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Abstract
The emergence of AIDS as a recognisable disease, its epidemiology, the clinical and laboratory data and the way in which they have been interpreted to deduce the currently acceptable hypothesis of its aetiology and mechanism of transmission are critically examined. There is no compelling reason for preferring the viral hypothesis of AIDS to one based on the activity of oxidising agents. In fact, the latter is to be preferred, since unlike the viral hypothesis it leads to possible methods of prevention and treatment using currently available therapeutic substances.
Introduction
Acquired Immune Deficiency Syndrome (AIDS) was first recognised in 1981 and by late 1985 more than 14,000 people had been diagnosed with the disease in the United States alone. The patients belong almost exclusively to a number of high-risk groups. Homosexual or bisexual males constitute the largest group, followed by intravenous drug abusers, Haitians and haemophiliacs. The main clinical signs of the disease are lymphadenopathy, opportunistic infections and malignancies especially lymphomas and Kaposi's Sarcoma (KS). The patients also have a pronounced depression of cellular immunity. There is an absolute lymphopenia and reversal of the usual ratio of phenotypic T-helper (OKT4+) to T-suppressor (OKT8+) cells whereby the latter come to dominate among circulating lymphocytes. The circulating lymphocytes have decreased capacity to form rosettes with red blood cells,respond poorly to mitogenic stimulation, have decreased natural killer cell activity and other functional abnormalities.
...
The possibility arises that the immunosuppressive agents used in organ transplantation, some parameter(s) associated with ageing and the risk factors in AIDS share a common property by which they induce similar effects. Evidence will be presented that: All the above agents are oxidising agents and by their oxidative nature induce malignancies, immunosuppression and increased susceptibility to infection. In AIDS viral infection including HTLV-III/LAV, if it exists, is the result of the disease and not its aetiology, although once present can further aggravate the disease.
AIDS-like Symptoms in Other Subjects
The aged individual, like the homosexual male, has a significantly higher probability than a young heterosexual of developing opportunistic infection. Even the seropositivity for HTLV-III/LAV in apparently healthy individuals increase with age (17). It is widely known that with age there is a marked decline in immune function and a marked increase in all cancers including KS. The increase in oxidative stress with age and its relationship to cancer development is also well known (18). Less well known is the evidence that the decline in cellular immunity is mainly due to lymphopenia and the alteration in cell function as a result of oxidative stress (19). In vivo (animals) age-associated cancers, decline in immune function and even death can he postponed by treating the animals with antioxidants. Similarly in vitro, antioxidants enhance the immune response of both young and old cells, the effect being 10 times (21,22) greater in old cells.
A striking resemblance seems to exist between organ transplant patients who are treated with radiation, chemotherapy or a combination of the two and the AIDS patients in terms of their increased susceptibility to opportunistic infection and the development of KS and immunosuppression (23,39) . The in vivo and in vitro effects on the immune system of these agents is similar to that seen in AIDS (24). In the organ transplant patient there is a lack of helper cells and an inverted T4/T8 ratio which persists beyond one year post-transplantation independently of graft versus-host disease status. The lymphocyte is also abnormal for more than one. year after transplantation (25). All the agents with which organ transplant patients are treated are either (21) alkylating or oxidising agents. Their effects can be prevented by the use of reducing agents. Even KS has been observed to regress when immunosuppression therapy is reduced or stopped (23).
AIDS in Homosexuals
The diseases fitting the AIDS definition appeared in homosexuals before 1981 when their symptoms started to be reported in the medical literature under the inclusive term of AIDS (21). The dramatic increase of their incidence after 1981 is generally believed to be due to infection of these groups with HTLV-III/LAV and to its transmission by sexual contact. However, other factors often associated with homosexual practice such as anal deposition of sperm and nitrites could produce the clinical and immunological abnormalities seen in these patients.
...
Gonorrhoea, syphilis, hepatitis B, herpes and amoebiasis are much more common among homosexual males than among heterosexuals. They also have a number of bowel infections which cause persistent and recurrent diarrhoea (30,51). Many of the agents used for the treatment of these conditions are oxidising agents, mitogenic and immunosuppressive (52,53,54). Furthermore, viruses, like all other cells, require SH for division and growth (54) which they obtain from the host, thus oxidising its tissues. Because oxidation of the host's immune system leads to immunosuppression, the possibility that all viruses are immunosuppressive to a greater or lesser degree is very likely. Two viruses, cytomegalovirus and Epstein-Barr virus although present among homosexual men, seem to be universal in AIDS patients as a result of reactivation of latent viruses (23,51). Both viruses produce clinical and immunological abnormalities similar to those seen in AIDS patients. Fever, rash, lymphadenopathy and enhanced susceptibility to other infections are common manifestations of infection with these viruses (51). These viruses induce immunosuppression in vitro and in vivo, including abnormalities in the T4/T8 ratio both in humans and animals (15,30,51,55). Both viruses have been isolated from many sites, including KS, from almost all AIDS patients (30,51). Unlike the above viruses, HTLV-III/LAV has never been isolated in fresh AIDS tissues. Nor is there any evidence that it produces in humans the clinical and immunological abnormalities attributed to it. Yet HTLV-III/LAV and neither the above viruses nor any other factor(s) is considered as the etiological factor of AIDS.
