Genetica 95: 5-24, 1995
A CRITICAL ANALYSIS OF THE HIV-T4-CELL-AIDS HYPOTHESIS
Eleni Papadopulos-Eleopulos,1 Valendar F.Turner,2
John M. Papadimitriou,3 David Causer,1 Bruce Hedland-Thomas,1
& Barry Page1
1: Department of Medical Physics, 2: Department of Emergency
Medicine, Royal Perth Hospital, Perth, Western Australia; 3: Department
of Pathology, University of Western Australia.
Knowledge is one. Its division into subjects is a concession
to human weakness.
Halford John Mackinder
The data generally accepted as proving the HIV theory of AIDS, HIV cytopathy,
destruction of T4 lymphocytes, and the relationsip between T4 cells, HIV
and the acquired immune deficiency clinical syndrome are critically evaluated.
It is concluded these data do not prove that HIV preferentially destroys
T4 cells or has any cytopathic effects, neither do they demonstrate that
T4 cells are preferentially destroyed in AIDS patients, or that T4 cell
destruction and HIV are either necessary or sufficient prerequisites for
the development of the clinical syndrome.
With few exceptions by workers who either reject it (Duesberg, 1987,
1992; Papadopulos-Eleopulos, 1988; Papadopulos-Eleopulos et al., 1989a;
Papadopulos-Eleopulos, Turner & Papadimitriou, 1992a, 1993b), or who
postulate the necessity for cofactors (Lemaitre et al., 1990; Root-Bernstein,
1993), the currently accepted HIV theory of AIDS pathogenesis states that:
1. HIV causes destruction of T4 (helper) lymphocytes, that is, acquired
immune deficiency, AID;
2. AID leads to the appearance of Kaposi's sarcoma (KS), Pneumocystis
carinii pneumonia (PCP) and certain other "indicator" diseases
which constitute the clinical syndrome, S.
For this to constitute a valid theory of AIDS pathogenesis the minimum
1. HIV, is both necessary and sufficient for destruction of T4-cells;
2. Decrease in T4 lymphocytes (AID) is both necessary and sufficient
for the appearance of the clinical syndrome, S;
3. All AIDS patients are infected with HIV.
Evidence will be presented which shows that the HIV/AIDS hypothesis
as stated above, cannot be considered proven by the data presently available.
Reference will be made to an oxidative theory (Papadopulos-Eleopulos, 1988;
Papadopulos-Eleopulos, Turner & Papadimitriou, 1992a, 1992b) which
claims that the immunological abnormalities seen in AIDS patients, including
decreased numbers of T4 lymphocytes, as well as the clinical syndrome,
are induced by oxidising agents and not HIV.
Cytopathic effects of HIV
According to Gallo and his colleagues, "HIV has been shown to have
a direct cytopathic effect" (cell killing effect) on CD4+ cells, firstly
by Montagnier and his colleagues in 1983, and then by him (Gallo) and his
colleagues in a series of four papers published in Science in 1984 (Shaw
et al., 1988). However, in the 1983 paper where Montagnier and his colleagues
describe the isolation of HIV from a homosexual patient with lymphadenopathy,
no evidence is presented regarding the biological effects of HIV (Barré-Sinoussi
et al., 1983). Although Gallo claims that in the four Science papers (Gallo
et al., 1986) he and his colleagues "provided clearcut evidence that
the aetiology of AIDS and ARC was the new lymphotropic retrovirus, HTLV-III",
no such data were presented. (Papadopulos-Eleopulos et al., 1993b) Reference
to the cytopathic effects is made only in the first paper where it was
stated "The virus positive cultures consistently showed a high proportion
of round giant cells containing numerous nuclei", (syncytia) (Popovic
et al., 1984). The cultures described in that paper utilised clones of
the HT cell line; however, it subsequently became known that the HT line
used by Gallo is in fact HUT78, (Rubinstein, 1990) a cell line established
from a patient with mature T4-cell leukaemia (Gazdar et al., 1980; Gallo,
1986). It has been shown however, that other cell lines established from
patients with mature T4-cell leukaemia have multinucleated giant cells
(Poiesz et al., 1980) and therefore, one may expect to find giant cells
containing numerous nuclei in the HT (clones) cell cultures even in the
absence of HIV. At present, evidence also exists showing that other cells
permissive for HIV, monocyte-derived macrophages, "in the absence
of infection", form syncytia during cultivation (Collman et al., 1989).
Later, Gallo expressed the view that syncytial formation and direct
cell killing are unlikely to be the major pathway for cell loss. In addition,
cells infected by several viruses produce extensive syncytia without cytopathy
(Shaw et al., 1988).
In 1985, Gallo and his colleagues (Gallo et al., 1985) showed that in
mitogenically stimulated lymphocyte cultures from AIDS patients or in cultures
from healthy donors "infected" with HIV, there is a decrease
in the total number of viable cells. However:
(i) the decrease in viable cells begins before a significant increase
in reverse transcriptase activity (RT), that is, HIV expression;
(ii) the rate of cell loss remains the same even when the expression
of HIV (RT), is maximum.
These suggest that the cause of the decrease in viable cells may not
be HIV. Since then other researchers have shown that:
(a) "lymphocytes may be productively infected in the absence of
cell death" (Hoxie et al., 1985);
(b) the presence or absence of the cytopathic effects is a function
of the cell type (cell line), culture conditions (presence or absence of
interleukin-2 (IL-2), presence or absence of serum, fibrinogen, fibronectin,
alpha-globulin), and the origin of the HIV preparation (von Briesen et
al., 1987; Ushijima et al., 1992);
(c ) early in 1986, Zagury, Gallo and their colleagues reported that:
"T4 lymphocytes from normal donors infected by HTLV-III in vitro,
as well as HTLV-III-infected primary T4 cells from AIDS patients, have
been difficult to maintain in culture for longer than 2 weeks, and it has
often been assumed that the virus has a direct cytolytic effect on these
cells". However, by avoiding PHA stimulation and by reducing the number
of cells per millilitre of culture medium from 105-106 to 103-104, they
were able to "grow the infected cells for 50-60 days" without
cellular degeneration which, according to them, was due to "the lack
of further antigenic stimulation and, presumably, the reduced concentrations
of toxic substances released by the mature cells" (Zagury et al.,
(d) cytopathy does not always correlate with RT activity, that is, HIV
expression. "In fact, there was sometimes an inverse correlation in
CEM cells, with the high RT isolates exhibiting a slower inhibition of
cell division and reduction of viability than the low RT-producing viruses"
(Cloyd & Moore, 1990).
In other words, the correlation between HIV production and decreased
cellular viability is not as the HIV hypothesis predicts, especially if,
as is presently accepted, that "Although the effect of HIV on the
immune system resembles autoimmune disease, it is driven by persistent
active, viral expression" (Weiss, 1993). Despite all these data, consensus
still prevails that HIV infection leads to a "quantitative decrease
in the TH-cell population that will lead to acquired immune deficiency
syndrome (AIDS)" (Ameisen & Capron, 1991) [TH=T4]. However, no
agreement exists as to the mechanism by which HIV kills T4 cells.
According to Claude Ameisen and André Capron from the Pasteur
Institute, not one of the mechanisms "proposed to account for these
TH-cell defects, including: (1) immune suppression, or its opposite, hyperactivation
and exhaustion of the TH cells, (2) inhibitory signals mediated by HIV
viral or regulatory gene products, (3) autoimmune responses, (4) selective
infection and destruction of memory TH cells, (5) syncytia formation between
infected and uninfected cells, and (6) inappropriate immune killing of
uninfected cells", is satisfactory.
Instead, in 1991 they put forward the hypothesis "that a single
unique mechanism, activation-induced T-cell death [also known as programmed
cell death (PCD) or apoptosis] can account for both the functional and
numerical abnormalities of T4 cells from HIV infected patients...We propose
that the simplest explanation of TH-cell defects leading to AIDS is that
HIV infection leads to an early priming of TH cells for a suicide process
upon further stimulation. In HIV infected patients, circulating gp120,
gp120-antibody immune complexes or anti-CD4 autoantibodies, that all bind
CD4, may represent appropriate candidates for the priming of T cells for
a PCD response following activation" (Ameisen & Capron, 1991).
In support of their theory they reported that stimulation of peripheral
blood mononuclear cells (PBMC) of asymptomatic HIV infected individuals
with pokeweed mitogen (PWM) or staphylococcal enterotoxin B (SEB), "was
followed by cell death", whereas no death was observed at 48h in the
unstimulated cells. Cell death was only observed in the CD4+ enriched population
and not in the CD8+ lymphocytes. Cell death was not found in unstimulated
or stimulated PBMC from HIV- negative individuals (Groux et al., 1991;
Groux et al., 1992). However, to date, "no evidence for circulating
soluble gp120 has yet been reported" (Capon & Ward, 1991), or
for gp120- antibody immune complexes in AIDS patients. Furthermore, although
in the following years, researchers from many institutions published data
confirming the apoptotic death of PBMC cultures from HIV infected individuals,
their data seem to contradict both Ameisen and Capron's experimental findings
as well as their proposed mechanism of HIV induced apoptosis:
1. Addition of anti-gp120 or anti-CD4 monoclonal antibodies (MCA) to
HIV infected cultures permitted sustained high levels of viral replication,
but blocked apoptosis and cell death (Terai et al., 1991; Laurent-Crawford
et al., 1992);
2. Experiments performed on cultures with or without stimulation showed
"both CD4+ and CD8+ cells from HIV-infected individuals die as a result
of apoptosis" (Meyaard et al., 1992).
In a 1991 paper, published in Virology (Laurent-Crawford et al., 1991),
Montagnier and his colleagues showed that:
(a) in acutely HIV infected CEM cultures in the presence of mycoplasma
removal agent, cell death (apoptosis) is maximum at 6-7 days post infection,
"whereas maximal virus production occurred at Days 10-17"-that
is, maximum effect precedes maximum cause;
(b) in chronically infected CEM cells and the monocytic line, U937,
no apoptosis was detected although "These cells produced continuously
(c ) in CD4 lymphocytes isolated from a normal donor, stimulated with
PHA and infected with HIV in the presence of IL-2, apoptosis becomes detectable
3 days post infection and clearly apparent at 4 days. "Intriguingly,
on the 5th day" apoptosis "became detectable in uninfected,
PHA stimulated cells". Figure 9, where the data are presented, shows
approximately the same degree of "apoptotic events" in the PHA
cultures at 5 days as in the PHA+HIV cultures on the 4th day
They concluded: "These results demonstrate that HIV infection of
peripheral blood mononuclear cells leads to apoptosis, a mechanism which
might occur also in the absence of infection due to mitogen treatment of
these cells... Interestingly, HIV infection of such mitogen stimulated
cells resulted in a slight acceleration of the first signs of apoptosis,
thus indicating the intrinsic effect of HIV infection" (Laurent-Crawford
et al., 1991).
The conclusion that HIV has an "intrinsic effect" on PCD can
be questioned on several grounds:
1. The "slight acceleration of the first signs of apoptosis"
in the stimulated HIV infected cultures, as compared to the non-HIV infected
stimulated cultures, may not be due to HIV but to the many non-HIV factors
present in "HIV" inocula, including:
(a) Mycoplasmas and other infectious agents;
(b) The many cellular proteins present in the "HIV preparation"
(Henderson et al., 1987);
(c ) PHA, present in the cultures from which the "HIV preparation"
2. That HIV is not the cause of apoptosis is also indicated by the fact
that in chronically infected cell lines in which virus is continuously
produced, apoptosis is not detected;
3. That HIV may play no role in apoptosis is also suggested by the presently
accepted mechanism of apoptosis. Apoptosis occurs both in healthy and in
pathological conditions, is frequently prominent amongst the proliferating
cells of lymphoid germinal centres, and can be enhanced by numerous agents
including radiation, cytotoxic drugs, corticosteroids and the calcium ionophore
A23187 (Kerr & Searle, 1972; Don et al., 1977; Wyllie et al., 1980;
Wyllie et al., 1984). Apoptosis is cellular death characterised by morphological
criteria: cellular condensation, DNA fragmentation, and plasma membrane
"blebbing" leading to the release of "apoptic bodies"
which vary widely in size and some of which contain pyknotic chromatin
surrounded by intact membranes (Kerr & Searle, 1972; Don et al., 1977;
Wyllie et al., 1980; Wyllie et al., 1984). These changes are thought to
be induced by increased concentration of Ca++ which in its turn induces
contraction of the cytoskeleton whose main components are known to be the
ubiquitous proteins, actin and myosin (Jewell et al., 1982; Cohen &
Duke, 1984; McConkey et al., 1988; McConkey et al., 1989; Reed, 1990).
However, evidence exists indicating that intracellular Ca++ concentration
and contraction of the actin-myosin system (cellular condensation), are
induced by perturbances in the cellular redox state (Papadopulos-Eleopulos
et al., 1985; Papadopulos-Eleopulos et al., 1989b). In fact, for more than
a decade, evidence has existed showing that oxidising agents, including
all mitogenic (activating) agents, can induce: reversible cellular changes;
cellular activation; malignant transformation; mitogen unresponsive cells;
or cellular death, including death by apoptosis. The ultimate outcome depends
on the concentration of the agent, its rate of application, the initial
state of the cells and the cellular milieu (See reference (Papadopulos-Eleopulos,
More recent data confirm the fact that the intracellular free Ca++ concentration
is regulated by the cellular redox state. Oxidation leads to an increased,
and reduction to a decreased, Ca++ concentration (Trimm et al., 1986).
