Genetica 95: 111-132, 1995
FIVE MYTHS ABOUT AIDS THAT HAVE MISDIRECTED RESEARCH AND
Robert S. RootBernstein
Department of Physiology,
Michigan State University, East Lansing, Ml 48824, USA
A number of widely repeated and factually
incorrect myths have pervaded the AIDS research literature, misdirecting
research and treatment. Five of the most outstanding are: 1) that all risk
groups develop AIDS at the same rate following HIV infection; 2) that there
are no true seroreversions following HIV infection; 3) that antibody is
protective against HIV infection; 4) that the only way to treat AIDS effectively
is through retroviral therapies; and 5) that since HIV is so highly correlated
with AIDS incidence, it must be the sole necessary and sufficient cause
of AIDS. A huge body of research, reviewed in this paper, demonstrates
the falsity of these myths. 1) The average number of years between HIV
infection and AIDS is greater than 20 years for mild hemophiliacs, l 4
years for young severe hemophiliacs, 10 years for old severe hemophiliacs,
10 years for homosexual men, 6 years for transfusion patients of all ages,
2 years for transplant patients, and 6 months for perinatally infected
infants. These differences can only be explained in terms of riskgroup
associated cofactors. 2) Seroreversions are common. Between 10 and 20 percent
of HlVseronegative people in high risk groups have Tcell immunity
to HIV, and may haye had one or more verified positive HIV antibody tests
in the past. 3) Antibody, far from being protective against HIV, appears
to be highly diagnostic of loss of immune regulation of HIV, and some evidence
of antibodyenhancement of infection exists. 4) Nonretroviral
treatments of HIV infection, including safer sex practices, elimination
of drug use, high nutrient diets, and limited reexposure to HIV and its
cofactors have proven to be effective means of preventing or delaying onset
of AIDS. 5) Many immunosuppressive factors, including drug use, multiple
concurrent infections, and exposure to alloantigens, are as highly correlated
with AIDS risk groups as HIV. These data are more consistent with AIDS
being a multifactorial or synergistic disease than a monofactorial one.
Many commentators on AIDS have neatly divided
the AIDS world into those who believe that HIV is the sole necessary and
sufficient cause of AIDS, and those who believe that it plays no role in
AIDS at all. In fact, many investigators believe that HIV definitely plays
some role in AIDS, but that its role is as yet undefined. Whether it is
necessary but not sufficient to cause AIDS, one of the many factors acting
synergistically, or a player in the induction of lymphotoxic autoimmune
processes is still an open question (BuimoviciKlein et al., 1988;
Donohoe & Falek, 1988; Duesberg, 1987, 1989, 1990, 1992; FernandezCruz
et al.. 1988: Haverkos. 1988: Hoff & Peterson. 1989; Hoff et
al., 1991; Kion & Hoffmann, 1991; Littlefield, 1992; Lo et al.,
1991; Lusso, Lori & Gallo, 1990; Macon er al., 1993; Mathe,
1992; McClean & Nowak, 1992; Montagnier et al., 1990; PapadopulosEleopulos,
1988; Pifer et al., 1987; RootBernstein, 1990a, 1990b, 1990c,
1992a, 1992b, 1993, 1994; RootBernstein & Hobbs, 1993; RootBernstein
& DeWitt, 1994; Rubin, 1988, Shearer & Levy, 1984; Sonnabend &
Saadoun, 1984; Sonnabend, Witkin & Portillo, 1984; Sonnabend, 1989,
Stott, 1991; Wang et al., 1992; Ziegler & Stites, 1986).
The crucial point for any theory of AIDS
is to account for not only the presence of HIV and antibodies to it in
the vast majority of AIDS patients, but also why some people develop all
of the symptoms of AIDS in the absence of HIV, why others remain healthy
for decades after HIV infection and may even serorevert, and why the time
between HIV infection and fullblown (CDC stage 4) disease varies dously
between patients. I will argue that neither the theory that HIV is necessary
and sufficient, nor the theory that it is irrelevant to understanding AIDS,
is satisfactory for explaining AIDS because both theories are based upon
misleading, but widely held myths about the disease and about how biomedical
research should best demonstrate the cause(s) of AIDS.
Five myths, in particular, are often repeated
in the medical literature, and are demonstrably incorrect: 1) that all
risk groups develop AIDS at the same rate following HIV infection; 2) that
there are no true seroreversions following HIV infection; 3) that antibody
is protective against HIV infection; 4) that the only way to treat AIDS
effectively is through retroviral therapies; and 5) that since HIV is so
highly correlated with AIDS incidence, it must be the sole necessary and
sufficient cause of AIDS. We will not be able to understand and effectively
treat AIDS until these myths are exploded and the facts of AIDS installed
in their place.
Myth 1: HIV progresses to AIDS at the
same rate in all risk groups
The most powerful and oftencited argument
against the need for cofactors and for the sufficiency of HIV is that people
in all risk groups progress to AIDS at the same rate following HIV infection.
Roy Anderson, for example, states, 'The median incubation period of AIDS
(time from infection to the development of AIDS) appears to be approximately
10 years in sexually active adults in developed countries irrespective
of risk group' (Anderson, 1993). He, James Curran and many others have
argued from such evidence that cofactors associated with particular risk
groups cannot have any effect of AIDS progression. Similarly, Robin Weiss
states that the development of AIDS is a purely 'stochastic process' and
agrees with Anderson 'that population groups with different lifestyles
have similar rates of progression to AIDS' (Weiss,1993, his Fig. 2; see
my Fig. 1). The one admitted exception are hemophiliacs under the age of
25 who progress more slowly to AIDS than other groups. Weiss claims, however,
that after a lag period, they have 'a similar rate of progression to AIDS'
as all other risk groups (Weiss, 1993). A review of the relevant literature
casts doubt on these crucial claims, however, and thereby on the implication
that cofactors are irrelevant to AIDS progression.
Weiss, Anderson, and Curran have evidently
failed to examine all of the available studies, or have not paid attention
to sophisticated mathematical models of epidemics. For one thing, most
hemophilia studies differentiate between hemophiliacs age 2544 and
those over the age of 44, because the rate of AIDS development in the over
44 group is two or four times faster than that of the 2544 age group.
Weiss can make hemophiliacs have the same rate of AIDS progression as homosexual
men only by lumping the 2544 and over 44 age group together. (Weiss,
1993). Furthermore, reference to a large body of studies not cited by Weiss
or Anderson reveals a rate of progression to AIDS among hemophiliacs less
than 25 years of age that is significantly different from that found in
Figure 2 of Weiss's article, and with a slope different than that for homosexual
and hemophiliac men in general (Fig. 1) (Derby et al., 1990; Schinaia
et al., 1991; Sorice et al., 1989; Giesecke et al., 1988;
Eyster et al., 1987).
The discrepancy in the two sets of data
is due to reliance by most experts (including Weiss, Anderson, and Curran)
on studies performed at hemophilia treatment centers (HTCs) in the United
States and Britain. HTCs see only a fraction of all hemophiliacs, generally
the most severe cases, but do not see symptomfree hemophiliacs (StehrGreen
et al., 1989; Eyster et al., 1987). The majority of the patients
studied in the references cited by Weiss (1993), for example, are severe
type A hemophiliacs (see Lorenzo et al., 1993 for another example
in which 64% of the cohort had severe disease and had exactly the rate
of development predicted by Weiss). Less than a third of hemophiliacs have
severe disease, however, and the incidence of AIDS in mild hemophiliacs
is 1/7 that of severe hemophiliacs (Goedert et al., 1989; Hardy
et al., 1985). Thus, incubation periods based on severe hemophiliacs
overestimates rate of progression to AIDS, and are not representative of
all hemophiliacs (Giesecke et al., 1988). Severity of hemophilia
is independently predictive of development of AIDS, possibly due to increased
frequency of use of clotting concentrates, transfusions, viral contaminants,
and steroidal, colloidal gold, and opiate drugs associated with joint injury
treatment (Rosendaal, Smit & Briet, I 991; RootBernstein,1993). In
consequence, several studies have shown that reliance on data from HTCs
results in large overestimates of rates of AIDS and of total numbers of
AIDS cases among hemophiliacs (StehrGreen et al., 1989; Evster
et al.. 1987). Overall, only about 15 percent of HIV infected hemophiliacs
have developed AIDS in the United States and the United Kingdom at present
(CDC, 1993), although one would expect over 40 percent according to the
rates of development projected by Anderson and Weiss (Weiss, 1993; StehrGreen
et al., 1989).
Further data also contradict the current
dogma concerning rate of disease development. Weiss and many other investigators
attribute the lower rate of development of AIDS in young hemophiliacs to
age. Perhaps, he conjectures 'younger persons have greater CD4 lymphocyte
reserves and precursors for renewal' (Weiss, 1993; see also Goedert er
al., 1989). Studies of people infected with HIV through transfusions prove
this conjecture wrong. Transfusion patients younger than 5 years of age
develop AIDS significantly faster than older children, while children over
the age of 2 but under 13 years of age develop AIDS at almost exactly the
same rate as people between the ages of 13 and 39 and between 40 and 60
(Lui et al., 1986; Medley et al., 1987; Wang & See, 1992; Krasinski,
Borkowsky & Holzman, 1989; KopecSchraderetal., 1993).Only people
over the age of 59 have a rate of AIDS onset that is shorter than that
of younger patients, and the difference is not statistically significant
(KopecSchrader et al., 1993). Weiss's conjecture also fails to address
why hemophiliacs over the age of 44 should have greatly increased rates
of progression to AIDS compared with 2544 year olds when such a phenomenon
is not apparent in transfusion patients, nor can it explain why hemophilic
men age 20 to 44 years who have additional risk factors such as drug abuse,
homosexual activity, or both, have significantly decreased rates of survival
(Holman et al., 1992). Moreover, no one has ever reported that age affects
the rate of progress to AIDS among HIV infected homosexual men, although
a substantial number of these men contract the disease either prior to
the age of 25 or after their 44th year. I presume that no age
effect has been reported among gay men because no such effect exists although
I can find no studies specifically addressing this question.
