VIRUSMYTH HOMEPAGE

EOS - J. Immunol. Immunopharmacol. Vol. XII, n. 4, 1992

HIV and Immunosuppressive Cofactors in AIDS

R.S. Root­Bernstein
Department of Physiology, Michigan State University, East Lansing, MI, USA

INTRODUCTlON

Susceptibility to infection is as important to disease acquisition as is the causative agent. During the 1880s, Pasteur himself considered the "terrain" as important as the germ (1), and Koch noted that alcoholics were much more susceptible to cholera than anyone else (2). More recently, Evans has suggested that as yet unidentified, "clinical illness promotion factors" may be required to understand why some people infected with certain microbes (including HIV) become ill when others do not (3, 4). Unfortunately, this principle of differential susceptibility to disease has largely been ignored in AIDS despite the fact that AIDS may develop at any time between a few months to decades (or perhaps not at all) following HIV infection (4­6), and despite the fact that all identified risk factors for AIDS convey risk not only of exposure to HIV, but to a multitude of other infectious and noninfectious immunosuppressive agents that may predispose for AIDS or even cause it (7­12). The presence of these other agents suggests that AIDS is much more complicated than a mere HIV infection and that its control may require more than vaccines or pharmacological agents directed at HIV (7­ 12).

IMMUNOSUPPRESSIVE FACTORS ASSOCIATED WITH AIDS RISK GROUPS

Identified risk factors for homosexual men include repeated receptive anal intercourse, promiscuity, frequent use of inhalant nitrites, and infections with cytomegalovirus and hepatitis viruses (13­15). Receptive anal intercourse exposes people to semen antigens, which can be immunosuppressive (16­19), and give rise to antibodies cross­reactive with T­cells (20). Indeed, sperm contains multiple proteins with CD4­1ike homologies that may induce an autoimmune response against T­helper lymphocytes and macrophages. (Root­Bernstein and Hobbs, submitted) Semen also contains a high proportion of lymphocytes that may induce crossreactive allogeneic immune responses (21). Promiscuity increases the frequency and range of allogenic exposure and the probability of contracting all sexually transmitted diseases, including syphilis, gonorrhea, chlamydia, adenoviruses, cytomegalovirus (CMV) Epstein­Barr virus (EBV), hepatitis B virus (HBV), and human T­cell lymphotropic viruses (HTLVs).

Active or chronic infections with the viruses just listed are extremely rare in heterosexuals, but very common in homosexual men (22­24). CMV, EBV, HBV, and HTLVs are each, independently immune suppressive (Table 1); (25) each can cause an inversion of the T­helper/T­suppressor lymphocyte ratio (25); and each can trans­activate HIV or cause pseudoviron formation extending its range of cellular infectivity (26­29). These viruses also act synergistically with HIV to increase progression to AIDS and death among HIV­infected homosexual men (30­33). Illicit use of "street", drugs (including amphetamines, barbiturates, methaqualone, cocaine, LSD, marijuana, and alcohol), often in various combinations, is common in homosexual men, especially those who develop AIDS (34, 35). Most of these drugs depress immune function (36). Particularly noteworthy is unusually prolonged or high­dose exposure to inhalant nitrites, which also cause thymus degeneration and T­ cell suppression (37), and which are extremely carcinogenic when mixed with most antibiotics (38). Parasitic infections, especially of the intestines, are also extremely frequent in promiscuous gay men, causing what is often known as ,"gay bowel syndrome" ­ a complex of amoebal, protozoal, and fungal infections. Most antiparasitic drugs are immune suppressive (36). As a result of these multiple immunosuppressive risks, many HIV­negative homosexual men are as immune suppressed as HIV­positive, asymptomatic individuals (23, 30, 35, 39­42). Prolonged exposure to a sufficient combination of these factors may induce AIDS in the absence of HIV infection, since dozens of HIV­negative homosexuals have developed AIDS­associated opportunistic disease (43­48).

