spread in an epidemic fashion and that the identification of any disease is always accompanied by an exponential increase in diagnoses, whether the disease is new or not. This statement can be verified simply by analysing the rate at which reports of cryptococcosis, Pneumocystis pneumonia, or KS, for instance, appear following their initial identification.

A similar history characterizes disseminated CMV infections. According to the CDC, CMV disease of an organ other than the liver, spleen, or lymph nodes in a patient greater than one month of age is diagnostic of AIDS (CDC, 1987). Cases of CMV matching these requirements exist in the medical literature since the disease was first identified in adults.

The first adult case of CMV was identified in a 36-year-old male by von Glahn and Pappenheimer in 1925. The patient had CMV inclusion bodies in the lungs, liver and colon; had no evidence of cancer; and had not been treated with antibiotics, chemotherapy, steroids, or blood transfusions (von Glahn and Pappenheimer, 1925). Between 1925 and 1962, 40 more cases of CMV were identified in adults, of which 15 fit the surveillance definition of AIDS (reviewed in Wong and Warner, table 1). Wong and Warner reported another 14 cases in 1962 from the University of Chicago Clinics and Hospitals, of which 3 cases are AIDS-like (Wong and Warner, table 2) and 4 more cases in 1964, of which 1 (case 1) was AIDS-like (Levine et al., 1964). Klemola et al. (1972) recognized 18 cases of CMV mononucleosis between 1965 and 1968 at the Aurora Hospital in Helsinki, Finland, of which 17 were in previously healthy adults, and one in a previously healthy 1-year-old girl who also developed CMV pneumonia. A further 14 cases in previously healthy adults occurred at the same hospital from 1969-1971, of which 2 developed CMV pneumonia (Klemola et al., 1972). In 1967, physicians at the same hospital established adult CMV disease as a cause of neuropathies - a frequent problem for AIDS patients - which led to the recognition of a large number of such cases in the succeeding decade (Ho, 1982; Lindboe et al., 1986). CMV infections have also been associated with known risk factors for AIDS. A New York City heroin addict was found to have acquired a CMV infection by sharing needles (Smolar et al., 1975), and a surgical patient developed a fatal, disseminated CMV infection following massive blood transfusion (Brownig et al., 1980).

Altogether, no less than 1 in 10 cases of adult CMV, and perhaps as high as 3 in 10, may have qualified as AIDS cases prior to 1979. Since the vast majority of cases of adult CMV infections were diagnosed at a handful of hospitals where CMV specialists resided, it is probable that the actual incidence of cases is far greater than existing reports indicate. A Mayo Clinic autopsy study performed in 1975 found that 44 of 502 (8.8 %) unselected autopsies yielded CMV isolates from lungs, pleural and bronchial tissues, and kidney. The majority of patients had been treated for various cancers and renal allograft rejection, but 13 of 296 patients (4.4 %) who had died of cardiovascular, cerebrovascular and pulmonary diseases also developed disseminated CMV infections (Smith et al.,1975). These data suggest that CMV infections were far more common than generally thought but were neither diagnosed pre- nor postmortem at the vast majority of hospitals. Although I have not reviewed the literature on childhood CMV infection here, the same general figures appear to apply to the incidence of AIDS-like infections in infants over the age of 1 month (reviewed in Kinney, 1942; Medearis, 1957).

It is important to note that, like KS, disseminated cryptococcosis, PML and disseminated CMV infections, my preliminary reviews of other AIDS-related opportunistic infections such as Pneumocystis pneumonia, chronic and oeosophageal candidiasis, disseminated tuberculosis and atypical mycobacterial infections, all show the same pattern of AIDS-like cases reported for as long as the disease has been described in the medical literature with increasing numbers of such cases during the two decades prior to 1980. It is also interesting to note that medical reports of almost all the opportunistic diseases associated with AIDS grow at an exponential rate from the time of their first observation until the recognition of AIDS. This observation suggests either that the rate of all opportunistic infections is increasing as quickly as AIDS itself ; that as we conquer other infectious diseases, opportunistic diseases become a more common problem; and/or that our diagnostic ability has increased continuously. Whatever the cause of this phenomenon, we must consider the possibility that at least part of the recognition of AIDS resulted from factors other than the emergence of a new disease agent. Certainly, a quite significant proportion of AIDS-like cases existed prior to the recognition of AIDS, and probably continue to contribute significantly to the current epidemic. This baseline of pre-existing AIDS-like cases must be taken into account in any future epidemiological study of AIDS, and cer-tainly makes all previous studies unreliable since all have assumed that AIDS did not exist as a significant problem prior to 1979.