Those who claim that AIDS develops at the
same rate in all risk groups also ignore data showing that transfusion
patients of all ages develop AIDS at a significantly greater rate (50 percent
have AIDS an average of 5.5 to 7.0 years after infection) (Lui et al.,
1986; Medley et al., 1987; Ward et al., 1989; Downs et al.,
1991; Msellati et al., 1990; KopecSchrader et al., 1993) than do homosexual
men or hemophiliacs (an average of cat 10 years or more). Moreover, the
slope of the progression for transfusion patients differs from that seen
for homosexual men or hemophiliacs (Figure 1), indicating that the increased
rate is not due simply to fewer Tcells at the time of infection, but
rather to ongoing synergistic effects with other factors. These factors
include the disease process that required surgery in the first place, infection
with, or reactivation of, latent immunosuppressive infections including
cytomegalovirus, EpsteinBarr virus, and hepatitis viruses, the immunosuppressive
effects of anaesthetics, opiate analgesics, chronic and high dose antibiotics,
and (following some types of surgery) malnutrition, not to mention chronic
health problems that often follow major surgery (reviewed in RootBernstein,1990a,
c, 1991, 1992, 1993).
The proof that immunologic status and ongoing
exogenous immune suppression are determinants of progression to AIDS comes
from studies of organ transplant patients who are infected with HIV (and
often other viruses and bacteria) at the time of their operation (Fig.
l). Fifty percent of these patients develop AIDS within 1.2 to 2.8 years,
depending on the types of transplant and the type of immunosuppressive
treatment they receive (Cooper et al., 1993; Schwarz et al.,
1993; Ribot&Eslami, 1992;Langeetal.,1991; Tzakis et al., 1990;
Atkinson et al., 1987).
It is clear from all of the published studies
that the type of immunosuppressive regimen used to control transplant rejection
has a very significant effect on the rate at which AIDS develops and on
survival, but different investigators have found contradictory results
concerning the influence of cyclosporine. Lang et al. (1991) found that
four year survival of HIV+ transplant patients treated with the
triple drug therapy (azathioprine + steroids + cyclosporine) was 19% compared
with 57% in HIV+ patients without cyclosporine. Schwarz et al. (1993),
however, have reviewed published cases and claim that the cumulative incidence
of AIDS (not survival!) after 5 years was 31 % in patients treated
with cyclosporine versus 90% in those receiving immunosuppressi·ve
treatments other than cyclosporine. These data may be compatible if one
considers the possibility that patients treated with cyclosporine do not
generally live long enough to develop AIDS, or that their risk of other
forms of death are increased so that AIDS is a less probable diagnosis.
Indeed, one problem evaluating all data concerning transplant patients
is the very high rate of mortality among these patients regardless of their
HIV status. For example, mean survival time for HIV+ dialysis patients,
most of whom were intravenous drug abusers in this particular study, was
found to be a mere 1.5 years-too short for most of them to develop AIDS
(Lang et al., 1991). On the other hand, kidney transplant patients
who must return to dialysis because of transplant failure have much better
odds of survival than those whose transplanted kidney remains functional
(Lang et al., 1991), suggesting that treatments such as plasmapheresis,
which have been reported to help some AIDS patients, may indeed be effective.
In any event, Lang et al. (1991) summarize their study with words
that aptly convey the conclusions of all of the cited transplant studies
by saying that 'survival is much lower than in nontransplanted patients
contaminated through blood transfusion . .. This shorter survival is due
to both a reduced AIDSfree time period and an accelerated course between
the diagnosis of AIDS and death.' Clearly, then, chronic treatment with
known immunosuppressive agents demonstrably and quite dramatically speeds
up the rate of onset of AIDS.
The conclusion that chronic immunosuppressive
treatments increase the rate of AIDS development is confirmed by studies
of patients who are treated for combined Hodgkin's diseaseHIV infection,
and have an average AIDSfree time of only 3 years as a result of cancer
chemotherapy (Roithmann et al., 1993). Blood transfusions are also
known to be acutely immunosuppressive, and are often given to AIDS patients
to correct antiretroviralinduced anaemia. Some evidence suggests
that this practice increases the rate at which AIDS progresses (Vamvakas
& Kaplan, 1993). One might expect that other immunosuppressive treatments,
such as systemic corticosteroids for autoimmune conditions, will also be
found to be contraindicated for people at risk for AIDS. On the other hand,
nonimmunosuppressivemedical treatments have little effect on AIDS
progression, as has been demonstrated by a study of HIVinfected individuals
who require cardiopulmonary bypass surgery (Arts, Pomar & Saura, 1993).
Finally, although everyone knows that perinatally
infected infants have the fastest rate of progression of any risk group
(Weiss, 1993), the huge magnitude of the rate of increase (median of 6
months) (Fig. 1) is often ignored (Blanche et al., 1990; Minkoff
et al., 1987; Mayers et al., 1991; Kraskinski, Borkowsky
& Holzmann, 1989). This huge increase in rate of AIDS progression has
never been explained adequately except in terms of predisposing immunological
debilitation caused by maternal cofactors experienced by the fetus or newborn.
These factors include drug addiction, multiple concurrent viral and bacterial
infections, exposure to blood products and anaesthetics, malnutrition and
anemia. A very large proportion of children who develop AIDS are also significantly
premature, underweight for their age, jaundiced, and malnourished-all factors
associated with immune suppression even in HIVseronegative infants
(ibid.; Rubenstein et al., 1983; reviewed in RootBernstein,
1990a, c, 1992, 1993).
I conclude that arguments as to the sufficiency
of HIV as the cause of AIDS are not supported by epidemiological evidence.
Different risk groups progress to AIDS at substantially different rates,
as do different individuals within risk groups. The socalled age factor
in hemophiliacs is unique to this group, and must therefore be related
to the very significant changes in the treatment of hemophilia over the
past few decades (e.g., the switch from heavily virus contaminated plasma,
to less contaminated factor concentrate, to ultrapurified and recombinant
DNA derived clotting factor), which has saved young hemophiliacs from many
cumulative immunosuppressive cofactors that affect older hemophiliacs (Rosendall,
Smit & Briet, 1991; RootBernstein, 1990a, 1993). Cofactors known
to cause immune suppression and to significantly increase the rates of
AIDS development, which are also known to be much more common in older
than younger hemophiliacs, include infections (sometimes chronic) with
herpes viruses, hepatitis virus types B and C, and cytomegalovirus (Sullivan
et al., 1986; Goedert et al., 1989; Webster et al., 1989; Higgins
& Goodall, 1991; Sabin et al., 1993) and exposure to alloantigens
in impure factor concentrates themselves (Hilgartner et al., 1993; Schulman,
1991; Goedert et al., 1989; Sullivan et al., 1986). All of these cofactors
are also present in other AIDS risk groups at unusually high rates compared
to the general population (RootBernstein, 1993). Attenuation or elimination
of these cofactor exposures through changes in hemophilia treatment since
the 1960s resulted in a rise in the average life expectancy of hemophiliacs
from 33 years in 1960 to nearly 57 years in 1980 (Aronson, 1988; Rosendaal,
Smit & Briet, 1991). (Life expectancy has unfortunately plunged again
to 40 years during the period 19871989 due primarily to AIDS, but
also to increases in nonAIDSassociated pathologies as well [Lorenzo,
et al., 1993; Mares, Sartori & GiroIami, 1992; Ritter, 1994]).
One crucial study that would help to clarify
the rateofprogression issue has not yet been done, and that is
to examine the rate of AIDS onset in spouses of HIVpositive
hemophiliacs and blood transfusion patients as a function both of HIV infection
and cofactor acquisition (e.g., exposure to hepatitis viruses, cytomegalovirus,
etc.). Presumably, spouses who acquire HIV heterosexually and have no drug
or medical problems of their own will have the longest AIDSfree time of
any group yet studied. Only two studies have been carried out that are
relevant to this issue (Peterman et al., 1988; Andes, Rangan &
Wulff, 1989), but neither calculates rate of onset of AIDS, nor gives the
elapsed time from HIV exposure. Notably, however, of four women who contracted
HIV from their hemophiliac husbands prior to 1985, none had developed AIDS
by 1989 and only one had developed AIDSrelated complex in one study
(Andes, Rangan & Wulff, 1989), while in the other study, one of 12
spouses had died of AIDS, three had developed lymphadenopathy, and eight
had remained asymptomatic by 1988 (Peterman et al., 1988). If one
AIDS case out of 16 infections over four to eight years is an approximately
accurate interpretation of these results, then the rate of AIDS onset among
this group is, indeed, very low.