Cellular surface blebbing (Jewell et al., 1982; Lemasters et al., 1987;
Reed, 1990), chromatin condensation (Pellicciari et al., 1983), and apoptosis
(Morris et al., 1984) are the direct result of cellular oxidation in general
and of cellular sulphydryl groups in particular. This is supported by Montagnier's
group's recent finding that apoptosis can be inhibited by reducing agents
(René et al., 1992). (In fact, at present, Montagnier (Gougeon &
Montagnier, 1993) agrees with our view that anti-oxidants should be used
for treatment of HIV/AIDS patients (Papadopulos-Eleopulos, 1988; Papadopulos-Eleopulos
et al., 1989a; Turner, 1990; Papadopulos-Eleopulos et al., 1992a; Papadopulos-Eleopulos
et al., 1992b)). At present it is also known that:
(a) for the expression of HIV phenomena (RT, virus-like particles, antigen/antibody
reactions), activation (mitogenic stimulation) is a necessary requirement
(Klatzmann & Montagnier, 1986; Ameisen & Capron, 1991; Papadopulos-Eleopulos
et al., 1992b);
(b) activation (stimulation) is induced by oxidation (Papadopulos-Eleopulos,
1982; Papadopulos-Eleopulos et al., 1992b);
Since both AIDS cultures and AIDS patients are exposed to mitogens (activating
agents), all of which are oxidising agents (Papadopulos-Eleopulos, 1988),
both apoptosis and the phenomena upon which the presence of HIV is based
(viral-like particles, RT, antigen/antibody reactions (WB), "HIV-PCR-
hybridisation"), may all be the direct result of oxidative stress
and therefore their specificity questionable (Papadopulos-Eleopulos, 1988;
Papadopulos-Eleopulos et al., 1992a; Papadopulos-Eleopulos et al., 1992b).
As far back as January 1985 Montagnier wrote, "....replication
and cytopathic effect of LAV can only be observed in activated T4 cells.
Indeed, LAV infection of resting T4 cells does not lead to viral replication
or to expression of viral antigen on the cell surface, while stimulation
by lectins or antigens of the same cells results in the production of viral
particles, antigenic expression and the cytopathic effect" (Klatzmann
& Montagnier, 1986). One year later Gallo and his colleagues wrote:
"the expression of HTLV-III was always preceded by the initiation
of interleukin-2 secretion, both of which occurred only when T-cells were
immunologically [PHA] activated. Thus, the immunological stimulation that
was required for IL-2 secretion also induced viral expression, which led
to cell death" (Zagury et al., 1986). Thus, relatively early after
the appearance of AIDS it was known that HIV is not sufficient for the
appearance of the cytopathic effects. For some unknown reason, up till
1991 very little (or no) data was presented regarding the effects of the
activating agents themselves on cell survival. However, in the above discussed
1991 Virology paper, Montagnier and his colleagues showed that activation,
in the absence of HIV, can induce the same cytopathic effects. In other
words, Montagnier and his colleagues have shown that HIV is neither necessary
nor sufficient for the induction of the cytopathic effects observed in
HIV infected cultures. Thus, the presently available evidence from the
in vitro studies does not prove that HIV has direct cytopathic effects
on any T-cells, T4 or T8. The cytopathic effects observed in the cultures
are most likely caused by the many activating (oxidising) agents to which
the cultures are exposed.
Even if HIV were shown to have cytopathic effects, since it is accepted
that "The hallmark of AIDS is a selective depletion of CD4-bearing
helper/inducer" lymphocytes (Shaw et al., 1988), the available evidence
must show that T4 cells are preferentially destroyed in individuals at
risk of developing the clinical syndrome.
HIV and the T4 cells
Using MCA for serial measurement of CD4 and CD8 expressing lymphocytes
in mitogenically stimulated HIV infected cultures, it has been shown that
in cultures prepared such that the majority (>95%) of lymphocytes are
purified T4 cells, there is a progressive disappearance of CD4 expressing
cells. This observation was interpreted by Gallo and others "that
HTLV-III has a cytopathic effect on OKT4-positive (OKT4+) cells" (Fisher
et al., 1985). However, according to Klatzmann, Montagnier and other French
researchers "this phenomenon could not be related to the cytopathic
effect" of HIV but is "probably due to either modulation of T4
molecules at the cell membrane or steric hindrance of antibody-binding
sites" (Klatzmann et al., 1984a Klatzmann et al., 1984b). That is,
the decrease in T4 cells is not due to destruction of cells but due to
a decrease in MCA binding to their surface. Nevertheless, the above data
were interpreted as evidence for selective infection and killing of T4
cells by HIV, and together with the fact that "we knew of no agents,
aside from a family of human T- lymphotropic retroviruses that we had discovered
three years earlier and named human T-cell leukaemia (lymphotropic) virus
(HTLV), that demonstrated such tropism to a subset of lymphocytes",
was presented as one of two arguments in support of the HIV hypothesis
of AIDS (Gallo et al., 1985). (The other argument was based on the perceptions
that AIDS was a new disease and the epidemiology was consistent with an
(a) HIV cultures/co-cultures are stimulated with such oxidising agents
as PHA, ConA, radiation, PMA, polybrene and IL-2;
(b) these agents at relatively low concentration can induce decrease
in CD4 expressing cells, in the absence of HIV (Acres et al., 1986; Hoxie
et al., 1986; Zagury et al., 1986; Scharff et al., 1988), without killing
(c ) in 1986, Zagury, Gallo and their associates (Zagury et al., 1986),
prepared T-cell cultures (which contained 34% CD4+ cells), from normal
donors. Cultures were stimulated with PHA and were (i) "infected"
with HIV; (ii) left uninfected. Control cultures remained both unstimulated
and uninfected. After 2 days of culture, the proportion of CD4+ cells in
the stimulated-uninfected and stimulated-infected cultures was 28% and
30% respectively, while at 6 days the number was 10% and 3%; the controls
not changing significantly.
Thus, HIV is not necessary for the disappearance of CD4 expressing cells,
as measured by the use of MCA in "HIV infected" stimulated cultures.
The stimulants can induce the effect in the absence of "HIV".
Furthermore, the decrease in T4 cells may not be due to destruction of
T4 cells but to a decrease in the number of cells binding MCA.
Even if the in vitro evidence shows that HIV is a cytopathic retrovirus
and that it preferentially infects and kills T4 lymphocytes, evidence must
exist that the same effect takes place in vivo, that is, patients infected
with HIV have diminished numbers of T4 cells which is caused by preferential
infection and killing of these cells by HIV.
Following the frequent diagnosis of KS, PCP and other opportunistic
infections (OI) in gay men and intravenous (IV) drug users, it was realised,
when T lymphocytes of these patients were reacted with MCA to the CD4 antigen,
the number of CD4 antigen bearing cells is diminished. This led to a diagnosis
of "acquired immune deficiency" defined as a decrease in T4 cell
number, which was thought then and now to be due to the death of T4 cells.
This finding, together with the then known fact that patients who were
treated with the so called immunosuppressive drugs or who suffered from
"immunosuppressive illness" had relatively high frequencies of
KS and OI, led to the conclusion that the high frequencies of these diseases
in gay men, IV users as well as haemophiliacs amongst others, were the
direct result of suppressed cellular immunity (immunosuppression) defined
by diminished numbers of T4 helper cells (cell-mediated immunodeficiency).
In 1982, the Center for Disease Control (CDC) defined a case of AIDS as
"illnesses in a person who 1) has either biopsy-proven KS or biopsy-or
culture-proven life-threatening opportunistic infection, 2) is under age
60, and 3) has no history of either immunosuppressive underlying illness
or immunosuppressive therapy" (CDC, 1982). The claim by Gallo and
his colleagues in 1984 that AIDS is caused by HIV led the CDC to redefine
In 1985 the CDC defined AIDS as: "I. one or more of the opportunistic
diseases listed below (diagnosed by methods considered reliable) that are
at least moderately indicative of underlying cellular immunodeficiency;
and II. absence of all known underlying causes of cellular immunodeficiency
(other than LAV/HTLV-III infection) and absence of all other causes of
reduced resistance reported to be associated with at least one of those
Despite having all the above, patients are excluded as AIDS cases if
they have negative result(s) on testing for serum antibody to LAV/HTLV-III,
do not have a positive culture for LAV/HTLV-III, and have both a normal
or high number of T- helper (OKT4 or LEU3) lymphocytes and a normal or
high ratio of T-helper to T-suppressor (OKT8 or LEU2) lymphocytes. In the
absence of test results, patients satisfying all other criteria in this
definition are included as cases" (WHO, 1986).
This definition presupposes that proof exists or can be obtained that
HIV is the sole cause of the acquired immune deficiency (decreased T4)
which, in turn, leads to the appearance of the clinical syndrome. Such
a proof can only be obtained by the administration of PURE HIV to healthy
humans or, as Montagnier (Vilmer et al., 1984) pointed out in 1984, "Definite
evidence will require an animal model in which such viruses could induce
a disease similar to AIDS". At present no animal AIDS model exists
and of course it is not ethical to administer HIV, pure or otherwise, to
humans (Papadopulos-Eleopulos et al., 1993a). In the absence of the above
one must, at the very least, have (indirect) evidence that:
(a) in HIV positive individuals, at least by the time diseases attributed
to HIV infection such as persistent generalised lymphadenopathy (PGL) and
AIDS-related complex (ARC) have appeared, there is an abnormally low T4
(b) in patients defined as AIDS cases the decrease in T4 cells follows
and does not precede "HIV infection", as evidenced by a positive
HIV antibody test;
(c ) patients before, during or after seroconversion have not been exposed
to any agents known to cause immunosuppression;
(d) following seroconversion there must be a steady decrease in T4 cell
However, three years after seroconversion the majority of HIV positive
individuals continue to have normal T4 cell counts (Detels et al., 1988).
Even in the presence of PGL and other "constitutional symptoms of
HIV-related diseases", a significant number of patients continue to
have normal T4 cell numbers (T4/T8 ratio). In some individuals, seroconversion
is followed by an increase, not a decrease in T4 cells (Detels et al.,
1988; Natoli et al., 1993).
When AIDS was first diagnosed in gay men and IV drug users, but before
the discovery of HIV, epidemiological data, some of which appeared in the
Morbidity and Mortality Weekly Reports published by the CDC, rapidly accumulated
which showed that in the 1970's, individuals from the AIDS risk groups
suffered from many infectious and non-infectious diseases unrelated to
AIDS. Data was recently presented from the Multicenter AIDS Cohort Study
(Hoover et al., 1993) (MACS) which shows that HIV seropositive gay men
"at least 1.67-3.67 years prior to a clinical diagnosis of AIDS",
as well as HIV seronegative gay men, although the frequency in the latter
is lower, suffer from a wide variety of complaints including fatigue, shortness
of breath, night sweats, rash, cough, diarrhoea, headaches, thrush, skin
discolouration, fever, weight loss, sore throat, depression, anaemia and
sexually transmitted diseases. Evidence which existed at the beginning
of the AIDS era, or which has accumulated since, shows that some of the
diseases which occurred in these individuals, or the agents which caused
them, including Epstein-Barr virus and CMV, are immunosuppressive (Papadopulos-Eleopulos,
1988). Many of the agents used in treatment, including corticosteroids
and some antibiotics, as well as the recreational drugs used by both gay
men and drug users, are also known to be immunosuppressive. From the start
of the epidemic, the CDC was aware that approximately 50% of gay men used
nasal cocaine and about the same proportion smoked marijuana. Nitrite use
was considered practically ubiquitous.
That the immunosuppression found in AIDS patients is not caused by HIV
is indicated by the fact that individuals from the AIDS risk groups may
have low T4 cell numbers (T4/T8 ratio), even in the presence of a persistently
negative HIV antibody test (Drew et al., 1985; Novick et al., 1986; Donahoe
et al., 1987; Detels et al., 1988). Although one such study showed "reduced
proliferative response to the T cell mitogen PHA in AIDS...PHA responses
in symptomless HIV infection, with or without lymphadenopathy, were also
significantly reduced compared to heterosexual controls. However seronegative
homosexuals had similarly reduced PHA responses. Thus, in symptomless infection,
HIV does not appear to cause more impairment than seen in their uninfected
peers...Our findings re-emphasise the importance of using seronegative
peer group controls in studies on HIV infection" (Rogers et al., 1989).
In considering the data from haemophiliacs, a group of British researchers,
including the well known retrovirologist Robin Weiss, concluded in 1985:
"We have thus been able to compare lymphocyte subset data before and
after infection with HTLV- III. It is commonly assumed that the reduction
in T-helper- cell numbers is a result of the HTLV-III virus being tropic
for T-helper-cells. Our finding in this study that T-helper- cell numbers
and the helper/suppressor ratio did not change after infection supports
our previous conclusion that the abnormal T-lymphocyte subsets are a result
of the intravenous infusion of factor VIII concentrates per se, not HTLV-III
infection" (Ludlam et al., 1985).