The recognition of a significant number of pre-1979 AIDS-like cases creates other problems for our current understanding of AIDS. If HIV is a new and necessary cause of AIDS as most AIDS researchers argue, then there must be some other cause of these pre-1979 AIDS-like cases. If non-HIV im-munosuppressive agents are sufficient to cause AIDS, then there is no reason to think that these agents are not at work during the present epidemic just as they were in the past. On the other hand, HIV may not be a new disease agent. Increasing numbers of reports maintain that both HIV-I and HIV-2 were present in Western Europe and the Americas in the 1950s and '60s (Elvin-Lewis et al., 1973; Witte et al., 1984; Garry et al.,1988; Froland et al.,1988; Nahmias et al.,1986; Dufoort et al., 1988; Corbitt et al.,1990). But if HIV is not new, then why has AIDS emerged as a major medical problem only in the last decade? In either case, significant rethinking of AIDS aetiology and epidemiology is required. Either the transmission of endemic HIV, non-HIV immunosuppressive agents, or some combination of these with HIV, increased dramatically in the past two decades. And, indeed, huge increases in the incidence of multiple immunosuppressive risk factors associated with groups at high risk for AIDS are documentable.

Homosexual and bisexual men are at the highest risk of developing AIDS (CDC, 1989). Although no direct measure of homosexual activity exists for any period in history, indirect measures universally indicate recent and significant increases in both the frequency of sexual encounters among "gay" men and in specific forms of sex associated either directly or indirectly with immunosuppression. For example, Kinsey et al. reported in 1948 that most of the homosexual men they interviewed had gone for months or even years between sexual encounters (Kinsey et al.,1948). "Gay liberation" during the 1970s, however, was often accompanied by sexual liberation and promiscuity so that by 1980 many gay men were having sexual relations with several partners each week (Dritz, 1980). It is typical of homosexual AIDS patients to have had hundreds or thousands of sexual partners during the course of only a few years.

Promiscuity and unusual sexual practices led to measurable changes in the types and numbers of sexually transmitted diseases recorded by health officials. Studies of the prevelance of syphilis around 1960 demonstrated that in Los Angeles and Vancouver at least 70 % of cases among men were associated with male homo- or bisexual activity (Larson, 1959; Tarr and Lugar, 1960). When the rate of syphilis among white males in the United States increased by 311 % between 1967 and 1979, it was found to be due mainly to increased homosexual activity (Fichtner et al., 1983). Cases of gonorrhoea increased from 259,000 in 1960, to 600,000 in 1970, to over 1,000,000 in 1980 (CDC, 1981), also in a large part due to increased homosexual activity.

The number of HBV cases also increased dramatically, from 1,500 cases in 1966 to 8,300 in 1970 to 19,000 in 1980 and 25,000 in 1987 (CDC, 1981; CDC, 1989b). Although some of this increase is undoubtedly due to intravenous drug use, many AIDS patients have both homosexuality and drug abuse as risks, and evidence suggests that the increase is mainly due to disease spread among homosexual and bisexual men (Szmuness et al., 1975). For example, over 60 % of 3,816 homosexual men examined in 5 US cities had immunological or other evidence of HBV infection in 1979 (Schreeder et al.,1982) although the rate among heterosexuals was less than 10 %. The rate of seropositivity was directly related to duration of homosexual activity, number of non-steady sexual partners and to the practices of receptive anal intercourse and other types of sexual activity, such as fitsting, that caused trauma to the rectal mucosa (Szmuness et al, 1975; Schreeder et al., 1982). A similar increase in hepatitis A during the same period was also noted among homosexual men, but in no other part of the population (Corey and Holmes, 1980).

