Reprinted from Medical Hypotheses No. 25, 151-162, © 1988
Is the Oxidation Induced by the Risk Factors the Primary
Royal Perth Hospital,
Medical Physics Dept., Perth, Western Australia.
by permission of the
publisher Churchill Livingstone
The emergence of AIDS as a recognizable 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
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.
account for the immunological abnormalities, especially the decrease in T4
cells believed to be unique to this disease, Françoise Barré-Sinoussi,
Jean-Claude Chermann and Luc Montagnier at the Pasteur Institute in Paris
and the group led by Robert Gallo at the National Cancer Institute in
America proposed that AIDS may be caused by infection of the T4 cells with
a virus from the family of human T-cell leukemia (lymphotropic)
retroviruses (HTLV). These include two major subgroups of human
retroviruses called human T-cell leukemia-lymphoma retroviruses HTLV-I and
HTLV-II. The supposed AIDS virus is called LAV (Lymphadenopathy Associated
Virus) by the Pasteur group and HTLV-III (Human T-cell Leukemia
(lymphotropic) Virus type III) by the Americans.
Because the viral envelope, which is required for infectivity, is very
fragile and tends to come off when the virus buds from the infected
T-cells, a direct infected T4-cell-to-non-infected T4-cell contact is
assumed to be required for the spread of the retrovirus(1). The main
immunological reason for postulating that a retrovirus of the HTLV family
may be the aetiological agent of AIDS was the finding that these viruses
are immunosuppressive in mitogenically stimulated cell cultures (see
below). The epidemiology of AIDS was also interpreted as supporting the
viral hypothesis. There is abundant evidence that immunological changes in
the AIDS patients and the development of KS and opportunistic infections
are related to the number of homosexual partners and frequent receptive
anal intercourse. According to the American Group, "This finding suggests
that HTLV-III is sexually transmitted and that the rectal mucosa may be
unusually vulnerable to passage of this lymphocytotoxic agent"(2). The
Carribean area, especially Haiti, and Africa, have been suggested as
possible sources of' the AIDS virus. The main reason for this suggestion
is the supposed high incidence of sera reactive for HTLV in Africa and
AIDS in Haitians eimigrating to the United States. There are a number of
findings which suggest causes other than HTLV-III/LAV:
(i) In diseases
which are known to have causes other than HTLV infections, the
immunological abnormalities are similar to those seen in AIDS. These
include Evan's, Gardner's and Behcet's syndromes, macroglobulinemia,
tuberculosis, malaria, diabetes, aplastic anaemia, and
thalassaemia(3,4,5,6,7,8,9,1O,11). Immunological abnormalities including
inversion of the T4/T8 ratio can be induced by other viral and non-viral
agents such as Epstein-Barr virus, chemotherapeutic agents, prednisone and
(ii) Areas with high seropositivity for HTLV infection appear to be
free of AIDS. About 25% of the population in Southern Japan appears to
have antibodies against the virus compared to about 5% in Haiti and 1% in
the United States, yet so far only 14 AIDS cases have been reported from
(iii) The epidemiological finding that AIDS development in homosexual
men is directly related to the number of homosexual partners and frequency
of receptive anal intercourse can be equally well or even better accounted
for if sperm is considered an etiological factor.
(iv) The high incidence of immunological and clinical abnormailities
found in the AIDS risk-groups, is also found in at least two other groups:
aged individuals and patients treated with immunosuppressive agents for
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
oxidizing 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 not its aetiology, although once present can further aggravate the
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 HTLVIII/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 be postponed by treating the animals with antioxidants(20).
Similarly in vitro, antioxidants enhance the immune response of both young
and old cells, the effect being 10 times greater in old cells(21, 22).
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 alkylating or oxidizing
agents(26). 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(27). 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.
According to Gallo et al, "The epidemiology of this syndrome - that is,
the increasing incidence and clustering of cases, particularly in New York
and California suggest the involvement of a transmissible agent."(28) .