HTLV-III/LAV Infection
Gallo and his group state "The cytopathic activity in vitro, the repeated isolation from patients with AIDS and people at risk, and results of the seroepidemiological studies are all consistent with HTLV-III being the aetiological agent of AIDS (56). It is proposed to examine the epidemiological and seroepidemiological evidence as well as the isolation of the virus in some detail.
...
Equally important is the fact that when normal T and B lymphocytes are stimulated either in vivo or in vitro with ConA they display viral antigens on their surfaces (66). The situation is as follows: There are two agents A (HTLV-III/LAV) and B (sperm, nitrites, opiates, factor VIII), however only B is pathogenic on its own. Yet A is considered as the primary causative agent. This becomes even less probable if one realises that the methods for the detection of A are non-specific. Because the AIDS patients are also exposed to mitogenic agents, activation of different viruses can be expected. Thus unlike the HTLV-III/LAV infected T4 cells hypothesis, these mitogenic agents could account for both the viral activation and the AIDS related malignancies. Furthermore the mitogenic agents, being oxidising agents, can also account for the cellular immunosuppression observed in these patients. The lymphocytes have a relatively high negative charge (96). Their functions, including response to mitogens, rosette formation, suppressor/helper activity and natural killer cell activity depend on this negative charge. Oxidation leads to suppression of the above activities (96,97,98,99). As has been pointed out earlier, the absolute lymphopenia, preferential decrease in T4-cell numbers and the inversion of the T4/T8 ratio is not specific to AIDS but is widespread and exists in many diseases without retrovirus infection. In AIDS these abnormalities in T-cell numbers could be real or apparent and result from: (i) The extremely high sensitivity of T cells to oxidative stress (ii) T4 cells having a lower negative charge than the T8 cells (99) could be the first to be destroyed by persistent oxidative stress. (iii) The T4 cells could be preferentially sequestrated in diseased peripheral tissues. (iv) The binding of antibodies to the cell surface depends on the environmental redox state and the relative charge between the cell (negative) and antibody (positive), surface antigen and binding of antibodies decreasing with cellular oxidation (100,101,102). Modification of the environmental conditions leads to changes in the T4/T8 ratio in a given population of lymphocytes (103,104).
AIDS in Non-Homosexuals
According to Gallo and his group "...epidemiological studies carried out chiefly by the Centers for Disease Control in Atlanta, Georgia, particularly those pertaining to transmission of the disease by filtered factor VIII in blood transfusion cases strongly implicated a viral agent as etiological factor of AIDS" (56). It seems logical and has been already stated by Gordon that, "This finding is, however, also compatible with the possibility that factor VIII induces immunosuppression without the intervention of an infectious agent (105). The evidence available in the literature supports this latter interpretation. Seventy percent of hemophiliacs have been reported as being seropositive for HTLV-III infection as compared to about 45% of a randomly selected homosexual group from an area of high AIDS incidence (57). But only 0.06% of hemophiliacs develop the disease (106). Like in all other AIDS patients, the virus in these groups has been isolated only in vitro (107) . Factor VIII has been found to be immunosuppressive both in vitro and in vivo, the T4/T8 ratio being inversely correlated with the quantity of factor VIII concentrate administered. The in vivo studies led the authors to conclude: "...It is difficult to explain all of the observed immunological differences between patients with severe hemophilia A and those with hemophilia B purely by the transmission of an infectious agent..." (108). Evidence exists that all clotting factors are oxidising agents, the strongest being factor VIII. Factor VIII is a high molecular weight glycoprotein complex, whose subunits are linked by a large number of SS bonds. The SS bonds are required for agglutination activity. Antioxidants induce a dose related activity decrease of all coagulation factors including factor VIII and IX (109,110). There are reports which claim that the virus and thus the disease is transmitted via blood/blood products other than clotting factor concentrates. The first and best known appear to be that of a prematurely born infant who died at 17 months from recurrent infection and the 18 cases reported to the CDC, by August 1983 (111,112). The authors of the first report, although concluding that the infant developed AIDS as a result of HTLV-III/LAV infection transmitted by multiple blood administration, do not exclude the possibility that he was born with a primary immunodeficiency disorder. More importantly, all blood was irradiated with 30Gy before administration. Radiation is known to produce both immunosuppression and activation of proviruses. The 18 cases reported to the CDC and classified as transfusion associated AIDS via HTLV-III/LAV were diagnosed during approximately a 12 month period when over 3 million Americans received transfusions. Two of the patients most probably had received radiation, chemotherapy or both. These 18 patients were older than other groups with AIDS (40% were over 60 years of age). Fifteen of these patients (83%) received transfusion in association with surgery. Surgery may be immunosuppressive (113) and is known to be associated with infections other than HTLV-III/LAV, the risk increasing with age. More importantly Grady et al (l14) have shown that an inverse relationship exists between the percentage of T4 cells and the number of units transfused. The above authors conclude: "Accordingly we suggest that studies which purport to show a relationship between the transfusion of blood/blood products and AIDS be viewed with caution". What is now reported as AIDS in a very small proportion of hemophiliacs receiving coagulation therapy and recipients of transfused blood is only manifested as opportunistic infection. Cases appearing before 1981 would not have been identified as AIDS. Since tissues of AIDS patients in general are likely to be abnormally highly oxidised, clotting and blood factors from these patients can he expected to contain more SS bonds and there fore be even more immunosuppressive. Heating the agglutination factors to inactivate a supposed AIDS virus will, in fact, break at least part of the SS bonds and thus decrease both their immunosuppressive activity and therapeutic effectiveness.