One interesting observation that has not
been made before is that the rate of onset of AIDS in infants and transplant
patients appears to level off after a few years, suggesting that those
HIVinfected people who remain AIDSfree for extended periods of
time have an everdecreasing probability of developing AIDS. The data
are not yet conclusive on this point, but if it is true, then one may predict
that the probability of developing AIDS in all HIV+ risk groups will come
to resemble sigmoidal curves. Longterm HIV+ survivors in all risk
groups will, in other words, become less and less likely to develop AIDS.
One indication that such a trend has already begun comes from a study of
HIV+ gay men in Los Angeles which found that among those infected in 1979,
28% developed AIDS within six years, whereas among those infected in 1983,
25% developed AIDS within six years (Taylor, Kuo & Detels, 1991). The
authors of the study suggest three possible explanations: mutation of HIV
toward less pathogenic strains; better health care for preAIDS HIVinfected
individuals, or control of cofactors through safer sex, clean needle, and
education programs. The phenomenon of everslowing progression to AIDS
has been observed in homosexual and bisexual men in Amsterdam as well,
where the hazard rate has been decreasing consistently (Hendriks et al.,
It is important to stress that cofactor
models of AIDS are completely consistent with current data concerning AIDS.
In fact, several mathematical models of AIDS epidemiology demonstrate that
the observed rates of development in each risk group can be explained only
by models involving two or more synergistic agents. Weyer and Eggers (1990),
for example, show that even if one assumes the rates of AIDS onset to be
the same for each risk group, the 'drastic overrepresentation of the sexually
highly active groups and drug abusers in the number of AIDS cases obviously
requires that the transmission of AIDS unequivocally depends on the sexual
and drug risk ...The observed parallel time series for the spread of AIDS
in groups with different risk of infection can be realized by computer
simulation, if one assumes that the outbreak of fullblown AIDS only
occurs if HIV and a certain infectious coagent (cofactor) are present.
Such studies of the accuracy and reliability of Western immunoprecipitation,
and polymerase chain reaction (PCR) testing report several cases of seroreversion
and loss of detectable virus among groups of tested individuals of varying
sizes (e.g., four of twelve cases in Gaffe et al., 1985; four in
a hundred in Horsburgh et al., 1990; and one of the 29 in KnuverHopf
et al., 1993).
Several very recent reports confirm the
existence of unexpectedly large numbers of serorev·erters. Scott
Tanenbaum and Cindy Leissinger, researchers at Tulane University found
five severe hemophiliacs (representing 10% of their cohort) with HlVseropositive
blood samples at one or more time points, all of whom subsequently seroreverted
(Tanenbaum et al., 1993; Anonymous, 1994). These researchers point
out that between 10% and 15% of severe hemophiliacs who were probably exposed
to HIVcontaminated factor one or more times have remained seronegative.
Indeed a substantial proportion of people exposed to HIVcontaminated blood
factor lots and blood transfusions have also been found to be seronegative
on later testing. Henrard et al. (1993), for example, studied 103
high risk seronegative individuals, including 85 hemophiliacs, of whom
52 were known to have been exposed to HIVcontaminated factor concentrates.
Seventysix plasma samples (72%) were consistently negative for HIVI
DNA by PCR; 24 (22%) were positive only once, but were not so upon multiple
retesting; and 4 (3%) were positive twice, and then negative thereafter.
When cellular DNAs were extracted from the blood specimens of PRCpositive
plasma samples, none were found to be positive for HIV1 DNA, suggesting
that the plasmabased PCR test has a very high rate of false positive
results when performed on HIVseronegative samples. On the other hand,
10 of 10 PCR tests of cellular DNA from HIVseropositive individuals
yielded PCRpositive results. Henrard and his collegues concluded that
HIVseronegative individuals who are known to have been exposed to
HIV have truly eliminated the retrovirus, and do not remain latently infected.
It is probable that the results reported
by Henrard et al. (1993), and Tanenbaum et al. (1993) are
very common. Ward and his collegues at the AIDS Program of the Centers
for Disease Control studied 765 people who received HIVtainted blood
transfusions. Only about 60% were found to be seropositive within an average
of 5 years after exposure (Ward e' al., 1989). Similarly, Ludlum
et al. (1985) found that of 34 hemophiliacs transfused an average
of over a dozen times each with a single batch of HIVcontaminated
clotting factor VIII concentrate, only 18 became HIVseropositive, and the
risk was not associated with number of transfusions since most of the men
seroconverted after receiving only three treatments while others remained
seronegative after more than a dozen.
Similarly, Clerici et al. (1992)
have documented dozens of instances of seronegativity among high risk individuals,
including gay partners of HIVinfected men who have engaged in repeated
acts of unprotected receptive anal intercourse, health workers exposed
to HIV by subcutaneous cuts and needlestick accidents, and drug users who
have shared needles with HIVinfected addicts (Brown, 1992). All of these
people, although antibodynegative at the time they were tested, nonetheless
displayed active Tcell responses to HIV antigens, suggesting that
they had, in fact, been infected previously by HIV. Berkeley researchers
have also reported seven healthy people-at least five of whom were definitely
exposed to HIV-with Tcell mediated immune responses to HIV, but without
HIV antibody. Two of the seven had urine samples positive for HIVantibodies
at one time, but seroreverted during the study (Urnovitz et al., 1993).
In addition, many research groups have
reported that the existence of significant numbers (hundreds all told)
of people who are at least transiently (and sometimes chronically) PCRpositive
for HIV, but persistently antibody negative (reviewed in Imagawa &
Detels, 1991). These are individuals who have normal immune responses,
with normal antibody production. While most of these investigators have
interpreted their results as evidence for chronic, latent infection with
HIV, Imagawa and Detels have argued that such data are more compatible
with the concept of transient or incomplete infection, because subsequent
verification of PCR positivity at later time periods is often impossible
(ibid.). The transient interpretation is given added weight by the
fact that all of the cases reported have been healthy individuals.
Documented cases of seroreversion, in sum,
appear to represent the tip of a very large iceberg consisting of thousands
of people who have been exposed to HIV and successfully fought off the
infection without developing antibodies, or who developed antibodies but
seroreverted prior to testing. The reasons for the iceberg being overlooked
can be understood if we now go back and reanalyze the methods used by large
cohort studies that report extremely low or nonexistent seroreversion
rates. These studies all have major flaws in their design. First, most
cases of seroreversion seem to occur in people with limited exposure to
HIV and who have no ongoing cofactor exposure (FribourgBlanc, 1988;
RootBernstein, 1993). People involved in most AIDS cohort studies,
on the contrary, are by the design of the studies in high risk groups and
very often have continued exposure to both HIV and putative cofactors.
Second, the timing of seroreversion appears to be such that many people
may have been infected with HIV but seroreverted prior to first
being tested for the cohort study, and some appear to remain HIVseronegative
during the study despite being exposed to HIV. These people are not identifiable
as having been exposed to HIV because of the use of antibody tests for
initial screening for infection. Exposure leading to successful Tcell
immunity without antibody cannot be documented without the more tedious
efforts of Tcell antigen recognition studies, which are very rarely
performed. And third, the U.S. Army study is irremediably flawed by the
very fact that their data base consists of confirmatory tests, which are
normally carried out within a few weeks or months of one another, rather
then over the several years that appear to be necessary for loss of HIV
antibodies and elimination of HIV from infected cells to occur. Thus, the
Armed Forces study is not at all relevant to determining the rate of true
seroreversion (Tanenbaum, Leissinger & Garry, 1993).
FribourgBlanc concludes that 'these
observations [of seroreversion] are certainly not rare, but authentification
of such cases requires conditions that are difficult to satisfy'. His work,
and that of an everincreasing number of other investigators tells
us that we must stop assuming that if a person is infected with HIV, they
will necessarily produce antibody, and that following infection, they will
necessarily remain infected forever. For many people, HIV infection is
transient, and such people hold the keys to understanding how to combat
Myth 3: Antibody to HIV is protective
so vaccination is possible
The third myth that I want to discuss is
one that is shared alike by those who believe that HIV accounts for all
of the immune suppressions in AIDS, and by those (such as Duesberg) who
believe that HIV has nothing to do with AIDS. This myth maintains that
antibody against HIV is protective, and therefore that the presence of
antibody indicates that the retrovirus has adequately been controlled.
Duesberg uses this argument in order to contend that since all AIDS patients
have high levels of antibody against HIV, therefore HIV cannot be doing
any significant damage to the immune system or body (Duesberg, 1989, 1990).
Those who believe that HIV is the sole cause of AIDS argue, to the contrary,
that if only people can be vaccinated against HIV so that antibodies are
present prior to infection, then exposure to HIV will carry no risk of
AIDS. Old and new evidence suggests that both of these positions are wrong.
The most important evidence in this regard
has already been reported under Myth #2 above, and consists of the fact
that HIVseropositivity is usually associated with low CD4 counts that
rectify themselves when seroreversion occurs. Additionally, as we have
just seen, a significant proportion of people repeatedly exposed to HIV
become PCR positive but remain antibody negative and healthy. Other people
repeatedly exposed to HIV remain antibody negative, are PCRnegative, but
demonstrate Tcell activation toward HIV antigens, strongly suggesting
that they have previously mounted an effective Tcell response to HIV
(or some crossreactive alloantigen [Stott, 1991; Kion & Hoffman,
1991]). In short, HIV is controlled by the Tcell response, and antibody
positivity to HIV is negatively correlated with control of HIV infection.