However around the time of the first AIDS report two important changes
took place in homosexuals' lifestyle in these areas: increase in
promiscuity and exposure to drugs, especially nitrites(29,30). Although
nitrites came into use in the United States in the late 1960's their use
became widespread around 1975. It is of great interest that the latency
for appearance of KS in patients treated with immunosuppressive agents for
organ transplantation appears to be the same as that between homosexual.
exposure to nitrites and appearance of AIDS. Of interest also is the fact
that these drugs were first manufactured in California and then
transported to New York, the two areas with the highest incidence of
AIDS(23). These drugs are immunosuppressive, mitogenic and
carcinogenic(31,32). Nitrites are oxidizing agents and by this property
they play a significant role in many biological functions(33.34,35). For
example anaerobic bacteria use nitrites in place of oxygen as the terminal
electron acceptor for growth and respiration(36,37,38)
It has been shown in a number of studies and should be emphasised that,
unlike all sexually transmitted diseases, where both partners are equally
susceptible to the disease, in homosexual males immunosuppression appears
in the anal sperm.recipients but not in the exclusive sperm donors.(39)
The risk factors in AIDS development are the number of homosexual partners
and frequency of receptive anal intercourse(2). Furthermore many of the
AIDS ceases diagnosed in women may have resulted from the practice of anal
intercourse by heterosexual couples (39,40,41). More importantly,
carefully designed ainimal experiments leave no doubt that sperm is a
strong immunosuppressive agent (41,42,431,44) Sperm is one of the best
known mitotic agents and like all other mitogens is an oxidizing agent,
its electrophilicity being a prerequisite for fertilisational(45). During
spermatogenesis two main processes take place in the testes: morphogenesis
of the maturing gamete whose chromatin becomes progressively condensed and
replacement of the somatic histories with protamines by the oxidation of
the sulphydryl groups (SH) to disulphide (SS). Although maturation starts
in the testes, spermatozoa released from the seminiferous epithelium are
not fully mature from a functional standpoint and must complete their
maturation by the oxidaition of the SH groups to SS during the passage
through the epididymis. The amount of cysteine residues present as SH in
the spermatozoa from the caput, corpus and cauda epididymis and vas
deferens being 50, 15, 5, and 3% respectively(46,47,48,49). Of pivotal
significance to the present discussion is the finding of Hurtenback that
mature sperm is much more effective in producing immunosuppression than
immature sperm(43) . Since the significant difference between sperm
derived from the semineferous tubules and mature ejaculated sperm is its
degree of oxidation, it is highly probable that this property determines
its immunosuppressive effects. This is reinforced by the finding that
sperm from older animals, whose tissues are known to be more oxidized, is
more effective in inducing immunosuppression(43). For the same reason, the
homosexual male's sperm may be even more immunosuppressive than that of
healthy heterosexuals. The fact that sperm does not seem to produce
immunosuppression during vaginal sexual intercourse can be accounted for
by it critical structural difference between the epithelium of the rectum
and vagina(39,50). The vagina is lined by thick stratified squamous
epithelium which makes ulceration and penetration of the semen into the
vascular lamina unlikely. In contrast the semen in the rectum is separated
from blood vessels and lymphatics by a single layer of cells which is
easily penetrated and ulcerated during anal intercourse. In addition to
lymphoma and KS the homosexuals have two other malignancies, cancer of the
tongue and rectum(51). The increased incidence of these two cancers like
carcinoma of the cervix in women, may be related to periods of high local
concentration of sperm.
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 oxidizing agent, mitogenic and immunosuppressive(52,53,54).
Furthermore, viruses, like all other cells, require SH for division and
growth(45) , which they obtain from the host, thus oxidizing 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-Bar
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
aetiological factor of AIDS.
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.
Many researchers have predicted that AIDS, like other sexually
transmitted diseases, will spread by any type of sexual intercourse and
more and more cases will appear among heterosexuals. So far this has not
happened. According to Harold Jaffe, head of epidemiological studies of
AIDS at CDC, as quoted in a Science editorial, the epidemiological pattern
of the disease has undergone "remarkable little changes". Unlike many
other viral diseases, AIDS cannot be spread even by prolonged close
exposure to AIDS patients. According to the Acting Assistant Secretary for
Health James 0. Mason, "This is a very difficult disease to
An antibody molecule like that of all other proteins is determined by
the linear ordering of amino acids in the polypeptide chain and by its
three dimensional structure. The prevailing opinion is that the linear
chain is determined by gene transcription. However evidence exists that
both DNA and gene structure and function are regulated by the state of
condensation-decondensation (contraction-relaxation) of the chromatin,
which in turn depends on the cellular redox and its oscillation(45,58).