...
According to Gallo the HTLV-III/LAV and thus AIDS originated in Africa (56). He bases his hypothesis on: (i) The isolation from the lymphocytes of the African Green Monkey of a retrovirus closely related to HTLV-III/LAV (119). (ii) The reported high seropositivity for HTLV infection in Africans (56). (iii) The finding of HTLV-III/LAV, antibodies in sera collected from Africans before the recognition of AIDS (71). (iv) The diagnosis of AIDS in Haitians via which the HTLV-III/LAV is supposed to have been transmitted from Africa to America. The virus was isolated in vitro cell cocultures and the monkeys were healthy and free of AIDS. Although some authors claim high seropositivity for HTLV infection in Africans, others find only negative results. Thus Weiss et al did not find antibodies to HTLV-I in 1225 sera from donors of different African countries nor did Karpas et al in sera from Israeli Falashas in which others have reported a 37% positivity (73,120). The prevalence of antibodies against the HTLV-III/LAV virus has been reported to vary from 6-50% in different African countries. Yet relatively few AIDS cases have been reported from this continent (117). It is important to note that the test for HTLV-III/LAV antibodies in Africans are non specific and that the reported AIDS cases from this continent seem to correspond geographically to these regions where anal intercourse is a common practice among heterosexual couples (17,121). Equally important is the fact that African sera tend to be "sticky", which means that antibody tests can give relatively high levels of false positives and some investigators contend that this problem increases with age of the serum (71). As far as the Haitian connection is concerned, "This speculation is based on no data..." (51). Furthermore, recent evidence became available which shows that "risk factors are present among most patients with AIDS in Haiti" (122).
Conclusion
There are good reasons to doubt that HTLV-III/LAV can be regarded as the exclusive single variable in the pathogenesis of AIDS. There is therefore a spectrum of possibilities. Either it plays no role at all, is of minor significance or it contributes significantly but not exclusively to the disease. Be that as it may the one major significant variable is the concurrent exposure of the patients to oxidising agents including sperm, nitrites, opiates and factor VIII. If this is true then prevention, and possibly even cure, may be achieved with the use of appropriate antioxidants.
Acknowledgements
I thank Dr. R. A. Fox, E. R. Scull and all my colleagues for support and stimulating discussions, Dr. J. A. Armstrong, Prof. R. L. Dawkins for valuable conversations, Mrs. C. Quinn and Y. Town for preparing the manuscript and the staff of the Royal Perth Hospital Library for their assistance over many years. I particularly thank Prof. J. Papadimitriou, Dr. V. Turner and Mr. B. Hedland-Thomas for invaluable help and continuous support. This work would not have come to fruition without the urging and encouragement of my husband, Kostas Eleopulos, to whose memory it is dedicated.
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Historical Note
This paper was first prepared in 1985/86 and was twice rejected by Nature. Its inclusion in the pages of Medical Hypotheses was only after the author convincingly argued the lack of evidence for a sexually transmitted epidemic of HIV/AIDS in Africa. This latter data was later incorporated into a paper published in the World Journal of Microbiology and Biotechnology. This oxidative theory of AIDS pathogenesis (which also explains the genesis of the in vitro phenomena inferred as HIV) grew out of the author's redox theory of cellular functioning (see reference 45). The following predictions of this theory can be aruged or have been fulfilled: (i) AIDS will remain restricted to the original risk groups; (ii) AIDS is not infectious; (iii) HIV/AIDS patients will be oxidised, that is, have lower amounts of cellular sulphydryl groups than healthy persons; (iv) anti-oxidants (reducing agents) will decrease or inhibit the production of "HIV" or the "effects of HIV".
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