In relation to patients with haemophilia A, von Willebrand's disease
and "hypertransfused patients with sickle cell anaemia" Kessler
et al found that: "Repeated exposure to many blood products can be
associated with development of T4/T8 abnormalities" including "significantly
reduced mean T4/T8 ratio compared with age and sex-matched controls"
(Kessler et al., 1983). In 1984, Tsoukas et al observed that amongst a
group of 33 asymptomatic haemophiliacs receiving factor VIII concentrates,
66% were immunodeficient "but only half were seropositive for HTLV-III",
while "anti-HTLV-III antibodies were also found in the asymptomatic
subjects with normal immune function". They summarised their findings
as follows: "These data suggest that another factor (or factors) instead
of, or in addition to, exposure to HTLV-III is required for the development
of immune dysfunction in haemophiliacs" (Tsoukas et al., 1984).
By 1986 researchers from the CDC concluded: "Haemophiliacs with
immune abnormalities may not necessarily be infected with HTLV-III/LAV,
since factor concentrate itself may be immunosuppressive even when produced
from a population of donors not at risk for AIDS" (Jason et al., 1986)
(factor concentrate=factor VIII). In 1985 Montagnier (Montagnier, 1985)
wrote: "This [clinical AID] syndrome occurs in a minority of infected
persons, who generally have in common a past of antigenic stimulation and
of immune depression before LAV infection", that is, Montagnier recognised
that in the AIDS risk groups, AID appears before "HIV infection"
[LAV=HIV]. A recent study of IV drug users in New York (Des Jarlais et
al., 1993) showed that "The relative risk for seroconversion among
subjects with one or more CD4 count <500 cells/uL compared with HIV-negative
subjects with all counts >500 cells/uL was 4.53". A similar study
in Italy (Nicolosi et al., 1990) showed that "low number of T4 cells
was the highest risk factor for HIV infection", that is, decrease
in T4 cells is a risk factor for seroconversion and not vice versa. The
observations that T4 decrease precedes a positive antibody test ("HIV
infection"), is additional (Papadopulos-Eleopulos et al., 1993a) evidence
that factors other than HIV lead to both T4 decrease and positive "HIV"
Thus gay men, IV users and haemophiliacs, have "known underlying
causes of cellular immunodeficiency (other than LAV/HTLV-III infection)",
and therefore, according to the 1985 CDC AIDS definition, these individuals
cannot be AIDS cases. The finding in individuals belonging to the above
groups of a decreased T4 cell number and decreased T4/T8 ratio, even if
due to killing of T4 cells and not to "modulation of T4 molecules
at the cell membrane or steric hindrance of antibody-binding sites",
cannot be interpreted as being caused by HIV. Nonetheless, from 1981 to
the present, gay men, IV users and haemophiliacs form the vast majority
of AIDS cases.
From the beginning, it was realised that in AIDS patients the decrease
in T4 lymphocytes is accompanied by an increase in T8 lymphocytes while
the total T cell population remains relatively constant. This has recently
been confirmed by Margolick et al who showed that the decline in T4 cells
in HIV positive individuals is accompanied by a T8 increase "with
kinetics that mirrored the loss of CD4+ cells, resulting in a CD8 polarization"
(Margolick et al., 1993; Stanley & Fauci, 1993).
This finding has been neglected until recently when a theory has been
put forward to explain how infection of even a small proportion of T4 cells,
(perhaps 1/1000) can have this effect. This theory states that "loss
of either CD4+ or CD8+ T cells is detected by the immune system only as
a decrease in CD3+ T cells. The compensatory response to such a selective
decrease, then, is to generate both CD4+ and CD8+ T cells in order to bring
the total CD3+ T cells back to a normal level. The consequence of this
nonselective T cell replacement after a selective depletion of one T cell
subset would be an alteration in the CD4 to CD8 ratio after normalization
of the total T cell count with a polarization toward the subset that had
not been initially depleted...repeated events of selective CD4+ T-cell
killing will result in higher and higher CD8+ T- cell count and lower and
lower CD4+ T-cell count" (Adleman & Wofsy, 1993; Margolick et
al., 1993; Stanley & Fauci, 1993)
However, a brief look at the history of the discovery of the T4 and
T8 cells and the presently available data show that the above theory may
not be valid.
In 1974, a group of researchers from the National Cancer Institute USA
observed that when normal lymphocytes were cultured with T-cells from hypogammaglobulinaemic
patients in the presence of PWM, the synthesis of immunoglobulin (antibodies)
by the normal lymphocytes was depressed by 84% to 100%. They put forward
the hypothesis "that patients with common variable hypogammaglobulinemia
have circulating suppressor T lymphocytes that inhibit B-lymphocyte maturation
and immunoglobulin synthesis" (Waldman et al., 1974). Subsequently,
it was shown that ConA stimulated T cells from healthy animals "can
under appropriate circumstances perform helper, suppressor, and killer
functions" (Jandinski et al., 1976). By 1977 many studies of the cellular
basis of the immune response had indicated that T cells have both suppressive
and helper activities and it was concluded that "these activities
are specialized functions of distinct subclasses of T cells", which
could be distinguished by cell- surface components thought to be specific
to each subclass (Cantor & Boyse, 1977). In the late 1970s the discrimination
and separation of these two subclasses were facilitated by the development
of MCA to cell-surface antigens considered specific for each subclass,
the subclasses being given the name T4-helper and T8-suppressor cells (Reinherz
et al., 1979). By 1980 it was generally accepted that:
(a) in humans the CD4 antigen and the CD8 antigen are expressed on helper
and suppressor T cell subsets respectively. "Each T-cell subclass
has a unique set of biological properties and immunologic functions"
(Cantor & Boyse, 1977). "T4+ T cells provide helper function for
optimal development of cytotoxicity in cell-mediated lympholysis...In addition,
the T4+ subset produces a variety of helper factors that induce B cells
to secrete immunoglobulin and all lymphocyte subpopulations (T,B and null)
to proliferate". The T8 subset "suppresses the proliferative
response of other T cells and B-cell immunoglobulin production and secretion"
(Reinherz et al., 1981).
(b) "cells of these two subclasses do not give rise to one another...they
represent products of separate subclasses of thymus dependent maturation",
that is, "although both T4+ and T5+ subsets arise from a common progenitor
cell within the thymus, they diverge during ontogeny and result in separate
(c ) "stimulation of T cells by conventional antigens, histocompatibility
antigens and mitogens results in the formation of suppressor T cells"
(Cantor & Boyse, 1977;
Reinherz et al., 1980; Reinherz et al., 1981).
The conclusion in (a) and (b) are at odds with evidence published in
the 1980s. In 1989 it was shown that when "monocytes adhered to plastic
(but not when cultured on Teflon), a significant decrease in CD4 expression
was observed between 1 and 24 h post-adherence. CD4 expression could not
be detected in macrophages adhered to plastic for 5 days by using four
anti-CD4 monoclonal antibodies in flow cytometry or direct immunofluoresence.
Conversely, an increasing proportion of adherent cells expressed LeuM3
and OKM5 surface antigens over the 5 days". It was also shown that:
(a) "The down-regulation of CD4 was post-translational";
(b) unlike monocytes cultured on Teflon, the adherence of monocytes
to plastic resulted in superoxide anion generation, that is, oxidative
stress (Kazazi et al., 1989).
In the early 1980s, many researchers found that under certain conditions,
while the number of T4 cells decreases, the number of T8 cells increases
and the total number of cells remains constant or even increases. In 1982
Birch et al showed that incubation of T lymphocytes with adenosine or impromidine,
(an H2 histamine agonist), leads to a decrease in the number of T- cells
expressing the CD4 antigen and to an increase in the number of T-cell expressing
the CD8 antigen whilst the sum (T4 + T8) remains constant (Birch et al.,
1982). In an experiment conducted in the same year by Burns et al (Burns
et al., 1982), normal human peripheral blood lymphocytes from different
subjects were grown in conditioned medium containing IL-2, and, after varying
periods of time in culture, the cells were tested by indirect immunofluorescence
for OKT4 and OKT8. The "conditioned medium" (CM) consisted of
"cell-free supernatant passed through a bacterial filter" from
7-day cultures of PHA stimulated leucocytes obtained from patients with
hemochromatosis. "For some experiments CM was freed of residual PHA
by passage over a thyroglobulin-Sepharose column". They found that
"...the cell population progressively increased in size to large blasts...but
most striking was the rapid change in the OKT4:OKT8 ratio of cells within
the population, from 60:40 to 40:60...The change in the surface phenotype
of the major population also occurred in cultures maintained in medium
containing IL2 which had been freed of PHA". They also found that
the "change in phenotype of the culture as a whole took place very
rapidly, often within one day", by 3 weeks the ratio OKT8:OKT4 was
about 70:30, and that the "change did not appear to be simply the
preferential outgrowth of OKT8+ cells", but to a "possible change
in phenotype of cultured human lymphoblasts, from OKT4 to OKT8" (Burns
et al., 1982). One year later in 1983, Zagury, an eminent HIV researcher
(Zagury et al., 1983) and Gallo collaborator, and his colleagues, selected
normal human T cells for in vitro cloning according to the expression of
T4, T8 or T10 antigens on individual cells. The individual cells were cultured
in the presence of TCGF (IL-2) "Preparations deprived of PHA",
and "an irradiated lymphoid cell filler- layer". They summarised
their findings as follows: "Clones were produced from each of these
cells irrespective of the antigenic phenotype of the parental cell. The
cloned progeny manifested, in many cases, shifts in antigen expression.
Thus, T4+T8- cells gave clones expressing predominantly T4-T8+ and vice
versa. The clonal expression of T4 and T8 seemed to be mutually exclusive.
Antigenic shifts were recorded also in clones derived from T4-T8-T10- cells,
resulting in T10+ clones which were also either T4+ or T8+ and from T4+T8-T10+
cloned cells yielding clones of either T4+ or T8+ cells. Testing functional
properties we found that NK activity was mediated not only by T10+ cells
but also, in some cases, by T4+ and T8+ cells. Moreover, TCGF production,
which may reflect helper activity, was mediated not only by T4+ cells.
Only the cytotoxic (CTL) activity seems to be confined to the T8 phenotype.
Thus, it appears that T antigens, which seemed to be molecular markers
of differentiation, are not markers for terminal differentiation and do
not always reflect defined functional properties" (Zagury et al.,
Given the in vitro evidence that:
(1) HIV is neither necessary nor sufficient for the observed decrease
in T4 cell numbers;
(2) T4 cells can change into T8 cells while the sum of T4 + T8 remains
(3) stimulation of T cells by PHA, ConA, radiation, PMA and polybrene
all of which are oxidising agents leads to "down regulation"
of CD4 and change of T4 to T8; and the evidence that:
(i) individuals from the AIDS risk groups are exposed to many oxidising
agents including well known mitogens;
(ii) in individuals at risk for developing AIDS the decrease in T4 cell
number is paralleled by an increase in T8 cells (decrease in the T4/T8
ratio), while the total T cell numbers remains constant;
(iii) in individuals belonging to the main AIDS risk groups the above
changes can be observed in the absence of HIV,
one must conclude that:
(a) the decrease in the T4 cell numbers and increase in T8 cell numbers
in "HIV infected" cultures and individuals is due to agents other
than HIV; HIV is neither necessary nor sufficient for the induction of
the above phenomenon;
(b) in vivo the above changes may not be due to a selective destruction
of T4 cells and increased proliferation of T8 cells, but loss of T4 surface
markers and acquisition of T8 surface markers.
T4 and the clinical syndrome
The HIV/AIDS researchers consider T4 decrease as being the "hallmark"
and "gold standard" of HIV infection and AIDS (Shaw et al., 1988;
Levacher et al., 1992). In fact, in the most recent (1992) CDC AIDS definition,
an AIDS case can be defined solely on serological, (positive HIV antibody
test), and immunological (T4 cell count less than 200 X 106/L), evidence
(CDC, 1992). The new definition also requires that "the lowest accurate,
but not necessarily the most recent, CD4+ T- lymphocyte count should be
used" to define an AIDS case (CDC, 1992). However, ample evidence
exists that T4 cell decrease can be induced by many factors, some trivial,
such as sun bathing and solarium exposure, a decrease which can persist
for at least two weeks after exposure has ceased (Hersey et al., 1983;
Walker & Lilleyman, 1983). T4 cell counts "can vary widely between
labs or because of a person's age, the time of day a measurement is taken,
and even whether the person smokes" (Cohen, 1992). That many factors
can affect the T4 cell number is reflected by their large variation in
HIV positive patients. In one such study, patient measurements repeated
by one laboratory within 3-days showed a "minimum CD4+ cell count
of 118 cells/mm3 and a maximum CD4+ cell count of 713 cells/mm3" (Malone
et al., 1990). In the MACS, consisting of 4954 "homosexual/bisexual
men", it was stressed that physicians and patients should be "aware
that a measured CD4 cell count of 300X106/L really may mean it is likely
that the "true" CD4 cell state is between 178 and 505X106/L.
Thus there is no certainty this person's "true CD4" is less than
500X106/L or that it is greater than 200X106/L" (Hoover et al., 1992).
It is important to note that these variations were obtained despite the
fact that the CD4 measurements were undertaken in laboratories which "are
carefully standardized in an ongoing quality control program".