Practices associated with disease transmission or with increased risk of unusual infections and complications also began to be noticed by clinicians during the 1960s and early 1970s. Fisting was first described in the medical literature during the 1970s as a sexual practice leading to frequent medical sequelae, and medical experience and surveys by Sohn, et al. (1977) strongly suggested that this practice was an essentially new and rapidly proliferating activity exclusive to the gay community (see also Weinstein et al., 1981). The sale of inhalation nitrites among the gay community was also documented to have increased dramatically during the same period (Goedert, 1984), and since one of the major uses of such drugs among gay men is to facilitate anal intercourse and fisting (Newell et al., 1985), it is probable that the two practices evolved together.

Newell et al. (1985) have reviewed the various sources indicating that nitrite was virtually unknown among gay men as of 1960 and became nearly synonymous with gay life in various cities by the mid-1970s, approaching an estimated rate of 80 % incidence in the male homosexual community as a whole. They also summarize relevant data concerning the social spread of nitrite use since the non-prescription commercial availability in 1960 of amyl nitrite, its prescription limitation in 1969 followed by the commercialization of butyl and isobutyl nitrites in 1970, and the beginning of the "popper craze" - mainly among gay men - in the mid-1970s. Several studies have argued that nitrite use is correlated with the incidence of KS in gay men (Goedert, 1984; Newell et al., 1985; Jaffe et al., 1983; Marmor et al., 1982; Haverkos et al., 1985).

Forms of masochistic and traumatic sex other than fisting, popularized by the Eulenspiegel Society and Hellfire Clubs, also appear to have become more popular during the last two decades (Marotta, 1981). A 1980 study documented significantly higher rates of anal intercourse, fisting, and oral-genital contact among homosexual men in cities such as San Francisco and Los Angeles that have high rates of AIDS than in cities in which AIDS is rare, such as Denver and St. Louis (Corey and Holmes, 1980).

The first medical report of proctological lesions associated with homosexual activity came from a physician in New York City in 1964 who noted that among 18 avowedly homosexual patients, he had observed 4 instances of anal ulceration associated with trauma; 5 instances of granulomatous anorectal lesions; 5 instances of non-specific anorectal lesions; and 5 cases of perianal condyloma acuminata (Marino, 1964). He described these symptoms as very unusual. A decade later, such symptoms were no longer surprising. Of 260 gay men, comprising 10 % of a private proctological practice in New York City in 1976, 134 patients had condyloma acuminata, 43 haemorrhoids, 31 non-specific proctitis, 30 anal fistulas,18 perirectal abscesses, 18 anal fissures, 17 amoebiasis,16 pruritis ani and 7 "tauma and foreign bodies" (Kazal et al., 1976). It is now accepted that such injuries and infections greatly increase the risk of concurrent infections (HIV or otherwise) and of semen gaining access to the immune system following anal intercourse.

Other diseases such as amoebiasis, shigellosis and giardiasis, that are are now known to be associated with anal intercourse and anal-oral contact were first observed to be sexually transmitted during the past two decades as a result of their unusual occurance among gay men. The increasing prevalence of these diseases among male homosexuals therefore provides an indirect measure of the increasing frequency of sexual contacts among the gay community during the 1970s. All of these diseases were relatively rare in the US and England prior to the 1970s and outbreaks were almost alyways associated with faecal contamination and poor public hygiene (Mildvan et al., 1977). This picture changed dramatically in the aftermath of "gay liberation".

Cases of amoebiasis reported to the CDC, for example, rose from a relatively constant level of less than 2,500 prior to 1972 to more than 7,300 in 1982 (an increase of 320 %) (CDC, 1989b). Almost all of the new cases were among men, most of whom were identified as gay. Schmerin and his colleagues at The New York Hospital, for example, reported that amoebiasis was identified in the stools of 98 patients between 1971 and 1976. All of the 42 women for whom information existed acquired the disease from travel outside the US or were immunodeficient. Fifty-six patients were male. Thirty of these male patients had contracted the disease while visiting endemic areas outside the US. No information was available for 6 male patients. The remaining 20 male patients were all homosexuals who had not travelled outside of the New York. Metropolitan area. There were no cases of non-traveller amoebiasis in 1971 in their sample and the number grew yearly therafter. Almost half of these patients also had either concomitant shigellosis, giardiasis, syphilis, gonorrhoea, and/or hepatitis or a history of these diseases (Schmerin et al., 1977). By 1977, physicians recognized that the presence of any enteric pathogen in a man who had not travelled out of the country was likely to have resulted from homosexual activity (Vaisrub, 1977).