These data strongly suggest that the primary
line of defense, and the only effective one against HIV is a Tcell
response (Cleric) et al., 1992; Clerici & Shearer, 1993; Salk
et al., 1993). Tcell regulation is reasonably common for noncytolytic
encapsulated viruses, and antibody enhancement of infection is relatively
common for these viruses as well (see below). Antibody is only produced
when Tcell immunity fails to control viral replication and a sufficient
amount of free virus is present in blood, lymph, or tissues to activate
B cells. Clearly, as the cases of seroreversion prove, this antibody is
shortlived in the absence of active, ongoing infection, and does not
remain to protect against further infection. This phenomenon of rapid loss
of antibody is also consistent with a primarily Tcell regulated immune
response, rather than a primarily Bcell regulated immune response.
In fact, there exists a class of infectious
diseases, most of which consist of noncytopathic encapsulated viruses (of
which HIV is one), the pathological effects of which are actually exacerbated
by the presence of antibody. One example is Lymphocytic chor.iomeningitis
virus (LCMV) infection in mice, which has many similarities to hepatitis
B virus and HIV infection in man (Oehen, Hengartner & Zinkernagel,
1991). In LCMV, as in many other viral infections in which the immune response,
rather than the virus infection itself causes lymphocyte death, survival
is dependent on a successful Tcell response rather than upon antibody
production. Production of antibody, whether naturally occurring or as a
result of vaccination, is highly associated with death of the animal (Oehen,
Hengartner & Zinkernagel, 1991). Dengue virus infection in human beings
presents a similar picture. The severe hemorrhagic fever associated with
the virus is almost always a result of an anamnestic or secondary antibody
response. Presence of antibody has been found to be a strong predictor
of severe disease following reinfection with a variant strain of the virus
(Halstead, 1988; Kliks et al., 1989). Since HIV mutates very quickly,
and an extremely large number of HIV strains are known, probability of
antibodymediated enhancement of secondary infection with variant HIV
strains in AIDS becomes a very likely event, which may, indeed, explain
the long latency found in the syndrome.
LCMV and dengue virus are only two of many
examples antibodyenhanced disease. Porterfield (1986) and Burke (1992)
have summarized the relevant data for a very wide range of noncytopathic
viruses, including dengue, Japanese encephalitis, yellow fever, tickborne
encephalitis, Sindbis, respiratory synctial virus, rabies, reoviruses,
murine cytomegalovirus, corona viruses, and lentiviruses (e.g. the visna
virus of sheep). In some cases, vaccines (usually live attenuated strains)
against these viruses have been very effective, but in others, such as
respiratory synctial virus, measles virus, and visna virus, vaccination
with formalininactivated whole virus dramatically increased the probability
of severe or lifethreatening infection among recipients (Burke, 1992).
Burke has concluded that antibodydependent enhancement of infection
is a general in vitro property of all enveloped viruses, and that
this in vitro activity is more often than not mirrored by physiological
enhancement of infection as well, particularly when humoral immunity is
Particularly frightening in this respect
is significant data that antibodydependent enhancement of HIV infection
occurs in vitro and possibly in vivo as well (reviewed in
Burke, 1992). The problem is exacerbated by the mimicry between HIV proteins
and HLA proteins of lymphocytes that results in immunologic crossreactivity
between HIV and lymphocyte cellular receptors (Golding et al., 1988;
Vega, Guigo & Smith, 1990; Garry et al., 1991; Bjork, 1991;
Kion & Hoffman, 1991; Stott, 1991; Clerici et al., 1992; Dalgliesh
etal., 1992; SOsal et al., 1993; RootBernstein &
Hobbs, 1991, 1993; RootBernstein & DeWitt. 1994).
Thus, a recent study of the immunological
effects of recombinant HIV gpl60 resulted in 3 of 5 human volunteers developing
antiidiotypic antibodies that cross reacted with their CD4 protein.
The study concluded that such vaccineinduced antiCD4 antibodies
'potentially may: (1) limit the use of vaccines which elicit them; (2)
contribute to the immunodeficiency occuring in HIV I infected individuals,
and (3) provide evidence of HIVI infection during the period when
antiHIV1 antibodies are not detectable, (Keay et al., 1992;
see also Sabin, 1988).
The presence of nonHIVinduced
HIVlike immune responses in several animal models of AIDS (Stott,
1991; Kion & Hoffmann, 1991) also raises the uncomfortable possibility
that allogeneic exposure may confound all tests for AIDS, including Tcell
tests. Salk et al. (1993) have argued, on the other hand, that allogeneic
exposure might be protective, thus providing an alternative explanation
for why people with apparent Tcell responses to HIV antigens
may have avoided infection (Cleric) & Shearer, 1993; Clerici et
It follows that presence of HIV antibody
is symptomatic of a failure of Tcell immunity. The issue in understanding
AIDS now becomes that of establishing what causes the failure of Tcell
mediated immunity. Since this failure does not occur in a large proportion
of people exposed to HIV (e.g., the 15% of severe hemophiliacs who have
not become HIV seropositive and perhaps susbstantially higher percentages
of mild hemophiliacs), it is unlikely that HIV is, itself, the cause of
this failure. HIV is more likely an opportunistic or synergistic infection
that becomes manifest only in people predisposed to or with ongoing causes
of immune suppression, just as cytomegalovirus and EpsteinBarr virus,
which are also extremely highly correlated with AIDS, remain latent in
immunologically healthy people, but are reactivated to produce significant
viremia and immune suppression in people whose immune systems are suppressed
(see references below).
Primary Tcell regulation of HIV explains
why HIV is such a good marker for AIDS, regardless of whether it is a causative
agent, a synergistic one, or an opportunistic one. If we assume 1) that
reexposure to HIV is quite frequent among high risk groups; 2) that exposure
to variant HIV strains is therefore common; 3) that only those with concomitant
and ongoing immune impairment actually become infected; and 4) that of
those infected, only those with ongoing immunological stimulation that
adversely effects Tcell control of HIV go on to produce antibody;
then HIVseropositivity becomes a very selective criterion for AIDS
One would expect that whatever processes
make an active HIV infection possible will also activate other latent viral
disease agents. This is, in fact, the case. Both EpsteinBarr virus
and cytomegalovirus reactivation and viremia-not the mere presence
of antibody-have been reported to be accurate markers of AIDS progression
(Bigger et al., 1983; Drew et al., 1985; Fiala et al.,
1986; Rinaldo et al., 1986; Rahman et al., 1989; Munoz,
et al., 1988; Sumaya et al., 1985), and so have diagnostic
signs of autoimmune processes such as the development of lymphocytotoxic
antibodies and circulating immune complexes (Cleric) et al., 1992;
Zarling et al., 1990; Sonnabend, 1989; Daniel et al., 1989;
Ozturk et al, 1987; Stricker, et al., 1987a, b; McDougal
et al., 1985). HIV antibody production and viremia, in other words,
are only one of a very large set of immunologic events that occur
simultaneously in people at high risk for AIDS, and any or all of these
events can trigger the very wide range of interferon, interleukin, tumornecrosisfactor,
and other immunological events that are often mistakenly attributed solely
to HIV (Sonnabend, Wirkin & Portillo, 1984; Sonnabend, 1989; PapadopulosEleopulos,
1988; RootBernstein, 1993; Fauci, 1993).
The treatment implications are manifest.
By the time active antibody production against latent viruses has begun
in people at risk for AIDS, Tcell disregulation is already severe.
Those people who seroconvert immediately following exposure to HIV can
therefore reasonably be conjectured to have been previously or concurrently
immunosuppressed by nonHIV agents, and I have summarized extremely
extensive evidence to this effect elsewhere (RootBernstein, 1990a,
c, 1992a, b, 1993). For example, progression to AIDS in hemophiliacs is
highly correlated with low Tcell counts (Thelpers < 500) at
the time of infection, whereas high Tcell counts (Thelpers >750)
are predictive of very slow progression (Lorenzo et al., 1993; Sabin
et al., 1993). The object of AIDS prophylaxis must therefore be
to prevent the immune system from decaying to the point that seroconversion
becomes possible, or to eliminate ongoing factors that prevent seroreversion.
It follows that antibodystimulating vaccines may actually be detrimental.
Alternative approaches for treating HIVseropositive
people are needed that eliminate ongoing Tcell sup pression and
rebuild immunity. Some approaches that embody these principles have
apparently been successful, as the next section will outline.
Myth 4: The only way to treat AIDS is
to treat HIV
The need for understanding how to treat
HIV infections and AIDS raises the fourth myth that has plagued AIDS research.
For a decade, the paradigm for preventing AIDS has been to treat HIV, since
it is believed that HIV was solely and completely responsible for all aspects
of the pathogenesis of AIDS. It is now well established that this HIVcentered
paradigm has not yielded any appreciable benefits for AIDS patients and
no miraculous antiretroviral drugs or effective HIV vaccines are on the
medical horizon (Weiss, 1993; Fauci, 1993). If we accept that AIDS is an
immunological disease (rather than a virological disease) in which the
major disruption occurs in T cells, and if we accept the fact that different
risk groups, and different individuals within risk groups, progress to
AIDS at different rates due to different cofactor exposures (see above,
Myth #1), and that it is possible for some people spontaneously to eliminate
HIV (see above, Myth #2), it becomes manifest that there must be effective
approaches to treating people at risk for AIDS that do not depend upon
targeting HIV. We need to identify and use these nonHIVcentered
approaches to AIDS on the widest possible scale, regardless of whether
we believe that HIV is needed to cause AIDS or not, if only because we
do not have any effective way of controlling HIV directly at present, and
have no real hopes of doing so within the next decade.