In a study (Brettle et al., 1993) which examined the impact of the 1993
CDC AIDS definition on the annual number of AIDS cases as compared to the
1987 definition, it was found that if the definition was based on:
(i) the "first of two consecutive CD4 cell counts < or equal
to 200 X 106/L", the number of AIDS cases doubled;
(ii) one abnormal CD4 count, the number of AIDS cases trebled.
Researchers at the University of California at Los Angeles School of
Medicine found that 5% of healthy persons seeking life insurance had abnormal
T4 cells counts, and that "In a subgroup of patients, the low T-cell
numbers or ratios appear to be stable findings". They concluded: "In
the absence of a history of a specific infection or illness or major abnormalities
on a physical examination, it is not worthwhile to attempt to find a specific
cause for the abnormality of T- cell subsets...A uniform approach to this
problem throughout the medical community will help alleviate patients'
anxiety and reduce the concern of the insurance industry about this relatively
common problem" (Rett et al., 1988).
If LAS, ARC, and the AIDS indicator diseases such as KS and PCP are
the consequence of T4 cell depletion then all groups of people who have
a low T4 cell count, irrespective of cause, should have high frequencies
of opportunistic infections and neoplasms. Conversely, all patients with
AIDS indicator diseases should have abnormally low T4 cells.
In a study on the effects of blood transfusion on patients with thalassaemia
major, researchers at the Cornell University Medical Center and the Sloan-Kettering
Institute for Cancer Research observed decreased T4 cell numbers and inverted
T4/T8 ratios associated with the transfusions, but no increase in KS or
PCP, and concluded that "...studies which define transfusion related
AIDS on the basis of analyses with monoclonal antibodies must be viewed
with caution" (Grady et al., 1985). Although patients with alcoholic
liver disease do not develop KS, PCP and other AIDS indicator diseases
more often than usual, they have both immune deficiency and positive HIV
antibody tests leading researchers from the Veterans Administration Medical
Centre to stress the importance of recognising these facts: "...lest
these patients be falsely labelled as having infection with the AIDS virus
and suffer the socioeconomic consequences of this diagnosis" (Mendenhall
et al., 1986).
Patients who have malaria have severe immunoregulatory disturbances
including decrease in T4 cells. A significant number of these patients
also test positive for HIV but they do not develop the AID clinical syndrome,
leading Volsky et al to conclude, "exposure to HTLV-III/LAV or the
related retrovirus and the occurrence of severe immunoregulatory disturbances
may not be sufficient for the induction of AIDS" (Volsky et al., 1986).
The MACS in the USA showed that "even in the absence of treatment,
close to 25, 15 and 10% of men were alive and asymptomatic 4, 5 and 6 years
after first CD4+ <200 X 106/L measurement" (Hoover, 1993). In the
same study comparing HIV positive individuals who within five years progressed
to AIDS (Group A) with that those who did not (Group B), it was found that:
"receptive anal intercourse both before and after seroconversion with
different partners was reported more frequently by men with AIDS. The ratio
of the differences in this sexual activity between groups A and B was higher
at 12 (2.3) and 24 (2.6) months after seroconversion than before seroconversion
(2.0)". It was concluded that "sexually transmitted co-factors,
preseroconversion and/or postseroconversion...augment (or determine) the
rate of progression to AIDS" (Phair et al., 1992). However, since:
(a) sexually transmitted infectious agents are bi- directionally transmitted,
that is, from the active to the passive partner and vice-versa;
(b) in the above study the only sexual act directly related to the progression
to AIDS was passive anal intercourse (unidirectionally);
one would have to conclude that the "co-factors that augment (or
determine)" progression to AIDS are non-infectious. These findings
are in agreement with the oxidative theory of AIDS which claims that both
HIV phenomena (RT, virus-like particles, antigen/antibody reactions, "HIV-PCR")
and AIDS are caused by the many oxidative agents (including semen), to
which the AIDS risk groups are exposed (Papadopulos-Eleopulos, 1988; Papadopulos-Eleopulos
et al., 1989a; Papadopulos-Eleopulos et al., 1992a; Papadopulos-Eleopulos
et al., 1992b) [PCR=polymerase chain reaction].
According to Canadian researchers, "In TB as well as in lepromatous
leprosy, an immunosuppressive state will frequently develop in the host.
This state is characterised by T lymphopenia with a decreased number of
T helper cells and an inverted T-helper/T-suppressor cell ratio ...immunosuppression
induced by the infection with M.tuberculosis can persist for life, even
when TB is not progressive" (Lamoureux et al., 1987). Yet these patients
do not have high frequencies of KS, PCP or other AIDS indicator diseases.
In other words, decrease in T4 cells is not sufficient for the AIDS indicator
diseases to appear. This is also supported by evidence from animal studies.
Experimental depletion of T4 cells in mice used as models for systemic
lupus erythematosus in humans did not lead to increased frequencies of
neoplasms, nor did mice "develop infectious complications, even though
they were housed without special precautions". In fact mice with low
T4 cell numbers had "prolonged life" (Wofsy & Seaman, 1985)
It is also of interest that despite the indispensable role attributed to
T4 and T8 lymphocytes in antibody production (helper and suppressor respectively),
AIDS patients in the presence of low numbers of T4 cells and high numbers
of T8 cells, have increased levels of serum gammaglobulins, and are not
hypogammaglobulinaemic as might be expected. Also, although human umbilical
cord T-cells produce suppressor factors(s), the factor(s) is produced by
T8- (T4+) not T8+ cells (Cheng & Delespesse, 1986). Thus, T4 and T8
cells do not seem to possess the generally accepted functions attributed
According to the HIV theory of AIDS pathogenesis, "The Human Immunodeficiency
Virus (HIV), the etiologic agent of the acquired immunodeficiency syndrome
(AIDS), has the capability of selectively infecting and ultimately incapacitating
the immune system whose function is to protect the body against such invaders.
HIV-induced immunosuppression results in a host defense defect that renders
the body highly susceptible to "opportunistic" infections and
neoplasms" (Fauci, 1988). Decrease of T4 cells to approximately 200X106/L
leads to the development of "constitutional symptoms", and to
less than 100X106/L to "Opportunistic diseases" (Pantaleo et
al., 1993). If this is the case then:
1. In all individuals with "constitutional symptoms", OI and
neoplasms, the T4 cell number should be abnormally low;
2. The decrease in T4 cells should precede the development of the clinical
symptoms since: (a) the cause must precede the effect; (b) for many neoplastic
and infectious diseases, there is evidence that the diseases themselves
and the agents used to treat them may induce immune suppression including
decreased numbers of T4 lymphocytes and reversal of T4/T8 ratios.
This is not the case even for the most serious and characteristic of
the AIDS diseases, KS and PCP. In the MACS it was reported that:
(a) "...persistent generalised lymphadenopathy was common but unrelated
to immunodeficiency", and "Although seropositive men had a significantly
higher mean number of involved node groups than the seronegative men (5.7
compared with 4.5 nodes, p<0.005), the numerical difference in the means
is not striking".
(b) weight loss, diarrhoea, fatigue, fever, which constitute the "wasting"
syndrome, (which at present is an AIDS indicator disease), night sweats,
herpes zoster, herpes simplex (another AIDS indicator disease), oral thrush,
fungal skin infections and haematological abnormalities, were present in
both seronegative and seropositive individuals, although some of them were
present at higher frequencies in the latter group. A relationship was found
between thrush, anaemia, fever and neutropenia and T4 cell deficiency.
However, "the clinical abnormalities were considerably better at reflecting
concurrent CD4 lymphocyte depression than the low CD4 lymphocyte counts
were at determining clinical involvement" (Kaslow et al., 1987). These
observations are just as compatible with the hypothesis that T4 lymphocyte
deficiency is the result and not the cause of the observed clinical abnormalities.
KS, the main reason for which the retroviral hypothesis was put forward,
was initially postulated to be caused by infection of normal cells with
the retrovirus. When, late in 1984 it became clear that the KS cells were
not infected with HIV, it was generally accepted that the disease was caused
by HIV indirectly, that is, as a consequence of T4 cell decrease.
At present, it is generally believed that KS is caused by "a specific
sexually transmitted etiologic agent" (Beral et al., 1990; Weiss,
1993) other than HIV, but "immune suppression (both in AIDS and in
transplant patients) is the dominant cofactor for subsequent disease"
(Weiss, 1993). However, unlike the Unites States CDC and most AIDS centres
around the world, for the Walter Reed Army Institute of Research "...the
presence of opportunistic infections is a criterion for the diagnosis of
AIDS, but the presence of Kaposi's sarcoma is omitted because the cancer
is not caused by immune suppression..." (Redfield & Burke, 1988)
In a study by a group of researchers from Amsterdam regarding the relationship
between the T4 cell number and the development of the clinical syndrome,
KS was excluded "Because Kaposi's sarcoma may manifest at higher CD4+
lymphocyte counts than other AIDS- defining conditions" (Schellekens
et al., 1992). This is not surprising since by the beginning of the AIDS
era, the immune surveillance hypothesis of carcinogenesis had been already
refuted (Kinlen, 1982). In fact, the presently available data indicate
that KS in all individuals, including gay men, may be caused by a non-infectious
agent (Papadopulos-Eleopulos et al., 1992a). Even in the early stages of
the AIDS era, it was reported that KS in gay men appeared following corticosteroid
administration (which was administered for diseases totally unrelated to
HIV or AIDS) and resolved when the drug was discontinued (Schulhafer et
al., 1987; Gill et al., 1989). Thus the HIV/AIDS hypothesis cannot account
for the very disease for which it was originally put forward.
In a study of 145 patients, 97% of whom were homosexuals, with biopsy
proven PCP at St. Vincent's Hospital and Medical Centre, New York, 17%
of AIDS patients had a T4 cell count higher than 500/mm3, and a further
14% between 301-500/mm3, "in addition, patients with T4-T8 ratio greater
than 1.0 and those with total T4 lymphocyte counts greater than 500/mm3
cells did not show improved survival compared with patients with abnormal
values....the degree of suppression did not influence mortality (Kales
et al., 1987). Researchers from the National Institute of Allergy and Infectious
Diseases and the National Cancer Institute, studied 100 HIV-infected patients
"who had 119 episodes of pulmonary dysfunction within 60 days after
CD4 lymphocyte determinations". T4 cells were less than 200X106/L
before 46 of 49 episodes of PCP, 8 of 8 episodes of CMV pneumonia, 7 out
of 7 Cryptococcal neoformans pneumonia, 19 of 21 episodes of Mycobacterium
avium-intracellulare pneumonia, 6 of 8 [pulmonary] KS and in 30 out of
41 non-specific interstitial pneumonia. However, "Before the 119 episodes
of pulmonary dysfunction were diagnosed in this study, the HIV- infected
patients had manifested the following clinical HIV- related disorders:
no disorders (4 episodes), Kaposi's sarcoma without opportunistic infections
(68 episodes), life- threatening opportunistic infection (44 episodes),
other AIDS- related conditions (11 episodes)". In addition before
the diagnosis of the pulmonary episodes the patients had received: "zidovudine
(36 episodes), interferon (23 episodes), recombinant interleukin-2 (3 episodes),
cytotoxic chemotherapy (16 episodes), dideoxycytidine (6 episodes), muramyl
tripeptide (1 episode), suramin (6 episodes), heteropolyanion 23 (5 episodes),
zidovudine plus interferon (5 episodes), nonablative bone marrow transplantation
(4 episodes). Twenty- two episodes occurred in patients who had been receiving
neither experimental therapy nor zidovudine" (Masur et al., 1989).
These data may be interpreted as showing that in some types of "pulmonary
dysfunction", most cases (but not all) appear to be preceded by a
CD4 count <200X106/L. However, given the well known fact that malignant
neoplasms, infectious diseases and the administration of chemotherapeutic
agents may themselves cause immunosuppression (Serrou, 1974; Oxford, 1980;
Reinherz et al., 1980; Rubin et al., 1981; Thomas, 1981; Weigle et al.,
1983; Williams et al., 1983; Kempf & Mitchell, 1985; Feldman et al.,
1989), it is equally plausible to argue that both "pulmonary dysfunction"
and the low CD4 cell counts observed in patients were the result of their
recent past illnesses and previous exposure to prescribed and illicit drugs
and other factors.
In a recent study it was found that 3 patients who developed PCP within
8-14 days of "symptomatic, primary HIV infection", had normal
T4 cell numbers and T4/T8 ratios 50-90 days before they became symptomatic.
During the symptomatic phase the T4 cell count dropped to 62-91 cells/uL.
However, "Within four months of symptom onset, their CD4 counts and
CD4/CD8 ratios returned to normal". In two of the patients, a bisexual
man and a gay man, "HIV-1 antibodies were detectable by EIA and WB"
30 days after these two individuals became symptomatic [EIA=ELISA].
"Twenty-nine to forty-eight months after acquiring HIV-1 infection",
all three patients still had normal T4 cell numbers and were asymptomatic.
The authors concluded "profound CD4 lymphocytopenia can revert to
normal without antiretroviral therapy" and stressed "it is important
that such cases are not misdiagnosed as AIDS" (Vento et al., 1993).