Table 1

Summary of AIDS-associated infectious agents known to replicate within macrophages and lymphocytes
Agent	Monocytes/ Macrophages	T Cells	B Cells	Low or inverted T4/T8	Transactivates HIV	HIV pseudo- virons
Adenoviruses	-	+	+	+	?	?
Cytomegalovirus	+	-	+	+	+	+
Epstein-Barr Virus	-	-	+	+	-	+
Hepatitis B Virus	-	+	+	+	+	?
Herpes Simplex Viruses	+	+	+	-	+	+
HIV	+	+	-	+
HTLV I & II	+	+	+	-	+	+
Mycobacteria	+	-	-	-	-	-
Toxoplasma Gondii	+	-	-	-	-	-
Varicella-Zoster Virus	+	?	?	-	-	?
(Adapted from reference 25-29 and 143)

AIDS risk factors of intravenous drug abusers include their addictive drugs, antibiotic abuse, multiple concurrent infections, and malnutrition. Heroin and morphine both cause cellmediated immune suppression resulting in inversion of the T4/T8 lymphocyte ratio (36, 49­50). Cocaine also induces immune dysregulation, particularly stimulating nonspecific B cell proliferation. At high doses, it also produces T cell immunosuppression (36, 50­52). Both morphine (53) and cocaine (54) stimulate HIV replication and cell­infection in vitro and may do the same for other latent viruses. Like homosexual men, most i.v. drug abusers use many other immune depressing drugs as well (55­56), and they have an unusual frequency of multiple, concurrent infections, including immunosuppressive viruses such as HBV, CMV, and HTLV, as well as Mycobacteria, Staphylococci, Candida, E. cold and Psseuodomonas aeruginosa (57­59). In the U.S., at least 60 percent of i.v. drug addicts buy illicit antibiotics along with their addictive drug, presumably as prophylaxis against their high rates of infections (60­61). Ironically, high doses of antibiotics and their chronic use are well­established causes of cell­mediated immune suppression (36, 62­63). So is malnutrition, which can result in lymphopenia and inverted T4/T8 ratios (64). Many drug addicts are chronically, and sometimes severely, malnourished (65­67). As a result, many HIVseronegative i.v. drug abusers (68­70) and their infants (71­72) display the same T­cell depletion and T4/T8 inversion that typifies asymptomatic HIV­infected patients.

The risks of hemophiliacs and blood transfusion patients include herpes and hepatitis virus infections, blood and concentrated blood factors, opiate pain relievers, steroids and anaesthetics. Blood transfusions themselves induce severe cell­mediated immune suppression (73­77), which is dose related. Both Factor VIII and Factor XI are also associated with cell­mediated immune suppression, particularly in high or frequent doses (78­81). Blood transfusions and factor therapy may transmit immunosuppressive viruses including EBV, CMV, hepatitis viruses, and HIV (82­85). Hemophiliacs suffering from bleeding in their joints and some surgery patients receive anaesthetics, opiate pain relievers, and steroids (or other anti­inflammatories) as part of their therapy. All of these cause cell­mediated immune suppression (36). Many hemophiliacs develop immune suppression equivalent in magnitude with that seen in HIV­seropositive patients in the absence of HIV infections (73­81). A significant number of AlDS­like cases (associated with disseminated candidiasis, Kaposi,s sarcoma, and pneumonias) were apparent more than a decade prior to the first documented instance of HIV in a hemophiliac (86­87) and more recently in HIV­seronegative hemophiliacs (88).

All AIDS patients also have one or more forms of autoimmune processes, including antibodies directed at T cells. According to Nature editor John Maddox, recent research in this area threatens to turn ,"AIDS research . . . upside down" (89). Lymphocytotoxic antibodies (LCTAs) occur in nearly all AIDS patients, many HIV­positive and HIV­negative homosexual men (90­99), most intravenous drug abusers (96, 97, 100), hemophiliacs (101 ­103), and many poly­transfused patients (104­109), but in no risk­free heterosexuals tested in any of these studies. The targets of the LCTAs are primarily T helper cells, macrophages and monocytes bearing CD4 and CD7 proteins, but can also include MHC class II and class I proteins (especially among drug addicts) and other T cell markers as well. (110­115) LCTAs have also been found associated with infectious disease agents such as cytomegalovirus (115, 116) and malaria (117) in non­AIDS settings. Given the prevalence of these disease agents among AIDS patients, these microbes may play a role in AIDS. The presence of LCTAs is correlated with clinically relevant immune suppression and a poor prognosis among HIV­positive individuals. (110­115) The importance of these LCTAs is further underscored by the fact that HIV­infected people who remain clinically healthy lack LCTAs (119, 120). HIV infection, in other words, does not invariably lead to autoimmunity, but autoimmunity almost invariable signals onset of AIDS. Thus, although some investigators have hypothesized that HIV is responsible for initiating autoimmune reactions against T cells (98, 121­123), strong evidence now exists that allogeneic stimuli, such as sperm (18, 20, 111 ­113) lymphocytes (124­126), and non­HIV infectious agents (127) may play a primary role in the induction of LCTAs.