These results confirmed previous studies by Most and Kean that the Manhattan homosexual community had begun to display the unusual disease profile typical of "a tropical isle" or third-world country beginning about 1968 (Most, 1968; Kean, 1976). Nearly 60 % of all cases of shigellosis in the New York metropolitan area were among gay men by 1976 (Drusin et al., I976) and an epidemic of the disease was noted in the gay community in San Francisco in 1974 (Dritz and Bach, 1974). Schmerin et al. similarly found that nearly 90 % of giardiasis cases among non-travellers living in New York were avowvedly homosexual in 1977 (Schmerin et al., 1977).

All of these reports are only a fraction of published and private observations by "physicians with homosexual male patients in New York City, San Francisco, and Boston [who] have also noted a marked increase in enteric protozoal infections occurring in those who practice analingus" (Mildvan et al., 1977). Much the same picture began to emerge in Great Britain at the same time (Kacker, 1973; Meyers et al.,1977). Not surprisingly, the recogni-tion of an epidemic of lymphadenopathy in gay men has also been traced back into the decade prior to the recognition of AIDS, but went unnoticed at the time (Miller et al., 1984).

These data strongly suggest that the gay liberation movement resulted in a great increase in promiscuity among gay men as well as significant changes in sexual practices that made rectal trauma, immunological contact with semen, use of recreational drugs and the transmission of many viral, amoebal, fungal and bacterial infections much more common than in the decades prior to 1970 (Sonnabend et al., 1984; Sonnabend, 1989). Promiscuity, engaging in receptive anal intercourse and fisting are the 3 highest risk factors associated with AIDS among gay men (Marmor et al., 1982; Darrow et al., 1987). Each of these risk factors is correlated with immunosuppression (Root-Bernstein, 1990; Sonnabend et al.,1984; Sonnabend, 1989), as are the other aspects of the gay lifestyle.

These data concerning medical problems associated with male homosexuality therefore strongly suggest that recent changes in lifestyle played a major role in vastly enlarging the homo- and bisexual male population at risk for developing immunosuppression, whether it resulted from transmitting HIV infections combined with other immunosuppressive agents, or from some combination of the non-HIV agents alone.

Thus, I maintain that AIDS is almost undoubtedly a very old disease among gay men, but that it is only recently, especially in Western nations, that newly-evolved gay sexual and drug practices spawned an environment in which the microbiological and immunological manifestations of these activities became widespread enough to affect a significant proportion of gay men and to be correlated with the underlying causes. We must also recognize that the willingness of gay men to identify themselves as such was crucial evidence in recog-nizing AIDS, evidence that was not available prior to gay liberation.

Intravenous drug abuse is also recognized as conferring a high risk of AIDS (CDC, 1989). Unfortunately; data on i.v. drug use seems to be nearly as difficult to obtain as that on homosexual behaviour. However, virtually all measures of opiate-related drug abuse indicate an escalating problem during the past three decades. In England, the number of registered heroin addicts rose from 10 in 1960 to 509 in 1966 (Bewley et al., 1968) and grew exponentially thereafter. Similarly, the Bureau of Narcotics of the United States Government reported that the total number of registered heroin addicts increased from 45,000 in 1960 to 68,000 in 1970 to 99,000 in 1973 (an increase of 120 %) (Golenpaul, 1975). Estimates of the actual number of addicts in the US in 1973 were between 300,000 and 500,000 (Golenpaul, 1975). About half of these addicts were to be found in New York City; other urban centres associated with AIDS, such as Los Angeles and San Francisco, were also among the cities reporting the most addicts (Hansen, 1964-1979) .