That no relationship exists between OI and T4 depletion was confirmed
in a recent study where it was shown that "The appearance of OI and
wasting syndrome was independent of T4 cells count" (Alejandro et
al., 1991), as well as other studies which show that the OI may appear
in the presence of normal T4 cell numbers (Stagno et al., 1980; Martinez
et al., 1991; Felix et al., 1992).
In conclusion, decrease in the number of T4 lymphocytes irrespective
of how it is induced, that is, by destruction of the T4 cells or by a phenotypic
change, and of its cause, is neither necessary nor sufficient for the appearance
of KS and OI including PCP, that is, of the clinical syndrome.
HIV and AIDS
If HIV is either necessary and sufficient, or necessary but not sufficient
for the appearance of AIDS, then the minimum requirement is that the virus
be present in all cases.
Three methods are used to demonstrate the presence of HIV: antibody
tests, viral "isolation", and PCR. At present, "the applications
of PCR in the evaluation of HIV-1 seropositive individuals are not completely
defined" (Conway, 1990). Although PCR has a very high sensitivity,
the test is not standardised and its reproducibility and specificity have
not been determined. The limited data presently available suggest that
PCR is neither reproducible nor specific (Fox et al., 1989; Conway, 1990;
Dickover et al., 1990; Long, Komminoth & Wolfe, 1992), even when the
serological status and not HIV, as should be the case, is used as a gold
standard (Defer et al., 1992). Furthermore, since the specificity of the
primers used in the PCR assay ultimately relate to the material originating
from "HIV isolates", the test specificity can be no more meaningful
(regarding the presence in AIDS patients of an exogenous retrovirus), than
"HIV isolation". However, HIV has never been isolated as an independent
particle separate from everything else. In fact, by isolation is meant,
at best, detection of two or more of the following phenomena:
(a) reverse transcriptase, either in the cultures/co-cultures or in
material derived from these cultures including nucleic acids and proteins
which in sucrose density gradients bands at a density of 1.16 gm/ml;
(b) proteins either in the cultures/co-cultures or banding at 1.16 gm/ml
and which react with AIDS patient sera;
(c ) virus-like particles in the cultures.
Lately, for many researchers including Montagnier (Learmont et al.,
1992; Henin et al., 1993), detection in cultures/co- cultures of only p24
or reverse transcription is considered synonymous with "HIV isolation".
The finding of the above phenomena cannot be considered synonymous with
"HIV isolation". They can be used only for viral detection, and
then if and only if, they have first been proven specific for the virus.
Not one of the above phenomena is specific to HIV or even to retroviruses
(Papadopulos-Eleopulos, Turner and Papadimitriou, 1993a). Furthermore,
and most importantly, HIV cannot be isolated unless the cultures are subjected
to oxidative stress (mitogenic stimulation, activation).
1. The normal human genome contains many copies of endogenous retroviral
sequences (proviruses), "including a complex family of HIV-1 related
sequences" (Horwitz et al., 1992), a "large fraction" of
which "may exist within a host cell as defective genomic fragments.
The process of recombination however may allow for their expression as
either particle or synthesis of a new protein(s)" (Weiss et al., 1982;
Varmus & Brown, 1989; Cohen, 1993; Löwer & Löwer, 1993;
Minassian et al., 1993);
2. Cultivation of normal "non-virus" producing cells leads
to retroviral production (expression), "the failure to isolate endogenous
viruses from certain species may reflect the limitations of in vitro cocultivation
techniques" (Todaro et al., 1976). The expression can be accelerated
and the yield increased by exposing the cultures to mitogens, mutagens
or carcinogens, co-cultivation techniques and cultivation of cells with
supernatant from non-virus producing cultures (Toyoshima & Vogt, 1969;
Aaronson et al., 1971; Hirsch et al., 1972). For HIV isolation, in most
instances, all the above techniques are employed. Thus, even if "true"
(Popovic et al., 1984) retroviral isolation can be achieved from the AIDS
cultures/co-cultures, it would be difficult if not impossible to be certain
that the retrovirus in question is an exogenous retrovirus. For such evidence
to be accepted as proof of the existence of HIV, the activation of an endogenous
provirus or a provirus assembled by recombination of endogenous retroviral
and cellular sequences would need to be rigorously excluded. For example,
in many cases of "HIV isolation", the human leukaemic cell lines
CEM or HT(H9) are co-cultured with tissue from AIDS patients which is assumed
to be "infected with HIV".
The finding of two or more of the following:
(i) reverse transcription; (ii) proteins which react with patient sera
either in the co-cultures or the material which bands at 1.16 gm/ml; (iii)
retrovirus-like particles in the culture; is considered as proof of the
isolation from the patient of a retrovirus (HIV) which infected the CEM
or HT (H9) cells.
However, when CEM (CEM-SS) cells "otherwise negative for known
human retrovirus", are stimulated with the mutagen ethyl- methyl-sulfonate
(EMS), "Large, syncytia-like cells reminiscent of those which appear
after a retrovirus infection were observed 5-6 days after treatment...Cell-free
supernatants from CEM-SS cells heavily treated with EMS were able to induce
a transmissible retrovirus infection in Jurkat and Molt 3 cells...All attempts
to identify viral expression in the unmutagenized parental cells by EM,
RT activity, or immunohistochemical methods were negative" (Minassian
et al., 1993) [EM=electron microscopy]. It has already been stated that
the HT cell line originated from a patient with adult T4 cell leukaemia,
a disease which Gallo claims is caused by another retrovirus, HTLV-I. If
this is the case, CEM and HT (H9) cultures would have retrovirus which,
under the right conditions, would be expressed even if the patient tissues
did not contain "HIV". Be this as it may, neither PCR nor "HIV
isolation" have ever been used to demonstrate a causal relationship
between HIV and AIDS.
At present, as was the case in 1984, the claim that a "causal relation
between HIV and AIDS is compelling" is based on the epidemiological
relationships between a positive "HIV antibody" test and AIDS
(Weiss, 1993). One of these tests, the Western blot (WB), is considered
to be both nearly 100% sensitive and specific, and is used as a gold standard
for the other tests. Despite knowledge that cellular constituents and/or
fragments of the same buoyant density as retroviral particles may contaminate
the supernatants of cell cultures (Papadopulos-Eleopulos, Turner &
Papadimitriou, 1993a), material for the WB is obtained by density gradient
centrifugation of the supernatant from "HIV infected" cell cultures
or even cell lysates, the latter being the case in the first "HIV
isolation" (Barré-Sinoussi et al., 1983), and subsequently
in other laboratories (Essex et al., 1985; Albert et al., 1988; Levinson
& Denys, 1988). Material which bands at 1.16 gm/ml is considered to
represent pure HIV and consequently the proteins found at this density
are considered to be HIV antigens. For the Western blot, these proteins
are electrophoretically separated according to molecular weight and charge.
The separated proteins are then transferred on to nitrocellulose strips
by electroblotting. When sera are added and the strips developed, coloured
bands appear representing sites of protein/antibody reactions. Each band
is designated by a small "p" for protein, followed by its molecular
weight in thousands. Although the material which bands at 1.16gm/ml is
considered to represent pure HIV, many of the proteins which band at this
density are accepted to be cellular proteins (Henderson et al., 1987),
including proteins which react with patient sera: "Sera from some
AIDS patients bound a lot of cellular protein. In ELISA this problem was
overcome by comparing the serum binding to the viral antigen with binding
to a lysate of uninfected lymphocytes. This binding was apparent in the
RIPA and only sera which specifically precipitated the p25 [p24] were regarded
as positive" [RIPA=radioimmune precipitation assay] (Brun-Vezinet
et al., 1984; Burke, 1989). Even the proteins which are considered to be
HIV proteins may not be so (Papadopulos-Eleopulos et al., 1993a; Papadopulos-Eleopulos
et al., 1993b). For example, the p41 band which is considered by most AIDS
researchers as one of the most specific HIV proteins, is regarded by Montagnier's
group as being cellular actin (Barré-Sinoussi et al., 1983). Furthermore,
the pattern of reaction, including that of the bands considered to represent
HIV proteins varies, from patient to patient and in the same patient from
time to time. Because of this, criteria for the interpretation of the WB
are necessary. Yet, even today, 10 years after the discovery of HIV, there
are no national USA or international agreed criteria as to what constitutes
a positive WB pattern. Some institutions have more "stringent"
criteria than others to define a positive WB. When the WB pattern does
not satisfy the definition for a positive test for a given institution,
but displays reactive bands, representing either cellular or "HIV
proteins", the test is considered to be indeterminate, (WBI). A WB
which has no reactive bands, representing either "HIV" or cellular
proteins, is considered by all institutions as negative (Lundberg, 1988).
For some time evidence has existed showing that:
(a) when the least "stringent" criteria used to define a positive
WB are [p24 or p31/32 and (p41 or p120/160)], only approximately 80% of
AIDS patients test positive for HIV and this decreases to less than 50%
when the most "stringent" [p24 and p31/32 and (p41 or p120/160)]
criteria are used. The remaining AIDS patients have either an indeterminate
or a negative test (Lundberg, 1988). Conversely, according to the USA Consortium
for Retrovirus Serology Standardization, 127/1306 (10%) of sera from individuals
at "low risk" of HIV infection, which "includes specimens
from blood donor centers" have a positive WB even when the most "stringent"
criteria are used to define a positive test (Lundberg, 1988). (The Consortium
authors did not comment on the significance of the occurrence of such stringently
positive tests in low risk individuals).
(b) WBI are very common in non-AIDS patients. For example, 42% of patients
transfused with HIV negative blood have WBI results. In about 30% of these
patients, the WBI contains the p24 band, the band considered by Montagnier's
group to be the most specific HIV band (Genesca et al., 1989). (In fact
at present, for many researchers, the detection of p24 in AIDS cultures/co-cultures
is synonymous with "HIV isolation"). These results lead some
HIV researchers to conclude that "WBI patterns are exceedingly common
in randomly selected donors and recipients and such patterns do not correlate
with the presence of HIV-1 or the transmission of HIV-1" (Genesca
et al., 1989).
(c ) the specificity of an antibody test must be determined by the use
of a gold standard. The only valid gold standard for the HIV antibody tests
is HIV itself. However, to date, nowhere in the AIDS scientific literature
has there been any report whatsoever of the use of "Human Immunodeficiency
Virus" itself as a gold standard for the verification of the sensitivity
and specificity of the HIV antibody tests. In fact, this may not be presently
possible since, even if one considers the phenomena detected in AIDS cultures/co-cultures
to be HIV and the methods used to represent unequivocal isolation, in the
best laboratories, and with no efforts spared, "HIV can be isolated"
only from 17-80% of HIV positive individuals (Chiodi et al., 1988; Learmont
et al., 1992). Since no gold standard has been used to confirm the specificity
of the WB results, the probability cannot be excluded that both WBI and
WB results do not indicate HIV infection and transmission, but are the
result of cross- reaction with antibodies directed against non-HIV antigens.
This is especially the case in AIDS patients and in individuals at risk
of AIDS, since both groups possess a vast array of antibodies directed
against many antigenic determinants (Matsiota et al., 1987; Calabrese,
1988). Thus, a positive "HIV antibody test" ought to be regarded
as a non- specific marker for the development of AIDS in the high AIDS
risk groups, and should not be regarded as a diagnostic and epidemiological
tool for HIV infection (Papadopulos-Eleopulos et al., 1993a). Notwithstanding,
(i) the sensitivity and specificity of the WB is nearly 100% as it is
(ii) only 50-80% (depending on which criteria are used to define a positive
WB) of AIDS patients test positive; then between 20-50% of AIDS patients
are not infected with HIV.
Lately, some of the best known HIV researchers (Moore & Ho, 1992)
have accepted that the clinical syndrome, including its most specific and
frequent manifestation, KS and PCP, may appear in the absence of HIV, that
is, in patients in whom all HIV tests including the WB and PCR, are negative.
For example, in 1991, Jacobs et al (Jacobs et al., 1991) reported that
at the New York Hospital-Cornell Medical Center during a three month period,
they diagnosed PCP in five adults. Two out of three patients tested for
T-lymphocyte subsets had T4>40% and all had normal T4/T8 ratios. "Cultures
of peripheral-blood mononuclear cells for retrovirus were negative"
in 4/5 patients, (the 5th apparently was not tested). The HIV-1,2
antibody tests were negative in all cases. One year later workers from
the same institution and three other centres had "identified five
other individuals from the New York City area (four who have known risk
factors for HIV infection), with profound CD4 depletion and clinical syndromes
consistent with definitions of the acquired immunodeficiency syndrome (AIDS)
or AIDS-related complex. None had evidence of HIV-1, 2 infection, as judged
by multiple serologies over several years, standard viral co-cultures for
HIV p24 Gag antigen, and proviral DNA amplification by polymerase chain
reaction" (Laurence et al., 1992). Similar cases have recently been
reported from other institutions including the CDC (Afrasiabi et al., 1986;
Pankhurst & Peakman, 1989; Safai et al., 1991; Seligmann et al., 1991;
Sirianni et al., 1991; CDC, 1992; Hishida et al., 1992; Tijhuis et al.,
The available data do not support the presently accepted hypothesis
that HIV is either necessary or sufficient for the pathogenesis of AIDS,
and thus it would seem logical to consider alternative theories (Papadopulos-Eleopulos,
1988; Duesberg, 1992). *
We would like to thank all our colleagues and especially Richard Fox, Livo Mina, Alun Dufty, Gary James, Iris Peter, the
staff of the Royal Perth Hospital Library and the clerical staff of the Department of Medical Physics. We also thank Harvey
Bialy, Udo Schuklenk, Charles Thomas, Gordon Stewart, Michael Verney Elliot and Joan Shenton for continual
encouragement, and Peter Duesberg for inviting us to submit this paper to Genetica.