CONTROLLING AIDS THROUGH NON­HIV PROPHYLAXIS

Fig. 1 - Caption: A synergistic, multifactorial model of AIDS (based on references 7-11)

To summarize, all people who develop AIDS have some subset of multiple, concurrent immunosuppressive factors at work on them (Fig. 1). The immune suppression that predisposes AIDS patients to opportunistic infections cannot, therefore, be attributed solely to HIV. On the contrary, the presence of multiple immunosuppressive factors in all groups at high risk for AIDS must be taken into account in any explanation of who becomes infected with HIV and how quickly AIDS subsequently develops. This conclusion forces us to revaluate the role of HIV in AIDS. First, HIV appears to be a latent retrovirus with no more immunocompromising activity than, say, CMV or EBV in a healthy individual (128). It is possible, therefore, that HIV is essentially an opportunistic infection having pathological consequences only for people who are concurrently or subsequently immunosuppressed, or it is activated by an appropriate, synergistic cofactor. (7, 8, 10) (Table 2) If so, then it must be concluded that HIV is not a sufficient, and may not even be a necessary, cause of acquired immune deficiency. It follows that eliminating non­HIV immunosuppressive factors from a patient at risk for AIDS should be as effective a way to treat AIDS as attempting to control their retroviral infection (7­11, 129, 130).

Table 2

Identified cofactors for HIV
	In vitro Evidence	Refs.	Epidemiological Evidence	Refs.
Viruses
Adenovirus	+	147
Cytomegalovirus	+	27, 147, 156	+	23, 40, 84, 1, 48
Epstein-Barr Virus	+	28, 155	+	157, 158
Hepatitis Viruses	+	147	+	149
Herpes Simplex 2	+	50, 156	+	150
Herpes Simplex 6	+	151
HTLV I	+	29, 152	+	30, 31
Bacteria
Mycoplasmas	+	140-142, 154
Mycobacteria			+	57, 127
Drugs
Opiates	+	53, 153	+	57, 131, 132
Cocaine	+	54	+	131, 132
Inhalant Nitrites			+	15

Some data support this prediction. Studies of intravenous drug abusers in both Italy (131) and Switzerland (132) indicate that reversal of longstanding malnutrition, prophylaxis against sexually transmitted diseases, and total withdrawal from drug use greatly slows or even prevents the development of AIDS among HIV­seropositive addicts. Furthermore, anecdotal evidence from longterm survivors of AIDS (that is, those remaining alive three or more years beyond diagnosis with full­blown AIDS) also indicates that few have been treated for HIV, but all have modified their sexual, drug" and nutritional habits to eliminate recognized immunosuppressive risks (133). Similarly, the voluntary adoption of safe sex practices by the homosexual community may be responsible for the latency between HIV infection and overt AIDS lengthening from a mere two years in 1984 to over ten today (23, 134­136). The necessity of cofactors in AIDS may also explain why various drugs that do not affect retroviruses, such as the anti­herpes drugs Foscarnet and Gancyclovir (137), prophylactic Bactrim or Pentamidine (138), and various prophylactic vaccinations, including hepatitis B and BCG (anti­tuberculosis) (139), have demonstrated effect in lowering AIDS risk and prolonging the life span of HIV­seropositive individuals. If Montagnier and Lo are correct in identifying various MycopIasma spp. as important or even necessary cofactors in AIDS (128, 140­143), then vaccines or drugs effective against these bacteria are also required.

PUBLIC HEALTH AND BIOMEDlCAL RESEARCH IMPLlCATIONS

The recognition of non­HIV risk factors in AIDS has implications both for public health policy and biomedical research whether HIV is a necessary agent or not. First, some heterosexuals may have the same immunosuppressive risks as other identified groups. Drug use need not be i.v. to be immunosuppressive. Thus, physicians exposed to HIV subcutaneously, while independently exposed to inhalant anaesthetics in the operating room, or who indulge in non­i. v. drugs recreationally may create the same end result as i.v. drug users exposed to HIV through the sharing of needles. Anorexia, bulemia, and anemia may all be signs of malnutrition decreasing resistance to AlDS­associated infections. As many as 10 percent of women engage regularly in anal intercourse (144­146) and may incurr some or all of the same risks of some homosexual men. Multiple, concurrent infections may result from heterosexual promiscuity or, rarely, by mere chance. Inherently immunosuppressive diseases such as diabetes may also increase AIDS risk. Blood transfusions and multiple surgeries may promote opportunistic infection even in the absence of HIV, or create susceptibility to the virus.