The number of arrests for breaking narcotic drug laws shows an even larger increase than that among registered drug addicts : 29,000 arrests in 1962; 100,000 in 1967; 190,000 in 1969; 400,000 in 1971; and 530,000 in 1977 (Hansen,1964-1979). The breakdown of figures by sex and race roughly mirrors AIDS risk among i.v. drug abusers: 6 times as many men as women were arrested for breaking narcotics laws; and almost equal numbers of whites and minorities.

A similar epidemic of i.v. drug abuse is also evident from the federal government's Drug Abuse Warning Network (DAWN). DAWN data indicates that in virtually every major city in the US, heroin overdoses seen at hospital emergency rooms quadrupled between 1976 and 1985 (USDHHS,1985). The use of cocaine, which may also be taken intravenously, increased nearly a 1,000 % in all major cities (USDHHS, 1985), and serum hepatitis cases, an indirect measure of i.v. drug abuse, tripled during the same period (CDC, 1981; CDC, 1989b). The medical literature also reflects these trends with a spate of arti-cles beginning in the late 1960s concerning the epidemic of heroin addiction that physicians began to encounter on a regular basis (e.g. Bewley et al., 1968; Dole, 1973).

Again, as is the case with gay men, the medical literature reflects the growing problem of drug abuse with the recognition of unusual immunologic and infectious complications in abusers. The high mortality and vastly decreased longevity of opiate addicts was studied (Bewley et al., 1968; Louria et al., 1967; Cherubin, 1967). Severe systemic infections with Gram-negative bacteria, Candida and other opportunistic organisms began to be reported (Hussey and Katz, 1950; Briggs et al., 1966; 1967; Cherubin, 1967 ; Cherubin and Brown, 1968; Louria et al., 1967).

Disseminated tuberculosis (another diagnostic indicator of AIDS) was identified as a major complication of drug addiction in 1973 (Firooznia et al., 1973) at the same time that lymphadenopathy was recognized as a common and often misdiagnosed problem in drug abusers (Sapira, 1968; Geller, 1973; Miller et al., 1984), and concomitant immunological dysfunction was identified in such patients (Brown, 1974). Malnutrition was recognized as an immunosuppressive risk associated with intravenous i.v. drug abuse by 1976 (Gambara and Clarke, 1976; Aylett, 1978; Nakah et al , 1979). The inversion of T-cell subsets accompanying opiate use had been identified by 1980 (McDonough et al., 1980).

These data provide a strong basis for concluding that acquired immunodeficiencies are not new among those groups at highest risk for AIDS; that non-HIV immunosuppressive agents play a significant role in debilitating individuals in these high-risk groups; and that behaviour associated with the spread of these non-HIV immunosuppressive factors proliferated at an alarming rate prior to and concomitant with the recognition of AIDS. A number of important questions are raised by these facts.

First, what is the role of HIV in AIDS? Current data do not permit an unambiguous answer to this question. HIV may be a necessary cause of AIDS, but the number and potency of non-HIV immunosuppressive agents may determine the rate at which AIDS develops. HIV may be a frequent but unnecessary agent that contributes to the immunosuppression that characterizes AIDS, but HIV may not be capable of initiating or causing AIDS on its own. Or HIV may simply be a common opportunistic organism, like so many others associated with AIDS, that serves as a highly selective marker for significant prior immune deficiency having other causes (Rubin, 1988). Each of these possibilities leads to very different and quite novel reinterpretations of AIDS aetiology and epidemiology.

If HIV is a necessary cause of AIDS, and a significant number of AIDS-like cases predate 1979 by a century or more, then HIV must be a far older infection than is generally recognized. If so, then HIV has been endemic in Western Europe and the Americas for some time, a point argued recently by Duesberg (in press) based upon a review of various epidemiological data.