One approach that has yielded positive
clinical trial results, but little fanfare, is immunologic reconstitution
utilizing thymomimetic compounds to treat preAIDS patients (reviewed
in Hadden, 1991). Gottlieb et al. (1991) have reported very good
results in slowing AIDS progression in a multicenter, doubleblind,
placebocontrolled trial of the leukocytederived immunomodulator,
IMREG 1, and the pharmaceutical agent has been approved by the U.S.
FDA for fullscale clinical trials. Interest has also been increasing
in the use of nonspecific potentiators of delayedtype hypersensitivity
(DTH) reactions, such as dinitrochlorobenzene (DNCB), that have been found
to stimulate Tcell responses, and limited trials suggest some success
(Mills, 1986; Stricker, Elswood & Abrams, 1991; Stricker et al.,
A second approach to AIDS is revealed by
reviewing of all known cases of true seroreversion (see references in Myth
#2 above). Such a review reveals that none of the seroreverters have been
treated with antiretroviral drugs. Few. if any, of the cases have been
treated for AIDSassociated infections at all. Other factors seem to
One factor seems to be limited reexposure
to HIV. FribourgBlanc (1988) noted that in the cases of spontaneous
seroreversion he documented, exposure to HIV was limited to only one or
a few instances. Certainly exposure was limited (by the death of the sexual
partner) in the case of the hemophiliac wife described by Burger et
al. (1985). Similarly, Farzadegan et al. (1988) report that
seroreversion in their four gay men followed substantial lifestyle changes
that included switching from multiple concurrent and multiple serial sexual
partners to a single, stable sexual relationship, and rigorous implementation
of safer sexual practices.
Personal interviews with three seroreverters
who have provided me with the records of their HIVtesting have revealed
that all underwent significant lifestyle changes. All three totally eliminated
drug use, began practicing safe sex measures, and went on highnutrient
diets. These same factors were reported to be common to all of the longterm
AIDS survivors profiled by Michael Callen in his book, Surviving AIDS
(1990) and by anecdotal and selfreporting in The Continuum
Magazine (England), Praxis (U.S.), and other publications by people
Unfortunately, no formal studies of longterm
survivors of HIV, or of significantly large groups of seroreverters have
yet been carried out, so that it is impossible to say for certain what
factors-genetic susceptibility, viral variation, viral load and reexposure,
immunological status and at time of infection, subsequent exposure to cofactor
infections or. immune impairments from other sources such as chronic medical
treatments, nutritional determinants-or other factors are responsible for
the difference between healthy seroreversion and fatal development of AIDS.
Some clues do exist, however, in a handful of wellcontrolled studies.
Substantial data indicating that elimination
of one or more of the nonHIV immunosuppressive risks listed above
substantially alters the rate of progression to AIDS in the absence of
retroviral treatments. Studies of HIVpositive intravenous drug abusers
show that the probability of progression to AIDS can be decreased by a
factor of three or more by simply eliminating ongoing drug use (Groenbladh
& Gunne, 1989; Weber et al., 1990). Additional treatment for
malnutrition and rigorous practice of safe sex procedures decreases the
rate of HIV progression among IVDUs even further (Moretti, 1992).
Additional evidence for controllable cofactors
in AIDS comes from studies of HIVseronegative hemophiliacs
who display pronounced decreases in CD4 counts, decreased capacity to produce
interleukin II, and immune suppression (Watson & Ludlum, 1992; Hassett
et al., 1993; Madhok et al., 1990; Hay, McEvoy & DugganKeen,
1990). This immune suppression has been related to factor VIII therapy
(ibid., and Farrugia, 1992), active cytomegalovirus and hepatitis
C infections, and lymphocytotoxic autoantibodies. It is believed that affected
hemophiliacs are consequently predisposed to HIV infection and an increased
rate of development of AIDS (Sabin et al., 1993; Goldsmitk et
al., 1991; Higgins & Goodall, 1991; Madhok et al., 1991;
Schulman, 1991; Webster et al., 1989; Daniel et al., 1989).
Replacing medium purity blood clotting factor concentrates with high purity,
antibody purified, or recombinant factor that lacks viral and alloantigenic
contaminates for the treatment of both HIVseronegative and HIVinfected
hemophiliacs has resulted in stabilization of Tcell counts, and in
some patients, increasing Tcell counts over several years (Hilgartner
et al., 1993; Mannucci et al., 1992; Gompert et al., 1992;
De Biasi et al., 1991; Schulman, 1991). Increased Tcell counts
are a very favorable prognosticator of continued health in HIVinfected
hemophiliacs (Daniel et al., 1991).
Another broadly effective approach to AIDS
prevention is prophylaxis against cofactor infections. Vaccinations that
have proven effective in delaying AIDS onset significantly include Mycobacteria
(Kallenius, Hoffner & Svenson, 1989). Prophylactic treatment of cofactor
infections such as cytomegalovirus and Pneumocystis pneumonia are
also associated with decreased disease progression and also significantly
improve survival among HIVseropositive individuals (Odell & Green,
1990; Montaner et al., 1991; Palestine et al., 1991; Hoover
et al., 1993). Such results suggest that approaches to AIDS prevention
that focus on cofactor prevention, elimination or control may be more effective
than treatment of HIV itself and demonstrate that HIV alone is not responsible
for AIDS. Thus, development of vaccines against cytomegalovirus, EpsteinBarr
virus, hepatitis C, and a set of more effective and less toxic antiviral
drugs might be more important for preventing AIDS than an HIV vaccine,
and more widely applicable in other medical settings (RootBernstein,
The evidence that cofactors are necessary
to the progression of AIDS has now convinced a number of investigators
that no comprehensive treatment of AIDS will be possible without addressing
the full range of cofactors that may influence disease progression. For
example, Lafeuillade and Quilichine (1992) argue that the study of cofactors
promises greater 'understanding of AIDS and hence its therapeutic approach'.
Littlefield (1992), in an even stronger statement, says that it has now
become clear that 'one or more supplemental mechanisms must be involved
in the pathogenesis of AIDS,' beyond HIV infection per se, and that
'identification of the nature of this [these] supplemental process[es]
has become essential for successful, nonharmful intervention'.
Since data concerning the role of cofactors
as regulators of AIDS are limited, four types of tests need to be carried
out to confirm the observation that elimination of ongoing immunosuppressive
risks (including reexposure to HIV) is effective in preventing progression
to AIDS. First, largescale, formal studies of people exposed to HIV
without seroconversion, people who have seroreverted, and longterm survivors
of both HIV infection and AIDS are desperately needed. Such studies can
conclusively demonstrate whether HIV is sufficient to cause AIDS.
Second, a largescale formal study
is needed of ongoing immunosuppressive risks among HIVseropositive
people progressing to AIDS. It is assumed, but by no means demonstrated,
that the immune suppression manifest in such people is due solely to HIV,
but no attempt has been made to investigate ongoing immunosuppressive exposures.
Third, a study of people exposed to the
same sorts of immunosuppressive agents in the absence of HIV is mandatory.
It is well established that all risk groups have some degree of immune
suppression independent of exposure to HIV (reviewed in RootBernstein,
1993). No study has ever been carried out that has examined HIVpositive
and HIVnegative individuals in the same risk groups, paired by ongoing
nonHIV immunosuppressive risks. Do all severe hemophiliacs actively
infected with hepatitis B virus, cytomegalovirus, EpsteinBarr virus,
and using intermediate purity clotting factor experience the same Tcell
depletion regardless of HIV infection, or not? To what degree is their
Tcell depletion greater than or less than uninfected hemophiliacs,
or those who use ultrapure factor, regardless of HIV status? (That we should
even have to ask for such studies a decade after the discovery of HIV is
a symptom of how poorly controlled and designed research on AIDS has been).
Fourth, a converse study is also necessary
that could potentially prove that HIV is both necessary and sufficient
to cause AIDS: I have challenged the medical community for four years now
to find me a significant number of people (say 100 or more) with AIDS who
have HIV as their sole immunosuppressive risk (as defined by the set of
clinically recognized factors known to cause immune suppression that are
listed in my book, Rethinking AIDS [RootBernstein, 1993]),
whose Tcell counts and other immunological parameters were normal
at the time of HIV infection, and who have nonetheless developed Tcell
counts below 500 and an opportunistic infection. So far, no one has responded
to this challenge. Surely it is not too much to ask that a hundred such
cases be found among the hundreds of thousands of AIDS cases that have
been documented, if we are to accept the oftrepeated assertion that
HIV alone is sufficient to cause AIDS.
One caveat that must be understood in setting
up the abovementioned studies is that AIDS itself (as opposed to HIV
infection) may not be reversible. AIDS may involve slowly progressive processes
including vicious cycles in which multiple sets of infections coactivate
one another, and autoimmune processes that inexorably cause immune system
or other forms of systemic decay. It may not be possible to reverse AIDS
by simple remediation of risk factors after a certain point in the disease,
as both Sonnabend and I have pointed out.