Aaronson, S. A., Todaro, G. J. & Scholnick, E. M., 1971. Induction of murine C-type viruses from clonal lines of virus-free
BALB/3T3 cells. Science 174:157-159.
Acres, R. B., Conlon, P. J., Mochizuki, D. Y. & Gallis, B., 1986. Rapid Phosphorylation and Modulation of the T4 Antigen
on Cloned Helper T Cells Induced by Phorbol Myristate Acetate or Antigen. J. Biol. Chem. 261:16210-16214.
Adleman, L. M. & Wofsy, D., 1993. T-Cell Homeostasis: Implications in HIV Infection. J. Acquir. Immune Defic. Syndr.
Afrasiabi, R., Mitsuyasu, R. T., Nishanian, P., Schwartz, K. & Fahey, J. L., 1986. Characterization of a Distinct Subgroup of
High-Risk Persons with Kaposi's Sarcoma and Good Prognosis Who Present with Normal T4 Cell Number and T4:T8 Ratio
and Negative HTLV-III/LAV Serologic Test Results. Am. J. Med. 81:969-973.
Albert, J., Pehrson, P. O., Schulman, S., Hakansson, C., Lovhagen, G. B., Berglund, O., Beckman, S. & Fenyo, E. M., 1988.
HIV isolation and antigen detection in infected individuals and their seronegative sexual partners. AIDS 2:107-111.
Alejandro, M., Volkow, P., Verástegui, E., Lazo de la Vega, S., Kato, M., Sánchez, P., Guarner, J., Gorodezky, G. &
Meneses, A., 1991. Malignancies Associated with HIV-1 Infection in Mexico, Volume I, pp. 289 in VIIth International
Conference on AIDS, Florence.
Ameisen, J. & Capron, A., 1991. Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol.
Barré-Sinoussi, et al., 1983. Isolation of a T-Lymphotrophic Retrovirus from a patient at Risk for Acquired Immune
Deficiency Syndrome (AIDS). Science 220:868-871.
Beral, V., Peterman, T. A., Berkelman, R. L. & Jaffe, H. W., 1990. Kaposi's sarcoma among persons with AIDS:a sexually
transmitted infection? Lancet 335:123-128.
Birch, R. E., Rosenthal, A. K. & Polmar, S. H., 1982. Pharmacological modification of immunoregulatory T lymphocytes. II.
Modulation of T lymphocyte cell surface characteristics. Clin. Exp. Immunol. 48:231-238.
Brettle, R. P., Gore, S. M., Bird, A. G. & McNeil, A. J., 1993. Clinical and epidemiological implications fo the Centers for
Disease Control/World Health Organization reclassifaction of AIDS cases. AIDS 7:531-539.
Brun-Vezinet, F., Barre-Sinoussi, F., Saimot, A. G., Christol, D., Montagnier, L., Rouzioux, C., Klatzmann, D., Rozenbaum,
W., Gluckmann, J. C. & Chermann, J. C., 1984. Detection of IgG antibodies to lymphadenopathy-associatated virus in
patients with AIDS or lymphadenopathy syndrome. Lancet I:1253-1256.
Burke, D. S., 1989. Laboratory diagnosis of human immunodeficiency virus infection. Clinics in Laboratory Medicine
Burns, G. F., Battye, F. L. & Goldstein, G., 1982. Surface Antigen Changes Occurring in Short-Term Cultures of Activated
Human T Lymphocytes: Analysis by Flow Cytometry. Cell. Immunol. 71:12-26.
Calabrese, L. H., 1988. Autoimmune manifestations of human immunodeficiency virus (HIV) infection. Clin. Lab. Med.
Cantor, H. & Boyse, E. A., 1977. Regulation of Cellular and Humoral Responses by T-cell Subclasses. Cold Spring Harbor
Symp. Quant. Biol. 41:23-32.
Capon, D. J. & Ward, R. H. R., 1991. The CD4-gp120 interaction and AIDS pathogenesis. Annu. Rev. Immunol. 9:649-678.
CDC, 1982. Update on Kaposi's Sarcoma and Opportunistic Infections in Previously Healthy Persons-United States.
CDC, 1992. 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS
Among Adolescents and Adults. MMWR 41:1-19.
CDC, 1992. Unexplained CD4+ T-Lymphocyte Depletion in Persons Without Evident HIV Infection-United States.
Cheng, H. & Delespesse, G., 1986. Human Cord Blood Suppressor T Lympocytes II. Characterization of Inducer
Suppressor Cells. Am. J. Reprod. Immunol. Microbiol. 11:39-43.
Chiodi, F., Albert, J., Olausson, E., Norkrans, G., Hagberg, L., Sonnerborg, A., Asjo, B. & Fenyo, E. M., 1988. Isolation
Frequency of Human Immunodeficiency Virus from Cerebrospinal Fluid and Blood of Patients with Varying Severity of HIV
Infection. AIDS Res. Hum. Retroviruses 4:351-358.
Cloyd, M. W. & Moore, B. E., 1990. Spectrum of Biological Properties of Human Immunodeficiency Virus (HIV-1) Isolates.
Cohen, J., 1992. Searching for Markers on the AIDS Trail. Science 258:388-390.
Cohen, J., 1993. Unlikely Recruit: Andrew Leigh Brown. Science 260:1264.
Cohen, J. J. & Duke, R. C., 1984. Glucocorticoid Activation of a Calcium-Dependent Endonuclease in Thymocyte Nuclei
Leads to Cell Death. J. Immunol. 132:38-42.
Collman, R., Hassan, N. F., Walker, R., Godfrey, B., Cutilli, J., Hastings, J. C., Friedman, H., Douglas, S. D. & Nathanson,
N., 1989. Infection of Monocyte-Derived Macrophages with Human Immunodeficiency Virus Type 1 (HIV-1). J. Exp. Med.
Conway, B. 1990. Detection of HIV-1 by PCR in Clinical Specimens. pp. 40-45, in Techniques in HIV Research, edited by
A. Aldovini and B. D. Walker, Macmillan, New York.
Defer, C., Agut, H. & Garbarg-Chenon, A., 1992. Multicentre quality control of polymerase chain reaction for detection of
HIV DNA. AIDS 6:659-663.
Des Jarlais, D. C., Friedman, S. R., Marmor, M., Mildvan, D., Yancovitz, S., Sotheran, J. L., Wenston, J. & Beatrice, S.,
1993. CD4 lymphocytopenia among injecting drug users in New York City. J. Acquir. Immune Defic. Syndr. 6:820-822.
Detels, R., English, P. A., Giorgi, J. V., Visscher, B. R., Fahey, J. L., Taylor, J. M. G., Dudley, J. P., Nishanian, P., Muñoz,
A., Phair, J. P., Polk, B. F. & Rinaldo, C. R., 1988. Patterns of CD4+ Cell Changes After HIV-1 Infection Indicate the
Existence of a Codeterminant of AIDS. J. Acquir. Immune Defic. Syndr. 1:390-395.
Dickover, R. E., Donovon, R. M., Goldstein, E., Dandekar, S., Bush, C. E. & Carlson, J. R., 1990. Quantitation of Human
Immunodeficieny Virus DNA by Using the Polymerase Chain Reaction. J. Clin. Microbiol. 28:2130-2133.
Don, M. M., Ablett, G., Bishop, C. J., Bundesen, P. G., Donald, K. J., Searle, J. & Kerr, J. F. R., 1977. Death of Cells by
Apoptosis Following Attachment of Specifically Allergized Lymphocytes In Vitro. Aust. J. Exp. Biol. Med. Sci.
Donahoe, R. M., Bueso-Ramos, C., Donahoe, F., Madden, J. J., Falek, A., Nicholson, J. K. A. & Bokos, P., 1987.
Mechanistic Implications of the Findings That Opiates and Other Drugs of Abuse Moderate T-Cell Surface Receptors and
Antigenic Markers. Ann. N. Y. Acad. Sci. 496:711-721.
Drew, W.L., Mills, J., Levy, J., Dylewski, J., Casavant, C., Ammann, A. J., Brodie, H. & Merigan, T., 1985. Cytomegalic
Infection and Abnormal T-Lymphocyte Subset Ratios in Homosexual Men. Ann. Int. Med. 103:61-63.
Duesberg, P. H., 1987. Retroviruses as carcinogens and pathogens: Expectations and reality. Cancer Res. 47:1199-1220.
Duesberg, P. H., 1992. AIDS acquired by drug consumption and other noncontagious risk factors. Pharmac. Ther.
Essex, M., Allan, J., Kanki, P., McLane, M. F., Malone, G., Kitchen, L. & Lee, T. H., 1985. Antigens of human
T-lymphotrophic virus type III/lymphadenopathy associated virus. Ann. Int. Med. 103:700-703.
Fauci, A. S., 1988. The Human Immunodeficiency Virus: Infectivity and Mechanisms of Pathogenesis. Science 239:617-622.
Feldman, S. B., Sexton, M., Glenn, J. D. & Lookingbill, D. P., 1989. Immunosuppression in men with Bowenoid Papulosis.
Arch. Dermatol. 125:651-654.
Felix, D. H., Watret, K., Wray, D. & Southam, J. C., 1992. Hairy leukoplakia in an HIV-negative, nonimmunosuppressed
patient. Oral. Surg. Oral. Med. Oral. Pathol. 74:563-566.
Fisher, A. G., Collati, E., Ratner, L., Gallo, R. C. & Wong-Staal, F., 1985. A molecular clone of HTLV-III with biological
activity. Nature 316:262-265.
Fox, C. H., Kotler, D., Tierney, A., Wilson, C. S. & Fauci, A. S., 1989. Detection of HIV-1 RNA in the Lamina Propria of
Patients with AIDS and Gastrointestinal Disease. J. Infect. Dis. 159:467-471.
Gallo, R. C., 1986. The First Human Retrovirus. Sci. Am. 255:78-88.
Gallo, R. C., Sarin, P. S., Kramarsky, B., Salahuddin, Z., Markham, P. & Popovic, M., 1986. First isolation of HTLV-III.
Gallo, R. C., Shaw, G. M. & Markham, P. D. 1985. The Etiology of AIDS. pp. in AIDS Etiology, Diagnosis, Treatment and
Prevention, 1st Edition, edited by V. T. DeVita, S. Hellman and S. A. Rosenberg, J.B. Lippincott Company, Philadelphia.
Gazdar, A. F., et al., 1980. Mitogen Requirements for the In Vitro Propagation of Cutaneous T-Cell Lymphomas. Blood
Genesca, J., Jett, B. W., Epstein, J. S., Shih, J. W. K., Hewlett, I. K. & Alter, H. J., 1989. What do Western Blot
indeterminate patterns for Human Immunodeficiency Virus mean in EIA-negative blood donors? Lancet II:1023-1025.
Gill, P. S., Loureiro, C., Bernstein-Singer, M., Rarick, M. U., Sattler, F. & Levine, A. M., 1989. Clinical Effect of
Glucocorticoids on Kaposi's Sarcoma Related to the Acquired Immunodeficiency Syndrome (AIDS). Ann. Int. Med.
Gougeon, M.-L. & Montagnier, L., 1993. Apoptosis in AIDS. Science 260:1269-1270.
Grady, R. W., Akbar, A. N., Giardina, P. J., Hilgartner, M. W. & De Sousa, M., 1985. Disproportionate lymphoid cell
subsets in thalassaemia major: the relative contributions of transfusion and splenectomy. Br. J. Haematol. 59:713-724.
Groux, H., Monte, D., Bourrez, J.-M., Capron, A. & Ameisen, J.-C., 1991. A mechanism for CD4+ T-cell dysfunction and
depletion in AIDS: activation-induced programmed cell death by apoptosis. C. R. Acad. Sci. 312:599-606.
Groux, H., Torpier, G., Monte, D., Mouton, Y., Capron, A. & Ameisen, J.-C., 1992. Activation-induced Death by
Apoptosis in CD4+ T Cells from Human Immunodeficiency Virus-infected Asymptomatic Individuals. J. Exp. Med.
Henderson, L. E., et al., 1987. Direct Identification of Class II Histocompatibility DR Proteins in Preparations of Human
T-Cell Lymphotropic Virus Type III. J. Virol. 61:629-632.
Henin, Y., Mandelbrot, L., Henrion, R., Pradinaud, R., Coulaud, J. P. & Montagnier, L., 1993. Virus Excretion in the
cervicovaginal secretions of pregnant and nonpregnant HIV-infected women. J. Acquir. Immune Defic. Syndr. 6:72-75.
Hersey, P., Bradley, M., Hasic, E., Haran, G., Edwards, A. & McCarthy, W. H., 1983. Immunological Effects of Solarium
Exposure. Lancet I:545-548.
Hirsch, M. S., Phillips, S. M. & Solnik, C., 1972. Activation of Leukemia Viruses by Graft-Versus-Host and Mixed
Lymphocyte Reactions In Vitro. Proc. Nat. Acad. Sci. 69:1069-1072.