There is, of course, no direct evidence for HIV infection in most AIDS-like cases prior to 1979, and for obvious reasons, there is not likely to be. Lack of evidence should not, hoywever, be interpreted as meaning that the opposite is true (i.e. that HIV must be new), but simply that some types of data are not, for historical reasons, available to us. The few documented cases of HIV infections prior to 1979 become all the more important in consequence. Assuming then that HIV is indeed an old infection, it follows that the sudden growth of AIDS cases during the past decade must be due to a combination of new forms of transmission of HIV, rather than the newness of HIV itself. The data reviewed here concerning changes in gay sexual and recreational drug habits and the separate but concurrent epidemic of i.v. drug abuse certainly demonstrates that unusual forms of transmission did grow tremendously in tandem with the recognition of AIDS. To what extent advances in diagnosis, definition of risk groups and dissemination of this information to physicians added to the numbers of patients recognized must, unfortunately, remain in the realms of conjecture.

The difficulty in maintaining that HIV is a necessary cause of AIDS is that the same modes of transmission that may have disseminated HIV - anal intercourse, fisting, i.v. drug abuse and contact with blood and blood factors - are known to be immunosuppressive in themselves and can also transmit other immunosuppressive agents such as CMV and HBV. Thus, it is impossible to maintain that any individual in a high-risk AIDS group was infected only by HIV and had no other immunosuppressive factors at work concurrently.

Indeed, in light of the fact that after more than a decade, AIDS continues to be associated almost completely with high-risk groups (CDC, 1990), it is highly improbable that AIDS is caused by a single, transmissible agent, and highly probable that non-HIV immunosuppressive factors act either synergistically with each other or with HIV to cause AIDS. I therefore predict that AIDS will have a signifiicant impact only on groups of people who have identifiable causes of immune suppression other than HIV. Among non-i.v.-drug-abusing heterosexuals contracting AIDS, it will therefore be necessary to study whether other risk factors such as anal intercourse, recreational drug abuse, malnutrition, anorexia and related factors are significant in the development of the disease.

The most important implication of a synergistic aetiology for AIDS is that contracting an HIV infection is not, in and of itself, predictive of developing AIDS. To some extent, this conclusion is already recognized: it is well established that AIDS may develop within months of an HIV infection in some patients while others are healthy decades later (Peterman et al., 1988; Dufoort et al., 1988). This wide variability can easily be explained either if HIV requires cofactors for its activation, or if HIV is itself opportunistic and is therefore active only in previously or concurrently immunosuppressed individuals. Certainly HIV is very difficult to transmit compared with other viruses such as HBV or EBV, and this fact argues strongly in favour of the necessity of cofactors. This fact may also explain why only individuals who have multi-ple non-HIV causes of immunosuppression actively express the retrovirus following infection. If these observations are admitted, however, it must be further admitted that HIV may not be a necessary cause of acquired immune deficiency, but may act only to exacerbate or opportunistically mark a preexisting deficiency.

Now, whatever form the synergistic theory of AIDS aetiology takes, it necessitates a re-evaluation of whether AIDS is transmissible. The current dogma is that AIDS is transmissible because HIV is a sufficient cause of the syndrome. Duesberg, on the other hand, argues that AIDS is not transmissible because HIV is irrelevant to the understanding of AIDS. AIDS, he claims, is due to drug abuse and gay male sexual practices. But when the full range of non-HIV immunosuppressive factors are included in the aetiology of AIDS, neither extreme seems tenable. HIV itself is, of course, transmissible, as are other immunosuppressive factors associated with AIDS, such as CMV, EBV , HBV, mycoplasmas, the sexually transmitted diseases and the infections associated with the "gay bowel syndrome". We do not know whether a sufficient combination of these factors can act synergistically to cause AIDS. They may, and research is needed to confirm this hypothesis.

If they can cause AIDS, either in the presence or absence of HIV, then AIDS could be transmissible. But many non-HIV immunosuppressive factors are not transmissible: blood transfusions, blood-derived factor exposure, i.v. and recreational drug use, malnutrition and semen-induced autoimmunity, for example. Again, we do not know whether combinations of these agents in and of themselves or in combination with HIV are sufficient to cause AIDS. If they are, then AIDS is not, in the strictest sense of the word, transmissible.