We will need, in addition to preventative
measures against AIDS, new, nonretroviral approaches to disease treatment
of multiple, concurrent infections (many of which are not susceptible to
individual antibiotics), ways to reverse autoimmune processes, and methods
to reconstitute immune function. The frightening fact is that very little
of this very necessary research has even begun. The HIV paradigm has blinded
most researchers to the undeniable fact that every AIDS patient (as opposed
to HIVinfected person) has one or more autoimmune diseases, and we
do not know how to treat adequately, let alone cure, any human autoimmune
disease; and that every AIDS patient, even if cured of their HIV infection,
would still have sustained possibly irreversible immunologic damage. It
is entirely possible that we may one day learn how to vaccinate against
or eliminate HIV in AIDS patients and still have people dying of AIDSassociated
autoimmune conditions and opportunistic infections simply because we have
nor yet begun to investigate the causes or cures of the relevant immuno1ogic
processes (RootBernstein, 1992a, b, 1993; Root-Bernstein &
Myth 5: AIDS must have a single etiologic
Another myth that has adversely affected
AIDS research is the assumption, common to much of modern biomedical research,
that every disease has a single etiological agent. As powerful as the onegerm/onedisease/onecure
paradigm has been in the development of modern medicine, it has now been
admitted by most HIV experts that the immune system destruction observed
in AIDS cannot be accounted for by any known mechanism of direct HIV pathogenicity
(Cohen, 1993; Fauci, 1993; Gougeon & Montagnier, 1993; Littlefield,
1992; Lo et al., 1991). Surprisingly, this admission has not, however,
caused any major AIDS researchers to question whether HIV is therefore
sufficient to cause AIDS. There are, however, other paradigms for disease
etiology that are relevant to AIDS besides the onegerm paradigm that
are fully consistent with existing data, as Sonnabend and Saadoun pointed
out as early as 1984 (Sonnabend & Saadoun, 1984). Unfortunately, these
alternatives are less wellknown than the onegerm/onedisease
dogma and their implications have been generally ignored (RootBernstein,
The least revolutionary alternative to
the onegerm paradigm is the twogerm or infectious synergism paradigm
(reviewed in RootBernstein, 1993). Perhaps the earliest proven case
of virusbacterium synergism was discovered by Shope in 1931, when
he showed that neither Hemophilus influenzae nor an unidencified
virus, each of which could be isolated from 100% of pigs who contracted
fatal swine flu, was capable of causing disease in healthy animals. A combination
of the virus and bacterium, however, nearly always caused a fatal pneumonia
(Shope, 1931). A similar synergism was found by Dudding et al. (1972)
between adenovirus and several bacteria, including Hemophilus influenzae,
which caused fatal pneumonias in man. Huang and Hong (1973; and Huang
et al., 1973) found that multiple viral infections often resulted
in the production of lymphocytotoxic antibodies in human patients, accompanied
by significant immune suppression. Hamilton, Overall and Glasgow (1976)
found similarly that combinations of murine cytomegalovirus with Pseudomonas,
Staphylococcus, or Candida infections were much more likely to be fatal
to mice than individual infections, even when the combined doses of infectious
agents were thousands of times smaller. Another wellestablished human
example is the combination of influenza virus with Staphylococcus aureus
to yield a severe and often lethal pneumonia (Klenk & Rott, 1988).
It is likely that the terrible influenza epidemic that killed so many people
after World War I was in fact the result of two or more epidemics (one
influenza, the other(s) unidentified bacteria that overlapped.
Significant evidence exists to suggest
that HIV may interact synergistically by mechanisms such as transactivation
or immunologic crossreactivity with other infectious agents associated
with AIDS, including herpes simplex viruses, cytomegalovirus, EpsteinBarr
virus, HTLVI, mycoplasmas, and mycobacteria (Littlefield, 1992; Lo
et al.. 1990, 1991; Lussoetal., 1990, 1991; Montagnier et al.,
1990; RootBernstein, 1990a, 1992a, 1992b, 1993; Wang et al.,
1992). All of these infectious agents are present in people in AIDS risk
groups and in people with AIDS at incidences hundreds of times higher than
in the general population (BuimoviciKlein et al., 1988; Macon
et al., 1993; RootBernstein, 1993; Sonnabend, Witkin &
Portillo, 1984; Sonnabend, 1989).
A second alternative to the onegerm
model is the multifactorial or predisposition model. HIV may be an opportunistic
agent that, like Pneumocystis carinii or cytomegalovirus, is not
deadly except in immunosuppressed individuals. In this case, a broad set
of immunosuppressive agents, including many addictive drugs, malnutrition,
immunosuppressive infectious agents, and exposure to alloantigens in semen,
blood, blood products, or contaminated needles may interact to set the
stage for active HIV infection (Sonnabend, Witkin & Portillo, 1984;
Sonnabend, 1989; Donohoe & Falek, 1988; Duesberg, 1990; FernandezCruz
et al., 1988; PapadopulosEleopulos, 1988; Pifer et al.,
1987; RootBernstein, 1990a, c, 1993).
A third alternative model is an autoimmune
model for AIDS. Virtually all people with AIDS have lymphocytotoxic antibodies
present. Such antibodies are associated with a number of agents, including
cytomegalovirus infection, exposure to blood and blood products, and immunologic
exposure to semen, in both HIV and nonHIV infected individuals (Huang
& Hong, 1973; Huang et al., 1973; reviewed in RootBernstein,
1990b, 1992 a, b, 1993; RootBernstein & Hobbs, 1993; RootBernstein
& DeWitt, 1994; RootBernstein & DeWitt, this volume). Significant
debate surrounds the issue of whether HIV is necessary or sufficient to
induce lymphocytotoxic autoimmune processes in AIDS, but significant data
point to alloantigen and infectious agents other than HIV as targets for
lymphocytotoxic antibodies in AIDS patients, in addition to HIV (Bjork,
1991; Dalgliesh et al., 1992; Garry et al., 1991; Kion &
Hoffman, 1991; Stott, 1991; Ziegler & Stites, 1986; Sonnabend, 1989;
Hoff & Peterson, 1989; Hoff et al., 1991; Zarling et al.,
1990; Morrow et al., 1991). I, personally, believe that the
only way to explain any autoimmune disease, including the type that appears
in AIDS, is by means of mutipleantigenmediated induction (RootBernstein,
1990b, 1991, 1993; RootBernstein & Hobbs, 1991; 1993).
It is extremely important to realize the
statistical implications of multipleagentinduced diseases (MAIDs),
whether they are cofactorial, synergistic or autoimmune, for the epidemiology
of such diseases. Very simply, MAIDs grow at rates that are multiplicative
functions of the rate of growth of the individual agents. If, for example,
two synergistic disease agents are each present in 1 in 1000 people, and
the diseases are randomly distributed, then the probability that they will
coinfect an individual is 1 in a million. Increasing the incidence of each
agent by a factor of ten (so that each is now present in 1 in 100 people)
results in a probability of combined infection of 1 in 10,000. In other
words, a 10fold increase in the incidence of individual disease agents
results in a 100foldincreased probability of acquiring a combined
infection. Increasing the incidence of each agent by a factor of 100 (so
that 1 in 10 people are infected) results in a probability of combined
infection of 1 in 100, a 10,000fold increased probability of coinfection.
Thus, relatively small increases in the incidence of cooperative agents
lead to extremely large increases in the incidence of the MAID they cooperatively
cause. If the two diseases are cotransmitted, or are transmitted in
a nonrandom way such as occurs in high risk groups for AIDS, then
the probability of coinfection is obviously increased even further
(RootBernstein & Hobbs, 1993). The MAID theory may therefore explain
the observation that people in the advanced stages of AIDS seem to be more
of an infectious risk to their partners than are people with uncomplicated
HIV infections (European Study Group, 1989; Padian, Shibosla & Jewell,
1990): people with fullblown AIDS are, by definition, multiply infected.
The application of the MAID concept to
AIDS is illuminating. One of the most important questions concerning the
current epidemic of AIDS is whether HIV is an old or new virus. A variety
of evidence suggests that both HIV and AIDS have existed in human populations
for decades, and probably for centuries, prior to the recognition of the
first AIDS cases or the discovery of the virus (reviewed in RootBernstein,
1990a, c, 1993). Why, then, did AIDS become epidemic only during the 1980s?
One possibility, for which extensive evidence exists, is that the modes
of transmission grew exponentially during the previous decade as can be
verified by huge increases in all sexually transmitted diseases and drug
use (both intravenous and otherwise) (Duesberg,1992; RootBernstein,
1993). But these increased modes of transmission spread not only HIV, but
many of its putative cofactors-whether they consist of coinfections,
drugs, or exposure to alloantigens or all three-simultaneously. The simultaneous
spread of HIV and cofactors (consider the cotransmission of
hepatitis viruses and HIV in gay men during the late 1970s), in this case
nonrandomly in specific risk populations, would have resulted
in increases several orders of magnitude larger in the incidence of any
disease manifestations that are multipleagent dependent. (Recall,
on this point, that the incidence of HIV seropositive individuals must
represent only a fraction of the people actually exposed to HIV-the fraction
that did not successfully combat HIV without developing an antibody response,
or who subsequently seroreverted-see Myth #2 above. Persistently HIV seropositive
individuals therefore probably represent people who have ongoing cofactor
exposure). I have, in fact, demonstrated that the incidence not only of
HIV, but of active cytomegalovirus and EpsteinBarr virus infection,
hepatitis viruses, Mycoplasma infections, addictive drug use, lymphocytotoxic
antibodies, and various other immunosuppressive agents is often hundreds
of times higher among high risk group populations than among low or nonrisk
heterosexuals and lesbians (RootBernstein, 1993), which would make
the incidence of MAIDs tens of thousands of times higher among risk groups
then in the general population. Thus, if AIDS is a MAID, both the time
course of the epidemic, its exponential growth, and its maintenance within
specific high risk populations can be explained by the unusual coincidences
of both HIV and all of its possible cofactors. If, on the other hand, AIDS
is caused solely and simply by HIV, then neither the timing of the current
epidemic nor its specificity for risk groups is comprehensible.