Hishida, O., Ido, E., Igarashi, T., Hayami, M., Miyazaki, A., Ayisi, N. K. & Osei-Kwasi, M., 1992. Clinically diagnosed
AIDS cases without evident association with HIV type 1 and 2 infections in Ghana. Lancet 340:971-972.
Hoover, D., 1993. Would Confirmatory Retesting of CD4+ Cells to Verify AIDS Status Be Too Expensive? J. Acquir.
Immune Defic. Syndr. 6:537-539.
Hoover, D. R., Graham, N. M. H., Chen, B., Taylor, J. M. G., Phair, J., Zhou, S. Y. J. & Muñoz, A., 1992. Effect of CD4+
Cell Count Measurement Variability on Staging HIV-1 Infection. J. Acquir. Immune Defic. Syndr. 5:794-802.
Hoover, D. R., Saah, A. J., Bacellar, H., Murphy, R., Visscher, B., Anderson, R. & Kaslow, R. A., 1993. Signs and
symptoms of "asymptomatic" HIV-1 infection in homosexual men. J. Acquir. Immune Defic. Syndr. 6:66-71.
Horwitz, M. S., Boyce-Janino, M. T. & Faras, A. J., 1992. Novel human endogenous sequences related to human
immunodeficiency virus type 1. J. Virol. 66:2170-2179.
Hoxie, J. A., Mathews, D. M., Callahan, K. J., Cassel, D. L. & Cooper, R. A., 1986. Transient Modulation and
Internalization of T4 Antigen Induced by Phorbol Esters. J. Immunol. 137:1194-1201.
Hoxie, J. S., Haggarty, B. S., Rackowski, J. L., Pillsbury, N. & Levy, J. A., 1985. Persistent Noncytopathic Infection of
Normal Human T Lymphocytes with AIDS-Associated Retrovirus. Science 229:1400-1402.
Jacobs, J. L., Libby, D. M., Winters, R. A., Gelmont, D. M., Fried, E. D., Hartman, B. J. & Laurence, J., 1991. A Cluster of
Pneumocystis Carinni Pneumonia in Adults without predisposing illnesses. NEJM 324:246-250.
Jandinski, J., Cantor, H., Tadakuma, T., Peavy, D. L. & Pierce, C. W., 1976. Separation of Helper T Cells from Suppressor
T Cells Expressing Different Ly Components. J. Exp. Med. 143:1382-90.
Jason, J. M., McDougal, J. S., Dixon, G., Lawrence, D. N., Kennedy, M. S., Hilgartner, M., Aledort, L. & Evatt, B. L., 1986.
HTLV-III/LAV Antibody and Immune Status of Household Contacts and Sexual Partners of Persons with Hemophilia.
Jewell, S. A., Bellomo, G., Thor, H., Orrenius, S. & Smith, M. T., 1982. Bleb Formation in Hepatocytes During Drug
Metabolism Is Caused by Disturbances in Thiol and Calcium Ion Homeostasis. Science 217:1257-1258.
Kales, C. P., Murren, J. R., Torres, R. A. & Crocco, J. A., 1987. Early Predictors of In-Hospital Mortality for Pneumocystis
carinii Pneumonia in the Acquired Immunodeficiency Syndrome. Arch. Intern. Med. 147:1413-1417.
Kaslow, R. A., Phair, J. P., Freidman, H. B., Lyter, D., Solomon, R. E., Dudley, J., Polk, F. & Blackwelder, W., 1987.
Infection with the Human Immunodeficiency Virus: Clinical Manifestations and Their Relationship to Immune Deficiency.
Ann. Int. Med. 107:474-480.
Kazazi, F., Mathijs, J.-M., Foley, P. & Cunningham, A. L., 1989. Variations in CD4 Expression by Human Monocytes and
Macrophages and Their Relationship to Infection with the Human Immunodeficiency Virus. J. Gen. Virol. 70:2661-2672.
Kempf, R. A. & Mitchell, M. S., 1985. Effects of Chemotherapeutic Agents on the Immune Response. II. Cancer Invest.
Kerr, J. F. R. & Searle, J., 1972. A Suggested Explanation for the Paradoxically Slow Growth Rate of Basal-Cell Carcinomas
that Contain Numerous Mitotic Figures. J. Pathol. 107:41-45.
Kessler, C. M., Schulof, R. S., Goldstein, A. L., Naylor, P. H., Luban, N. L., Kelleher, J. F. & Reaman, G. H., 1983.
Abnormal T-Lymphocyte Subpopulations Associated with Transfusions of Blood-Dertived Products. Lancet I:991-992.
Kinlen, L. J., 1982. Immunosuppressive Therapy and Cancer. Cancer Surv. 1:565-581.
Klatzmann, D., et al., 1984a. Selective Tropism of Lymphadenopathy Associated Virus (LAV) for Helper-Inducer T
Lymphocytes. Science 225:59-63.
Klatzmann, D., et al., 1984b. T-lymphocytes T4 molecule behaves as the receptor for human retrovirus LAV. Nature
Klatzmann, D. & Montagnier, L., 1986. Approaches to AIDS therapy. Nature 319:10-11.
Lamoureux, G., Davignon, L., Turcotte, R., Laverière, M., Mankiewicz, E. & Walker, M. C., 1987. Is Prior Mycobacterium
Infection a Common Predisposing Factor to AIDS in Haitians and Africans. Ann. Inst. Pasteur/Immunol. 138:521-529.
Laurence, J., Siegal, F. P., Shattner, E., Gelman, I. H. & Morse, S., 1992. Acquired immunodeficiency without evidence of
infection with human immunodeficiency virus types 1 and 2. Lancet 340:273-274.
Laurent-Crawford, A. G., Krust, B., Muller, S., Rivière, Y., Rey-Cuillé, M.-A., Béhet, J.-M., Montagnier, L. & Hovanessian,
A. G., 1991. The Cytopathic Effect of HIV is Associated with Apoptosis. Virol. 185:829-839.
Laurent-Crawford, A. G., Rivière, Y., Montagnier, L. & Hovanessian, A., 1992. Envelope Glycoprotein Gene Expression
Mediates Syncytia Formation and Apoptosis, Volume 2, pp. A65 in VIIIth International Conference on AIDS, Amsterdam.
Learmont, J., et al., 1992. Long-term symptomless HIV-1 infection in recipients of blood produces from a single donor.
Lancet 340: 863-867.
Lemaitre, M., Guetard, D., Henin, Y., Montagnier, L. & Zerial, A., 1990. Protective activity of tetracycline analogs against
the cytopathic effect of the human immunodeficiency viruses in CEM cells. Res. Virol. 141:5-16.
Lemasters, J. J., DiGuiseppi, J., Nieminen, A.-L. & Herman, B., 1987. Blebbing, free Ca2+ and mitochondrial membrane
potential preceding cell death in hepatocytes. Nature 325:78-81.
Levacher, M., Hulstaert, F., Tallet, S., Ullery, S., Pocidalo, J. J. & Bach, B. A., 1992. The significance of activation markers
on CD8 lymphocytes in human immunodeficiency syndrome: staging and prognostic value. Clin. Exp. Immunol. 90:376-382.
Levinson, S. S. & Denys, G. A., 1988. Strengths and weaknesses in methods for identifying the causative agent(s) of acquired
immunodeficiency syndrome (AIDS). Critical Reviews in Clincal Laboratory Sciences 26:277-301.
Long, A. A., Komminoth, P. & Wolfe, H. J., 1992. Detection of HIV provirus by in situ polymerase chain reaction. NEJM
Löwer, R. & Löwer, J., 1993. Endogenous retrovirus sequences in human teratocarcinoma cell lines. J. Acquir. Immune Defic.
Ludlam, C. A., Steel, C. M., Cheingsong-Popov, R., McClelland, D. B. L., Tucker, J., Tedder, R. S., Weiss, R. A., Philip, I.
& Prescott, R. J., 1985. Human T-Lymphotropic Virus Type-III (HTLV-III) Infection in Seronegative Haemophiliacs after
Transfusion of Factor VIII. Lancet II:233-236.
Lundberg, G. D., 1988. Serological Diagnosos of Human Immunodeficiency Virus Infection by Western Blot Testing. JAMA
Malone, J. L., SImms, T. E., Gray, G. C., Wagner, K. F., Burge, J. R. & Burke, D. S., 1990. Sources of Variability in
Repeated T-Helper Lymphocyte Counts from Human Immunodeficiency Virus Type 1-Infected Patients: Total
Lymphocyte Count Fluctutations and Diurnal Cycle Are Important. J. Acquir. Immune Defic. Syndr. 3:144-151.
Margolick, J. B., Donnenbery, A. D., Munoz, A., Park, L. P., Bauer, K. D., Giorgi, J. V., Ferbas, J. & Saah, A. J., 1993.
Changes in T and Non-T Lymphocyte Subsets Following Seroconversion to HIV-1: Stable CD3+ and Declining CD3-
Populations Suggest Regulatory Responses Linked to Loss of CD4 Lymphocytes. J. Acquir. Immune Defic. Syndr.
Martinez, E., Domingo, P. & Marcos, A., 1991. Pneumococcal bacteraemia in immunocompetent adults. Lancet 337:57.
Masur, H., Ognibene, F. P., Yarchoan, R., Shelhamer, J. H., Baird, B. F., Travers, W., Suffredini, A. F., Deyton, L., Kovacs,
J. A., Falloon, J., Davey, R., Polis, M., Metcalf, J., Baseler, M., Wesley, R., Gill, V. J., Fauci, A. S. & Clifford Lane, H.,
1989. CD4 Counts as Predictors of Opportunistic Pneumonias in Human Immunodeficiency Virus (HIV) Infection. Ann. Int.
Matsiota, P., et al., 1987. Detection of Natural Autoantibodies in the serum of Anti-HIV Positive-Individuals. Ann. Inst.
McConkey, D. J., Hartzell, P., Amador-Pérez, J. F., Orrenius, S. & Jondal, M., 1989. Calcium-Dependent Killing of
Immature Thymocytes by Stimulation via the CD3/T Cell Receptor Complex. J. Immunol. 143:1801-1806.
McConkey, D. J., Hartzell, P., Duddy, S. K., Hakansson, H. & Orrenius, S., 1988. 2,3,7,8-Tetrachlorodibenzo-p-dioxin Kills
Immature Thymocytes by Ca2+-Mediated Endonuclease Activation. Science 242:256-259.
Mendenhall, C. L., Roselle, G. A., Grossman, C. J., Rouster, S. D. & Weener, R. E., 1986. False Positive Tests for HTLV-III
Antibodies in Alcoholic Patients with Hepatitis. NEJM 314:921-922.
Meyaard, L., Otto, S. A., Jonker, R. R., Mijnster, M. J., Keet, R. P. M. & Miedema, F., 1992. Programmed Death of T Cells
in HIV-1 Infection. Science 257:217-219. Minassian, A., Merges, M., Garrity, R., Nagashima, K., Tsai, W. P., Oroszlan, S.
& Nara, P., 1993. Induction of a SMRV-like retrovirus from a human T-cell line after treatment with the mutagen
ethyl-methyl-sulfonate. J. Acquir. Immune Defic. Syndr. 6:738.
Montagnier, L., 1985. Lymphadenopathy-Associated Virus: From Molecular Biology to Pathogenicity. Ann. Int. Med.
Moore, J. P. & Ho, D. D., 1992. HIV-negative AIDS. Lancet 340:475.
Morris, R. G., Hargreaves, A. D., Duvall, E. & Wyllie, A. H., 1984. Hormone-Induced Cell Death. Am. J. Pathol.
Natoli, C., Dianzani, F., Mazzotta, F., Balocchini, E., Peirotti, P., Antonelli, G. & Icaobelli, S., 1993. 90K Protein: A New
Predictor Marker of Disease Progression in Human Immunodeficiency Virus Infection. J. Acquir. Immune Defic. Syndr.
Nicolosi, A., Musico, M., Saracco, A., Molinari, S., Ziliani, N. & Lazzarin, A., 1990. Incidence and risk factors of HIV
infection: A prospective study of seronegative drug users from Milan and Northern Italy, 1987-1989. Epidemiology
Novick, D. M., Brown, D. J. C., Lok, A. S. F., Lloyd, J. C. & Thomas, H. C., 1986. Influence of Sexual Preference and
Chronic Hepatitis B Virus Infection on T Lymphocyte Subsets, Natural Killer Activity, and Suppressor Cell Activity. J.
Oxford, J., 1980. Immunomodulating effects of antimicrobial agents. J. Antimicrob. Chemother. 6:691-699.
Pankhurst, C. & Peakman, M., 1989. Reduced CD4+ T Cells and Severe Oral Candidiasis in Absence of HIV Infection.
Pantaleo, G., Graziosi, C. & Fauci, A. S., 1993. The Immunopathogenesis of Human Immunodeficiency Virus Infection.
Papadopulos-Eleopulos, E., 1982. A Mitotic Theory. J. Theor. Biol. 96:741-758.
Papadopulos-Eleopulos, E., 1988. Reappraisal of AIDS: Is the oxidation caused by the risk factors the primary cause? Med.