In short, the multifactorial, synergistic aetiology of AIDS that I am proposing here predicts that there are many ways of acquiring secondary immunodeficiencies, and that all of these may be manifested in what we now call AIDS. Clearly, if we are to be able to predict who is going to get AIDS, if we are to devise public health policies to control AIDS, and if we are to devise strategies to prevent or cure AIDS, it is imperative that we find out whether HIV is necessary to cause AIDS or whether non-HIV immunosuppressive agents are sufficient. Even if only 5 % of AIDS patients are truly HIV-negative, as current data suggest, and even if we decide to recategorize these patients as suffering from some form of acquired immunosuppression other than AIDS (as some investigators are now urging) the fact remains that these people develop many or all of the same symptoms as AIDS patients, and it is just as important to discover the cause or causes of their problems as it is of those who have an HIV infection. What we cannot afford - in terms of human lives or misdirected research - is to ignore the exceptions to the HIV dogma. These exceptions tell us that we do not yet grasp the whole story of AIDS. We must be willing to research and rethink.

Many things must be researched and rethought in light of the role of non-HIV factors in AIDS. Epidemiological predictions based on AIDS being a new disease must be recalculated to account for a significant baseline of AIDS cases and HIV infections prior to 1979. Accounting for these factors may very well explain why the number of AIDS cases have not grown at nearly the rate predicted by early models of the syndrome. Certainly, models predicting the transmission of AIDS by a single infectious agent must be reworked to account for both infectious and non-infectious immunosuppressive cofactors. Treatments for AIDS must expand to include not only anti-retrovirus therapies, but therapies for all of the non-HIV factors as well (Papadopulos-Eleopulus, 1988). Indeed, we must recognize that anti-retrovirus therapies, some of which are themselves immunosuppressive, may actually harm patients rather than help them, particularly if HIV is itself opportunistic rather than causative, or if the patient is HIV-negative. Public health policies must expand to address the modes of transmission of both HIV and non-HIV immunosuppressive factors, the factors that are not transmissible and the behaviour patterns (whether sexual, drug-related, nutritional, or medical) that are associated with the epidemic growth of immunosuppressive factors in high-risk groups. If the multifactorial synergistic theory of AIDS summarized here is correct, we will not control AIDS until this rethinking and reacting is accomplished.

To summarize, I neither believe, as do Gallo and his colleagues, that HIV is sufficient to explain AIDS, nor do I accept Duesberg's claim that HIV is totally irrelevant to understanding AIDS, (Duesberg,1988; 1989; 1990). HIV clearly plays some role in AIDS; but so do other infectious agents such as CMV, EBV, HBV and mycoplasmas that are equally prevalent among AIDS patients; and so do non-transmissible and profoundly immunosuppressive agents such as semen, blood, drugs and malnutrition.

One final point is also worth consideration. The recognition that non-HIV immunosuppressive factors play a causative role in AIDS, far from undermining current public health attempts to control AIDS through "safe sex" and control of drug use, suggests that current HIV-based measures are not working because they are too narrow.

For example, providing clean needles to addicts does not obviate the immunosuppressive effects of opiate abuse, its frequent concomitant malnutrition, or the prostitution which is often used to pay for the illicit drugs. Gay men need to know that even "safe sex" measures will not protect them from the immunosuppressive effects of recreational drugs, antibiotic abuse, rectal damage following anal intercourse, fisting and anal masturbation, malnutrition following gay bowel syndrome, or from infections contracted by anal-oral contact.

Heterosexuals need to realize that a combination of recreational drug abuse, poor eating habits, bulimia or anorexia, and promiscuous anal intercourse (Lorian, 1988) can be profoundly immunosuppressive, whether they become infected with HIV or not.

Physicians also need to become more aware of the immunosuppressive risks of some of the common procedures they use such as blood transfusions, factor therapies and long-term antibiotic use.

Acquired immunosuppression is, in short, a much more multifarious and complicated affair than the current views of AIDS admit and our research and public policies must be altered to recognize this fact.

• AIDS = acquired immune deficiency syndrome.

• HIV = human immunodeficiency v.irus.

• CMV = cytomegalovirus.

• KS = Kaposi's sarcoma.

• EBV = Epstein-Barr virus.

• PML = progressive multifocal leukorocephalopathy.

• HBV = hepatitis B virus.

• HCV = hepatitis C virus.

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