It should also be noted that a direct consequence
of considering etiologies for AIDS that are more complex than a single
agent immediately invalidates two standard approaches to determining disease
causation: epidemiological correlations and Koch's postulates. If AIDS
is more complex than a simple HIV infection, then the high correlation
between HIV and AIDS (Koch's first postulate) is not sufficient to demonstrate
that HIV is the causative agent. The observed correlation strongly
suggests that HIV is one part of the cause of AIDS, but it should
be expected that other immunosuppressive agents and/or behaviours will
be as highly correlated with either all AIDS cases, or with individual
risk groups. Thus, it is not surprising to find that statistically significant
correlations exist between AIDS risk and unprotected receptive anal intercourse
in both men and women (Naz et al., 1990; Adams et al., 1988;
Morrow et al., 1991; Sonnabend, 1989; reviewed in RootBernstein
& DeWitt, this volume); to use of inhalant nitrites by gay men (Vandenbroucke
& Pardoel, 1989; Haverkos, 1988); to general use of drugs in all risk
groups (Duesberg, 1992); and to the incidence of active infection (not
presence of antibody) with cytomegalovirus, EpsteinBarr virus, and
mycoplasmas in all risk groups (BuimoviciKlein et al.,
1988; Munoz et al., 1988; Rahman et al., 1989; Rinaldo et
al., 1992; Lo et al., 1992; Wang et al., 1992). But just
as HIV is not sufficient to cause AIDS, so, apparently, are these agents
not sufficient to cause AIDS. Thus, demonstration that people with exposure
to these nonHIV agents do not get AIDS in the absence of HIV does
not prove that they are not part of the cause of AIDS. What
must be tested, both epidemiologically and experimentally, are their combinations.
Moreover, there is no requirement in a multifactorial disease
that one specific pair of agents be necessary to cause the disease. One
agent may have several different cofactors, none of which correlate highly
with the disease. Or there may be several combinations of agents
that can create the same pathological symptoms (as, for example, in the
case of pneumonia), and therefore no single agent or set of agents that
correlates one hundred percent with all clinically diagnosed cases of the
What is at issue here are the criteria
for evaluating disease causation. Koch's postulates, focusing as they do
on a single etiologic agent, do not apply to diseases that are caused by
multiple, interacting agents. Thus, the reason why HIV has failed to satisfy
Koch's postulates, despite its obvious presence in virtually all AIDS cases,
may have nothing to do with the oftcited species specificity of HIV
(an observation belied by the fact that HIV does infect and replicate in
chimpanzee and macaque lymphocytes) but rather may result from the fact
that Koch's postulates are irrelevant to testing AIDS etiology (RootBernstein,
1992b, 1993). HIV may not be able to cause AIDS because it is not sufficient
to cause AIDS. This is no different than saying that neither influenza
virus or Staphylococcus are sufficient to cause pneumonia. But both are
Diseases such as AIDS that are autoimmune
in nature, or are the result of synergistic or multifactorial processes
require the satisfaction of a set of postulates other than Koch's (Witebsky
et al., 1957; RootBernstein, 1991). For example, MAIDs may be characterized
by satisfying the following criteria: '(1) two or more infections or immunosuppressive
agents will be active simultaneously in individuals affected with a particular
disease; (2) people with only one of these agents will either have no symptoms
of the disease or symptoms of another disease that is associated with the
single agent; (3) these multiple agents will be isolatable or identifiable
individually; (4) no single one of these agents will be capable of inducing
the disease by itself when introduced into healthy human beings or animals
(although they cause different disease symptoms); (5) an immune response
to each agent will be demonstrable during disease induction and will be
significantly altered by the combination of agents as compared with any
agent individually; (6) the disease will be transmissible from one animal
or human being to another by means of an appropriate combination of the
putative causative agents. In the case of autoimmune diseases, the transmissible
factors may include tissue or purified proteins, immune serum, lymphocytes,
other cells or antibodies' (RootBernstein, 1993). As far as I am aware,
no one has yet set up an animal model of AIDS that would satisfy these
criteria, and therefore model AIDS as a MAID. We cannot, therefore, rule
out the possibility that AIDS is caused by some combination of agents,
of which HIV is likely to be one.
The fact is that until someone is able
to produce an animal model of AIDS using the exact set (or sets) of agents
found in human beings (not merely analogous agents such as feline or simian
immunodeficiency virus, for example), we will not know whether we are working
with correct or incorrect theories of causation. My tendency is to believe
that having failed to cause AIDS with HIV alone, we must assume that AIDS
is more complicated than a mere retroviral infection. On the other hand,
the same reasoning makes me reject Duesberg's suggestion that opiate or
other drug abuse is the cause of AIDS: investigators have worked with animal
models of addiction for decades without observing AIDS in their animals.
Thus, AIDS is more than just HIV or just drugs or just any single agent
that we currently understand. We must now build on what we know of HIV,
but in such a way as to expand our range of research to look at how it
behaves in the much more complicated conditions that actually exist in
real AIDS patients with multiple infections, blood product exposures, drug
exposures, malnutrition, and alloantigen exposure. These conditions have
never been duplicated in animals or test tubes.
On this final point I must insist upon
the accuracy of the following observations. First, there is no documented
case of anyone who has developed AIDS who does not have several of the
following immunosuppressive agents at work prior to, concomitant with,
or following their HIV infection: multiple, concurrent infections with
identified immunosuppressive viruses and bacteria (e.g. herpes viruses,
hepatitis viruses, and mycoplasmas); immunologic exposure to alloantigens
(e.g., semen, blood or lymphocytes); chronic or high dose treatments with
antibiotics; anaesthetics; chronic or high dose use of immunosuppressive
addictive drugs irrespective of mode of use (e.g., heroin); malnutrition;
and autoimmunity directed at Tcell subsets (reviewed in RootBernstein,
1990a, c; 1992 a, b; 1993). As a result of these immunosuppressive risks,
many hemophiliacs, blood transfusion patients, drug abusers, infants of
people in these risk groups, and homosexual men are significantly immunosuppressed
even in the absence of HIV infection (reviewed in Duesberg, 1992; RootBernstein,
1990a, 1993). Second, and conversely, there is no evidence that HIV can
cause disease in an immunologically healthy person free of these causes
of immune suppression: people with limited exposure to HIV and no ongoing
risks of the sort just enumerated, do not become infected with HIV or serorevert
(see above); and there appear to be no verifiable tertiary cases of AIDS
(i.e., nonrisk group heterosexual to heterosexual transmission) in
Western nations. AIDS is therefore remaining in identified risk groups
(National Research Council, 1993; Fumento, 1990)-a fact that cannot be
explained except if prior immune suppression or cofactors are necessary
for HIV transmission and seroconversion.
New directions in AIDS research
The recognition that AIDS may be more complex
than HIV is important because it allows us to reevaluate existing
data in new ways that reveal both new problems and new solutions to the
epidemic. For example, any multipleagentinduced disease (MAID)
can be eliminated by controlling any of the multiplicity of necessary agents.
Thus, we need not target only HIV in order to control AIDS, if AIDS can
be demonstrated to be a MAID. Both HIV and its cofactors (see Myth #4 above)
become viable targets for prophylaxis. treatment and cure. Indeed, one
of the reasons that current public health policies such as safer sex, elimination
of drug use, and clean needle exchanges may be working effectively in many
communities (Van Griensven et al., 1989; Judson, 1990; Winkelstein
et al., 1988; Weber et al., 1990) is that both HIV and many
of its cofactors are simultaneous!) being controlled. According
to the MAID theory, the result of simultaneous control should be a reduction
in new AIDS cases that is a multiplicative function of HIV and cofactor
prevalences. This possibility mandates a much higher interest in nonHIV
factors associated with AIDS than has thus far been manifest.
Beyond the obvious point that there are
models of disease causation (and therefore prevention and treatment) that
have been ignored by the majority of AIDS researchers lies an even more
important point: scientific research consists of elaborating all of the
possible explanations of a phenomenon and then eliminating, through controlled
observation and experiment, all but one of these (RootBernstein, 1989).
Because this is the way all good science works, philosophers and practitioners
of science both agree that one can never prove that the remaining answer
is true; one can only prove that all of the other possibilities are not
(Popper, 1962; Medawar, 1967). (Anyone who remembers learning Mendelian
genetics will recall that the key to solving genetics problems is not determining
what type of inheritance explains any particular cross, but remembering
all of the different possibilities and searching for the crucial evidence
that makes all but one of them untenable). Good scientific research therefore
consists primarily of performing experiments that disprove theories',
rather than gathering data that purport to support a preconceived notion.