The bonds which play an essential role in the three-dimensional
configuration of the molecule are the SS bonds. According to Karush ". . .
. the disulfide links of the antibody molecule play an essential role in
the acquisition of immunological specificity and by virtue of their
covalent nature, provide for the stabilization of the particular structure
underlying the specific activity of the molecule"(59). Furthermore the
pattern of pairing of sulfhydryl groups to form disulfides is not an
invariant property of the linear chain but depends on extrinsic factors
including the redox(59,60). In other words protein synthesis and
specificity in general and antibody synthesis and specificity in
particular is redox dependent. If this is so, then any agents which will
induce the same redox changes as a virus, could induce the synthesis of
viral antibodies and antigens in the absence of the virus.
Viruses including RNA tumour viruses share antigenic determinants with
normal host cell components, a phenomenon known as molecular mimicry(61).
The same phenomenon may exist in the case of the HTLV-III/LAV virus. The
most prominent and persistently detected antigen in AIDS tests is a
protein of a molecular weight of 41.000 (P41), which is appoximately the
molecular weight of polymerized actin, a protein found in all cells
including bacteria(62). A protein of the same molecular weight, isolated
from a number of viruses, has been shown to be actin and to be a major
constituent of many viruses including RNA tumour viruses(63) . It is of
interest to note that the polvmerised form of actin increases with
oxidation(64,65). Of interest is also the fact that mitogenic stimulation
of normal cells with ConA, leads to the expression of oncoviral antigens
without virus particle synthesis(66)
The presence of "natural" antibodies in the sera of physiologically
healthy animals, directed against a "variety of antigens has been well
established and documented"(67). Antibodies against the oncoviral proteins
are widespread in non-infected human sera and vary with age(68,69).
Furthermore substances as diverse as normal components of the serum,
extracts of bacteria and non-protein molecules such as glycogen are
important factors in determining whether a given human serum registers
positive for oncovirus infection. Snyder et al discussing their work on
human oncoviral antibodies concludes: "The results are consistent with the
idea that the antibodies in question are elicited as a result of exposure
to many natural substances possessing widely cross-reacting antigens and
are not a result of widespread infection of man with replication-competent
oncoviruses"(68). Barbacid et al state: "This finding not only
demonstrates that the antibodies were directed against cellular rather
than the virus-coded antigenic determinants but also exclude the
possibility that this immune response was elicited as a consequence of
There are two blood tests routinely used for AIDS detection, ELISA and
Western blot neither of which detects the virus itself. Although the
latter test is more accurate, both give persistent false positive results.
"The false positive problem has led to harrowing decisions about what to
tell patients whose samples appear positive, although manufacturers stress
that the current tests are not intended for use in diagnosis"(70) . It is
significant that the false positive results increase with age and
"stickyness" of the serum, and the "stickyness" (viscosity) is redox
dependent and increases with oxidation(71,72) . The outcome of the tests
seems also to depend on who is performing them. Thus one group found 7/10
sera positive for viral antibodies, whilst another group testing the same
sera found none(73) . Most importantly Biggar et al found that the
probability of having a positive ELISA for HTLV-I, HTLV-II and
HTLV-III/LAV increases with age, poverty, immune complexes concentration
and especially with malaria and other parasitic diseases. They conclude,
"If the human retrovirus reactivity observed in ELISA tests is frequently
non-specific among Africans the causes of the non-specificity need to be
clarified in order to determine how they might effect the seroepidemiology
of retroviruses in areas other than Africa . . ."(17) . The only sensible
conclusion is therefore that seropositivity does not mean virus
positivity. However Gallo and his collaborators are of a different opinion
and state: ". . . we should proceed with blood-bank antibody tests.."(56).
They base their opinion on the fact that HTLV-III/LAV can be isolated from
the peripheral blood of >80% of people with serum antibodies to the
virus. Although this is true, it is important to note that all the
isolations are done in vitro (see below), after some unusual and drastic
manipulation of the lymphocytes obtained from the patients.