Papadopulos-Eleopulos, E., Hedland-Thomas, B., Causer, D. A. & Dufty, A. P., 1989a. An alternative explanation for the
radiosensitization of AIDS patients. Int. J. Radiat. Oncol. Biol. Phys. 17:695-697.
Papadopulos-Eleopulos, E., Knuckey, N., Dufty, A. & Fox, R., 1985. Evidence that the redox state has a role in muscular
contraction and relaxation. Physiol. Chem. Phys. Med. N.M.R. 17:407-411.
Papadopulos-Eleopulos, E., Knuckey, N. W., Dufty, A. & Fox, R. A., 1989b. Importance of the redox state in
vasoconstriction induced by adrenaline and serotinin. Cardiovasc. Res. 23:662-665.
Papadopulos-Eleopulos, E., Turner, V. F. & Papadimitriou, J. M., 1993b. Has Gallo proven the role of HIV in AIDS? Emerg.
Med. [Australia] 5:113-123.
Papadopulos-Eleopulos, E., Turner, V. F. & Papdimitriou, J. M., 1992a. Kaposi's Sarcoma and HIV. Med. Hypotheses
Papadopulos-Eleopulos, E., Turner, V. F. & Papdimitriou, J. M., 1992b. Oxidative Stress, HIV and AIDS. Res. Immunol.
Papadopulos-Eleopulos, E., Turner, V. F. & Papdimitriou, J. M., 1993a. Is a Positive Western Blot Proof of HIV Infection?
Pellicciari, C., Hosokawa, Y., Fukada, M. & Romanini, M. G. M., 1983. Cytofluormetric study of nuclear sulphydryl and
disulphide groups during sperm maturation in the mouse. J. Reprod. Fertil. 68:371-376.
Phair, J., Jacobson, L., Detals, R., Rinaldo, C., Saah, A., Schrager, L. & Muñoz, A., 1992. Acquired Immune Deficiency
Syndrome Occuring Within 5 Years of Infection with Human Immunodeficiency Virus Type-1: The Multicenter AIDS
Cohort Study. J. Acquir. Immune Defic. Syndr. 5:490-496.
Poiesz, B., et al., 1980. T-cell lines established from human T-lymphocytic neoplasias by direct response to T-cell growth
factor. Proc. Natl. Acac. Sci. 77:6815-6819.
Popovic, M., Sarngadharan, M. G. & Read, E., 1984. Detection, Isolation,and Continuous Production of Cytopathic
Retroviruses (HTLV-III) from Patients with AIDS and Pre-AIDS. Science 224:497-500.
Redfield, R. R. & Burke, D. S., 1988. HIV Infection:The clinical Picture. Sci. Am. 259:70-78.
Reed, D. J., 1990. Status of Calcium and Thiols in Hepatocellular Injury by Oxidative Stress. Seminars in Liver Disease
Reinherz, E. L., Geha, R., Wohl, M. E., Morimoto, C., Rosen, F. S. & Schlossman, S. F., 1981. Immunodeficiency
Associated with Loss of T4+ Inducer T-Cell Function. NEJM 304:811-816.
Reinherz, E. L., Kung, P. C., Goldstein, G. & Schlossman, S. F., 1979. Separation of functional subsets of human T cells by a
monoclonal antibody. Proc. Natl. Acad. Sci. 76:4061-4065.
Reinherz, E. L., Morimoto, C., Penta, A. C. & Schlossman, S. F., 1980. Regulation of B cell immunoglobulin secretion by
functional subsets of T lymphocytes in man. Eur. J. Immunol. 10:570-572.
Reinherz, E. L., et al., 1980. The cellular basis for viral-induced immunodeficiency: analysis by monoclonal antibodies. J.
René, O., Dragic, T., Lopez, O., Herzenberg, L. & Montagnier, L., 1992. An Anti-Oxidant Prevents Apoptosis and Early
Cell Death in Lymphocytes from HIV Infected Individuals, Volume 2, pp. A65 in VIIIth International Conference on AIDS,
Rett, K., Wicklmayr, M., Dietze, G. J. & Schwabing, K., 1988. Abnormal T-cell subsets in normal persons. NEJM
Rogers, L. A., Forster, S. M. & Pinching, A. J., 1989. IgD production and other lymphocyte functions in HIV infection:
immaturity and activation of B cells at different clinical stages. Clin. Exp. Immunol. 75:7-11.
Root-Bernstein, R. S., 1993. Rethinking AIDS-The tragic cost of premature consensus. Macmillan, Inc., New York.
Rubin, R. H., Carney, W. P., Schooley, R. T., Colvin, R. B., Burton, R. C., Hoffman, R. A., Hansen, W. P., Cosimi, A. B.,
Russell, P. S. & Hirsch, M. S., 1981. The effect of infection on T lymphocyte subpopulations: a preliminary report. Int. J.
Rubinstein, E., 1990. The Untold Story of HUT78. Science 248:1499-1507.
Safai, B., Peralta, H., Menzies, K., Tizon, H., Roy, P., Flomberg, N. & Wolinsky, S., 1991. Kaposis's Sarcoma among
HIV-Seronegative- High Risk Population, Volume I, pp. 78 in VIIth International Conference on AIDS, Florence.
Scharff, O., Foder, B., Thastrup, O., Hofmann, B., Moller, J., Ryder, L. P., Jacobson, K. D., Langhoff, E., Dickmeiss, E.,
Christensen, S. B., Skinhoj, P. & Svejaard, A., 1988. Effect of thapsigargin on cytoplasmic Ca2+ and proliferation of human
lymphocytes in relation to AIDS. Biochim. Biophysica. Acta. 972:257-264.
Schellekens, P. T., Tersmette, M., Roos, M. T. L., Keet, R. P., de Wolf, F., Coutinho, R. A. & Miedema, F., 1992. Biphasic
rate to CD4+ cell count decline during progession to AIDS correlates with HIV-1 phenotype. AIDS 6:665-669.
Schulhafer, E. P., Grossman, M. E., Fagin, G. & Bell, K. E., 1987. Steroid-Induced Kaposi's Sarcoma in a Patient with
Pre-AIDS. Am. J. Med. 82:313-317.
Seligmann, M., Aractingi, S., Oksenhendler, E., Rabain, C., Ferchal, F. & Gonnot, G., 1991. CD4+ lymphocytopenia without
HIV in patient with cryptococcal disease. Lancet 337:57-58. Serrou, B., 1974. Rifampicin and Immunosuppression. Lancet
Shaw, M. S., Wong-Staal, F. & Gallo, R. C. 1988. Etiology of AIDS: virology, molecular biology, and evolution of human
immunodeficiency viruses. pp. in AIDS Etiology, Diagnosis, Treatment and Prevention, 2nd Edition, edited by V. T. DeVita,
S. Hellman and S. A. Rosenberg, J.B. Lippincott Company, Philadelphia.
Sirianni, M. C., Pandolfi, F., Verani, P., Guerra, E., Rossi, G. B. & Aiuti, F., 1991. CD4 defect without HIV in patients with
opportunistic infections or Kaposi's sarcoma. AIDS 7:130-131.
Stagno, S., Pifer, L. L., Hughes, W. T., Brasfield, D. M. & Tiller, R. E., 1980. Pneumocystis carinii Pneumonitis in Young
Immunocompetent Infants. Pediatrics 66:56-62.
Stanley, S. K. & Fauci, A. S., 1993. T Cell Homeostasis in HIV Infection: Part of the Solution, or Part of the Problem? J.
Acquir. Immune Defic. Syndr. 6:142-143.
Terai, C., Kornbluth, R. S., Pauza, D., Richmann, D. D. & Carson, D. A., 1991. Apoptosis as a Mechanism of Cell Death in
Cultured T Lymphoblasts Acutely Infected with HIV-1. J. Clin. Invest. 87:1710-1715.
Thomas, H. C., 1981. T cell subsets in patients with acute and chronic HBV infection, primary biliary cirrhosis and alcohol
induced liver disease. Int. J. Immunopharmac. 3:301-305.
Tijhuis, G. J., et al., 1993. AIDS Without Detectable HIV: A Case Report. Am. J. Med. 94:442-443.
Todaro, G. J., Benveniste, R. E. & Sherr, C. J. 1976. Interspecies Transfer of RNA Tumour Virus Genes: Implications for
the search for "Human" Type C Viruses. pp. 369-384, in Animal Virology, edited by D. Baltimore, A. S. Huang and C. S.
Fox, Academic Press Inc., New York.
Toyoshima, K. & Vogt, P. K., 1969. Enhancement and Inhibition of Avian Sarcoma Viruses by Polycations and Polyanions.
Trimm, J. L., Salama, G. & Abramson, J. J., 1986. Sulfhydryl Oxidation Induces Rapid Calcium Release from Sarcoplasmic
Reticulum Vesicles. J. Biol. Chem. 261:16092-16098.
Tsoukas, C., Gervais, F., Shuster, J., Gold, P., O'Shaughnessy, M. & Robert-Guroff, M., 1984. Association of HTLV-III
Antibodies and Cellular Immune Status of Hemophiliacs. NEJM 311:1514-1515.
Turner, V. F., 1990. Reducing agents and AIDS-Why are we waiting? Med. J. Aust. 153:502.
Ushijima, H., Unten, S., Honma, H., Tsuchie, H., Kitamura, T., Weiler, B. E. & Muller, W. E. G., 1992. Effect of Serum
Components on Syncytium Formation and Virus Production by Cells Infected with Human Immunodeficiency Virus In
Vitro. AIDS Res. Hum. Retroviruses 8:513-520.
Varmus, H. & Brown, P. 1989. Retroviruses. pp. 53-108, in Mobile DNA, edited by D. E. Berg and M. M. Howe, American
Society for Microbiology, Washington D.C.
Vento, S., Di Perri, G., Garofano, T., Concia, E. & Bassetti, D., 1993. Pneumocystis carinni pneumonia during primary
HIV-1 infection. Lancet 342:24-25.
Vilmer, E., Rouzioux, C., Vezinet Brun, F., Fischer, A., Chermann, J. C., Barre-Sinoussi, F., Gazengel, C., Dauguet, C.,
Manigne, P. & Griscelli, C., 1984. Isolation of new lymphotropic retrovirus from two siblings with Haemophilia B, one with
AIDS. Lancet I:753-757.
Volsky, D. J., Wu, Y. T., Stevenson, M., Dewhurst, S., Sinangil, F., Merino, F., Rodriguez, L. & Godoy, G., 1986.
Antibodies to HTLV-III/LAV in Venezuelan Patients with Acute Malarial Syndromes. NEJM 316:647-648.
von Briesen, H., Becker, W. B., Henco, K., Helm, E. B., Gelderblom, H. R., Brede, H. D. & Rebsamen-Waigmann, H., 1987.
Isolation Frequency and Growth Properties of HIV-Variants: Multiple Simultaneous Variants in a Patient Demonstrated by
Molecular Cloning. J. Med. Virol. 23:51-66.
Waldman, T. A., Broder, S., Blaese, R. M., Durm, M., Blackman, M. & Strober, W., 1974. Role of Suppressor T Cells in
Pathogenesis of Common Variable Hypogammaglobulinaemia. Lancet II:609-613.
Walker, D. A. & Lilleyman, J. S., 1983. Pseudo-AIDS. Lancet II:344.
Weigle, K. A., Sumaya, C. V. & Montiel, M. M., 1983. Changes in T-lymphocyte subsets during childhood Epstein-Barr
Virus Infectious Mononucleosis. J. Clin. Immunol. 3:151-155.
Weissy, R., Teich, N., Varmus, H. & Coffin, J., Ed. 1982. RNA Tumor Viruses. Cold Spring Harbor, New York, Cold Spring
Weiss, R. A., 1993. How Does HIV Cause AIDS? Science 260:1273-1279. WHO, 1986. Acquired Immunodeficiency
Syndrome (AIDS) WHO/CDC case definition for AIDS. Wkly. Epidem. Rec. 61:69-76.
Williams, R. C., Koster, F. T. & Kilpatrick, K. A., 1983. Alterations in lymphocyte cell surface markers during various
human infections. Am. J. Med. 75:807-816.
Wofsy, D. & Seaman, W. E., 1985. Successful Treatment of Autoimmunity in NZB/NZW F1 Mice with Monoclonal
Antibody to L3T4. J. Exp. Med. 161:378-391.
Wyllie, A. H., Kerr, J. F. R. & Currie, A. R., 1980. Cell Death: The Significance of Apoptosis. Internat. Rev. Cytol.
Wyllie, A. H., Morris, R. G., Smith, A. L. & Dunlop, D., 1984. Chromatin Cleavage in Apoptosis: Association with
Condensed Chromatin Morphology and Dependence on Macromolecular Synthesis. J. Pathol. 142:67-77.
Zagury, D., Bernard, J., Leonard, R., Cheynier, R., Feldman, M., Sarin, P. S. & Gallo, R. C., 1986. Long-Term Cultures of
HTLV-III-Infected T Cells: A Model of Cytopathology of T-Cell Depletion in AIDS. Science 231:850-853.
Zagury, D., Bernard, J., Morgan, D. A., Fouchard, M. & Feldman, M., 1983. Phenotypic Diversity within Clones of Human
Normal T Cells. Int. J. Cancer. 31:705-710.
retour à la page d'accueil