The public policy implication is that "safer sex" and "clean needle" approaches to AIDS, while necessary, are insufficient. Prophylaxis against non­HIV infectious agents is necessary. All drug use must be curtailed. Malnutrition must be identified and corrected. The immunosuppressive risks of blood transfusions, factor concentrate, many therapeutic drugs" and anaesthetics must be recognized and controlled or corrected. AIDS prophylaxis and treatment must therefore expand well beyond HIV, and physicians must take more than just a sexual, drug, and HIV history of a patient in order to evaluate them for immunosuppressive risks and susceptibility to AIDS. Vitamin and mineral profiles, tests for autoimmune conditions, and antibody profiles of current and past infections need to become regular aspects of evaluation. Prophylaxis against mycobacteria (BCG vaccine), hepatitis, and herpes viruses (experimental vaccines exist) should be instituted for anyone at risk of contracting HIV. Those already infected should be treated with Bactrim or other anti­Pneumocystis agents, put on anti­herpes virus medication where appropriate, and protected against sexually transmitted diseases. Plasmapheresis or other non­immunosuppressive approaches to treating autoimmunity may be necessary.

The biomedical implications are similarly broad. Pharmaceutical advances are desperately needed to combat herpes viruses, atypical mycobacteria, hepatitis, fungal and protozoal infections, and autoimmune conditions. Research on the possible synergistic effects of multiple, concurrent infections, of infectious agents and drugs must begin. The causes of AIDS­associated autoimmunity must be elucidated. Animal models incorporating factors conferring susceptibility to AIDS­associated infections must be developed, and the possibility that various combinations of these factors may be sufficient to cause AIDS in the absence of HIV needs to be studied. We particularly need to know whether there is transactivation and pseudoviron formation (and thus synergism) between viruses other than HIV that are prevalent in AIDS risk groups. Prospective studies of people in acknowledged risk groups are needed to determine to what extent immune suppression may develop in the absence of HIV; when HIV infection occurs during the development of immune suppression (if at all); and the specific factors that trigger full­blown AIDS. Studies of longterm survivors of both non­symptomatic HIV infections and of AIDS are desperately needed to provide clues to the proper management of AIDS in all risk groups. Until such studies are carried out, we can neither understand nor combat AIDS effectively.

SUMMARY

Despite the clearcut presence of HIV in most patients with AIDS, it is not clear that HIV is solely or even mainly responsible for their immune suppression. All people who develop AIDS are exposed to multiple, concurrent, and often chronic immunosuppressive factors besides HIV that include some subsets of the following: alloantigens, including semen, leukocytes, blood, and clotting factor concentrates; addictive and "recreational" drugs, including heroin, cocaine, and inhalant nitrites; pharmaceutical drugs, including anesthetics, opiate analgesics, antibiotics, antiparasitic agents, antidepressants, and steroids; malnutrition; multiple immunosuppressive infections, including HIV, CMV, EBV, HBV, HTLV­I, adenoviruses, Mycoplasmas, and Mycobacteria; and lymphocytotoxic autoimmune processes. Some combinations of these factors are capable of producing significant immune suppression in the absence of HIV so that even HIV­seronegative people at risk for AIDS are often immunocompromised. These facts suggest that either HIV is itself opportunistic, or that it requires cofactors to augment its immunosuppressive activity. In either case, AIDS may turn out to be a multifactorial, synergistic syndrome with more than one complex of causative agents. If this is true, then prophylaxis and treatment of AIDS will require a much broader approach to the syndrome than is generally taken, which will include nutritional elements, prophylaxis against non­HIV infectious agents, elimination of addictive and recreational drug use, treatment of autoimmune processes (e.g., plasmapheresis), and careful analysis of possible immunosuppressive results of medical procedures. Although a multifactorial, synergistic theory of AIDS makes the syndrome much more complex, many of the individual factors may turn out to be much more amenable to control than has HIV, and may therefore provide alternative ways to treat and prevent AIDS.

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