The initial reaction to the retrovirus hypothesis was one of
scepticism. However after the publications of the 1984 papers (Science 4
May) the theory became almost universally accepted. In these papers, in
vitro experimental evidence for the detection and isolation of HTLVIII/LAV
is documented. But in a paper subsequently published in the same journal
in the same year (Science 7 December) the Americans, by using the Southern
blot hybridization technique which can detect as little as one copy of
viral DNA per cell, obtained negative results on fresh peripheral
lymphocytes, lymph nodes, KS, bone marrow and spleen from AIDS patients
and AIDS related complex (ARC). They conclude: "Thus the lymph node
enlargement commonly found in ARC and AIDS patients cannot be due directly
to the proliferation of HTLV-III infected cells as occurs with HTLV-I in
adult T-cell leukemia. Whether the lymphocyte proliferation in lymph nodes
occurs in response to infection with HTLV-III or another agent, or both,
is not known. Similarly, the absence of detectable HTLV-III sequences in
Kaposi's sarcoma tissue of AIDS patients suggest that this tumor is not
directly induced by infec tion of each tumor cell with HTLV-III.
Furthermore the observation that HTLV-III sequences are found rarely, if
at all, in peripheral blood mononuclear cells, bone marrow and spleen
provides the first direct evidence that these tissues are not heavily or
widely infected with HTLV-III in either AIDS of ARC".
In an article published this year by the French group it is stated: "It
is unlikely however, that AIDS is the result of a direct progressive
destruction of T4 cells by the virus for at least two reasons . . ."(74) .
Thus the originators of the viral theory of AIDS agree that there is no
direct evidence to support their theory. What then about the claims of
repeated isolation of HTLV from AIDS patients? All the experiments for
detection, characterization, continuous production and isolation of
HTLV-III/LAV are done on in vitro cultures. Furthermore the cultures are
not solely with T-celis from AIDS patients, but cocultures with highly
selected neoplastic T-cell lines (75). It must be emphasised that unlike
other viruses HTLV-III/LAV has never been isolated as an independent
stable particle. By isolation of the virus, in fact, is meant transient
detection in the cell culture of: viral antigens, viral antibodies, the
enzyme reverse transcriptase (RT) and of virus like particles budding from
the cellular membrane into the extracellular space. In the vast majority
of cases isolation is synonymous with RT detection. However apart from RT
these cultures have almost any other enzyme implicated in DNA synthesis
and "it has not been excluded that viral reverse transcriptases are
cellular enzymes . . . ."(76) . The viral specificity of RT is believed to
be given by the template primer it uses (76). For HTLV-III/LAV isolation
the French and the Americans use either (dT)12-18*(A)n or (dT)15* (A)n as
template primer (75,17) . But, in earlier papers Gallo and his
collaborators present evidence that "DNA polymerase y, a component of
normal cells...." prefers exactly the same template as the one used for
HTLV-II/LAV isolation(78,79) . It is also significant that the kind of
template a polymerase uses and its activity depends on the culture
conditions and probably on the state of cellular development i.e. the
activity of the enzyme depends on the normality or subnormality of the
In rare cases by isolation is meant finding of virus-like particles
either T-cells in vitro or cells other than T in fresh AIDS tissue
(81,82). These particles are not only hard to detect but at least in some
cases may be normal organelles not HTLV-III/LAV viruses(83). Furthermore,
particle aggregation and budding have been proposed to be determined by
actin-myosin interaction(84,85). It is of interest to note that
actin-myosin interaction, particle aggregation and budding can be all
induced by oxidizing agents(84,85,86 ). Most importantly in vitro cultures
with normal cells, virus-free, ". . . can be induced to produce particles
which resemble RNA tumour viruses in every physical and chemical
respect"(76). Aaronson et al. discussing their particular experiments can
find only two explanations for this apparently universal phenomenon: "The
first was a chronic, low-level virus infection in the original primary
embryo culture which could not be detected by the methods available. Under
this hypothesis the virus could have persisted in a carrier state because
there always were a few infected cells in the population . . . The second
explanation was that virus began spontaneously in previously virus-free
cells during the course of establishment of the cell lines. These findings
provide strong support for the second model"(87). Although the
retroviruses can arise spontaneously in virus-free cell cultures, the rate
of appearance can be increased a million fold by the use of radiation
chemical mitogens or infection of the culture with other viruses(88).
Weiss et al. in a paper entitled Induction of Avian Tumor Viruses in
Normal Cells by Physical and Chemical Carcinogens conclude: "The mechanism
of induction is unknown. It is attractive to imagine that the endogenous
viral genome exists as an integral part of the host cell chromosome, but
there is little evidence for this assumption..... We call them RNA tumor
viruses in a taxonomic rather than an etiological sense..... One can
plausibly argue that the depression of natural endogenous viruses is the
result, not the cause of neoplastic changes.." (89). At present the French
believe that the AIDS virus does not belong to the "Superfamily" of
leukemia viruses but is in fact a member of the lentivirus family of
retroviruses as exemplified by visna virus(90). As far as the present
discussion is concerned, this makes no difference. Induction of the visna
virus as well as other viruses also requires in vitro activation(91,92).
Of pivotal significance to the present discussion is the fact that the
isolation and cytopathic effect of HTLV-III/LAV can be obtained and
observed only in cells activated with various mitogenic agents such as
ConA, PHA and irradiation. Notwithstanding heroic measures such as pooling
of AIDS sera, manipulation of culture conditions and selection of cell
lines are necessary to isolate a virus(75). After all these conditions are
satisfied "...only a small proportion of these cells is infected by the
virus . . . at the peak of virus replication only 5-10 per cent of the
cells express viral antigen . . . Furthermore only 10-20 per cent of
clones derived from the CEM T4 cell line are susceptible to LAV infection
even though they all express the T4 molecule on their surface"(74).
Meanwhile, the non- stimulated AIDS co-cultures behave like normal cell
cultures in respect to HTLV-III/ LAV infection, that is, there is no
infection(93). On the other hand HTLV-III/LAV has been isolated from
mitogenically stimulated co-cultures from cells lacking both HTLVIII/LAV
DNA and RNA(94). In a paper published this year in which Gallo is a
co-author, it is stated, "In the present study T4 cells from normal donors
that were infected with HTLV-III in vitro, after stimulation with PHA
followed the same pattern of secretion of IL-2 (day 1), production of
HTLV-III and cell death", that is the same pattern as PHA-stimulated cells
from AIDS donors(93). Whereas the same infected cells.........did not
produce IL-2 or express virus without immunological activation" (PHA
stimulation). Since this is the case, even assuming that HTLV-III/LAV
exists in vivo and is transmitted from a sick individual to a normal one,
the normal person would never become ill unless he is exposed to high
concentrations of mitogenic agents. In other words HTLV-III/LAV by itself
cannot produce ill effects while the mitogenic agents would produce the
immunological and clinical abnormalities associated with AIDS irrespective
of HTLV-III/LAV infection. It is important to note that in the
above-mentioned paper evidence is presented that PHA produces
immunological abnormalities in normal non-infected cell cultures,
including T4 loss. ConA is also immunosuppressive both in vivo and in
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 VIll),
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 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 oxidizing 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(19). (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 the aetiological 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
haemophiliacs 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 haemophiliacs
develop the disease (106). Like in all other AIDS patients, the virus in
these groups has been isolated only in vitro(107). Factor VIll has been
found to be immunosuppressive both in vitro and in vivo, the T4/T8 ratio
being inversely correlated with the quantity of Factor VIll 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 haemophilia B
purely by the transmission of an infectious agent.."(108). Evidence exists
that all clotting factors are oxidizing agents, the strongest being Factor
VIll. Factor VIll 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 VIll 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 3OGy 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(114) 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 haemophiliacs 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 oxidized, clotting and blood factors from
these patients can be 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
Immunological and clinical abnormalities similar to those seen in AIDS
have been reported in drug abusers as far back as 1973(115,116,117). The
immunological abnormalities include: absolute lymphopenia, decreased
concentration of Igm and IgG antibodies and false-positive serological
tests in as many as 40% of drug users. The clinical abnormalities include:
lymphadenopathy ranging from benign hyperplasia to malignant lymphoma,
other malignancies, fever, night sweats, chills, weight loss and increased
susceptibility to infection. Opiates, like nitrites, are oxidizing agents.
They produce their effects by binding to the membrane SH. Their effects
can be prevented and reversed by reducing agents. The effectiveness of the
reducing agents is directiv related to their negative redox potential,
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(7I). (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 co-cultures 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(17) . 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
There are good reasons to doubt that HTLVIII/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 oxidizing agents including sperm,
nitrites, opiates and Factor VIII. If this is true the prevention, and
possibly even cure, may be achieved with the use of appropriate
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. Hediand-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
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