In pointing out that too much AIDS research
has been directed by myths that have been accepted uncritically by the
majority of investigators, and that several wellestablished models
of disease causation have been ignored as well, I am therefore arguing
that AIDS research as a whole has not followed standard scientific practice
of skeptical elaboration of possibilities followed by disproof. Instead,
the community of AIDS researchers has reversed standard practice by leaping
to the conclusion that the first obvious answer (HIV) must also be the
best and the most correct answer. Until it can be demonstrated that no
other possible explanation of AIDS exists besides HIV alone, and
until specific tests are performed to attempt to disprove the HIV
theory, there is no methodological justification for limiting research
to HIV alone. This is basic scientific method. Einstein had some
advice to scientists. He said that when devising a theory, make it as simple
as possible and no simpler. My view of AIDS research, which owes a great
the pioneering work of Joseph Sonnabend, is that both those who study HIV
and those who refuse to acknowledge its role in AIDS have oversimplified.
AIDS is complex. AIDS is multifactorial, and the diverse factors that are
correlated with the various risk groups for AIDS all interact synergistically.
Until we understand these interactions in their full complexity and set
up appropriate experiments to test whether any of them are relevant to
AIDS pathogenesis, we will continue to act, as we act today, like the blind
men describing the elephant, each attributing all of AIDS to the part of
the thing with which we are in closest contact (RootBernstein, 1993).
Meanwhile, people with AIDS die as a result of our blindness.
Adams, L.E., R. DonovanBrand,
A. FriedmanKien, K. Ramahi & E.V. Hess, 1988. Sperm and seminal
plasma antibodies in acquired immune deficiency (AIDS) and other associated
syndromes. Clin. Immuno. Immunopathol.46: 442449.
Anderson, R., 1993. AIDS:
trends, predictions, controversy. Nature 363: 393394.
Andes, W.A.. S.R. Rangan
& K.M. Wulff, 1989. Exposure of heterosexuals to human immunodeficiency
virus and viremia: evidence for continuing risks in spouses of hemophiliacs.
Sex Transm. Dis. 16: 6873.
Anonymous, 1994. Fighting
HIV: A clue from hemophilia. Science 263:27.
Aris, A., J.L. Pomar &
E. Saura, 1993. Cardiopulmonary bypass in HlVpositive patients. Ann.
Thorac. Surg.55: 11041107.
Aronson, D.L., 1988. Cause
of death in hemophilia patients in the United States from 19681979.
Am. J. Haematol. 27: 712.
Atkinson, K., A.J. Dodds,
All. Concannon & J.C. Biggs, 1987. The development of the acquired
immunodeficiency syndrome after bone marrowtransplantation. Med. J. Aust.
Bames, D.M., 1988. Obstacles
to an AIDS vaccine. Science 240: 719721.
Biggar, R.J., H.K. Anderson,
R Ebbesen, M. Mebye & J.J. Goedert, 1983. Seminal fluid excretion of
cytomegalovirus related to immunosuppression in homosexual men. Br. Med.
J. 286: 20102012.
Bjork, R.L. Jr., 1991. HIVI:
seven facets of functional molecular mimicry. Immunology Lett. 28: 91 95.
Blanch, S.. M. Tardieu, A.
Duliege. C. Rouzioux, E le Deist, et al., 1990. Longitudinal study
of 94 symptomatic infants with perinatally acquired human immunodeficiency
virus infection. Evidence for a bimodal expression of clinical and biological
symptoms. Am. J. Dis. Child. 144: 12101215.
Brown, R. 1992. AIDS researchers
focus on immune response. New Scientist 8 August, 16.
M. Lange, K.R. Ong, M.H. Grieco & L.Z. Cooper, 1988. Virus isolation
and immune studies in a cohort of homosexual men. J. Med. Virol. 25: 371385.
Burke, D.S., 1992. Human
HIV vaccine trials: Does antibodydependent enchancement pose a genuine
risk? Perspectives Biol. Med. 35: 511531.
Burger, H. & B. Weiser,
1986. Transient antibody to human immunodeficiency virus. Ann. Intern.
Med. 105: 464465.
Burger, H., B. Weiser, W.S.
Robinson, J. Lifson, E. Engleman, et a/., 1985. Transient antibody
to Lymphadenopathyassociated virus/human Tlymphotopic virus type
111 and Tlymphocyte abnormalities in the wife of a man who developed
the aquired immonodeficiency syndrome. Ann. Int. Med. 103: 545547.
Calleq, M., 1990. Surviving
AIDS. New York: Harper Collins.
Centers for Disease Control,
1993. HIV/AIDS Surveillance Report, June 1993.
Clerici, M., J.V. Giorg i,
C.C. Chou, V.K. Gudeman, J.A. Zack, R Gupta, H.N. Ho, RG. Nishanian, J.A.
Berzofsky & G.M. Shearer, 1992. Cellmediated immune response to
human immunodeficiency virus (HIV) type in seronegative homosexual men
with recent sexual exposure to HIVI. J. Infect. Dis. 165: 10121019.
Clerici, M. & G.M. Shearer,
1993. A THI -TH2 switch is a critical step in the etiology of HIV infection.
Immunology Today 14: 107111.
Cohen, J., 1993. AIDS research:
the mood is uncertain. Science 260: 12541255.
Cooper, M.H.. D. Maraninchi,
J.A. Gastaut, P. Mannoni & Y. Carcassonne, l 993. HIV infection in
autologous and allogeneic bone marrow transplant patients: a retrospective
analysis of the Marseille bone marrow transplant population. J. Acquir.
Immune. Defici. Syndr. 6: 277284.
Cuthbert, R.J.G., C.A. Ludlum,
J. Tucker, er aL, 1990. Fve year
· prospective study
of HIV infection in the Edinburgh haemophiliac cohon. Br. tried. J. 301:
Dalgleish. A.G., S. Wilson,
M. Gompels, C. Ludlam, B. Gazzard, A.M. Coates & J. Habeshaw, 1992.
Tcell receptor variable gene products and early HIVI infection.
Lancet 339: 824828.
Daniel, V.,R. Weimer, K.
Schimpf & G. Opeiz, 1989. Autoanubodies against CD4 and CD8positive
T Lymphocytes in HlVinfected hemophilia patients. Vox Sang. 57: 172176.
Daniel, V., R. NVeimer, R.
Zimmerman, A. HuthKuhne, et al., 1991. Improving CD4+ Lymphocyte
counts in HlVinfected hemophilia patients: a favourable prognostic
indicator? Immuno. Lett. 30: 2730.
Darby, S.C., R. Doll, B.
Thakrar, C.R. Rizza & D.R. Cox. 1990. Time from infection with HIV
to onset of AIDS in patients with haemophilia in the UK. Stat. Med. 9:
De Biasi, R., A. Rocino,
E. Miraglia, L. Mstrulle & A.A. Quinno, 1991. The impact of very high
purity factor VlII concentrate on the immune system of human immunodeficiency
virusinfected hemophiliacs: a randomized prospective, twoyear
comparison with an intermediate purity concentrate. Blood 78: 19191922.
Donohoe, R.hl. & A.A.
Falek, 1988. Neuroimmunomodulation by opiates and other drugs of abuse:
relationship to HIV infection and AIDS. In: T.R Bridge (ed.) Psychological,
Neuropsychiatric, and Substance Abuse Aspects of AIDS. New York: Raven
Downs, A.M., R.A. AncellePark,
D. Costagliola, J.R Rigaut & J.B. Brunet.1991. Transfusionassociated
AIDS cases in Europe: Estimation of the incubation period, distribution
and prediction of future cases. J. Acquir. Immune. Defic. Syndr. 4: 805813.
Dudding, B.A., S.C. Wagner,
J.A. Zeller, J.T. Gmelich, G.R. French & EH. Top, Jr., 1972. Fatal
pneumonia associated with aden
ovirus type7 in three military
trainees. New Engl. J. Med. 286: 1 289 1 292.
Duesberg, PH., 1987. Retroviruses
as carcinogens and pathogens. Expectations and reality. Cancer Res. 47:
Duesberg, RH., 1989. Human
immunodeficiency virus and acquired immunodeficiency syndrome: Correlation
but not causation. Proc. Natl. Acad. Sci. U.S A. 86: 755764.
Duesberg, P.H., 1990. AIDS:
noninfectious deficiencies acquired by drug consumption and other
risk factors. Res. Immunol. 141: 517.
Duesberg, P.H., 1992. The
role of drugs in the ongin of AIDS. Biomed. & Pharmacother. 46: 315.
Drew, W.L., J. Mills, J.
Levy, etaL, 1985.Cytomegalovirusinfection and abnormal Tlymphocyte
subset ratios in homosexual men. Ann. Intem. Med. 103: 6163.
European Study Group on AIDS,
1989. Risk factors for male to female transmission of HIV. Br. Med. J.
Eyster, M.E., M.H. Gail,
I.O. Ballard, H. AlMondhiry & J.J. Goedert, 1987. Natural history
of human immunodeficiency virus infections in hemophiliacs: effects on
Tcell subsets, platelet counts and age. Ann. Intem. Med. 107: 16.
Farrugia, A., 1992. Purity
of factor concentrates and immune function in hemophiliacs. Blood 78: 19191922.
Fauci, A.S., 1993. Multifactorial
nature of human immunodeficiency virus disease: implications for therapy.
Science 262: 101 11018.
Farzadegan, H., M.A. Polis,
S.M. Wolinsky, C.R. Rinaldo Jr., J.J. Sninsky, S. Kwok, R.L. Griffiths.
R.A. Kaslow. J.R Phair, B.F. Polk & A.A. Saah, 1988. Loss of human
immunodeficiencyvirus type I (HIVI) antibodies with evidence of viral
infection in asymptomatic homosexual men. Ann. Med. 108: 785790.
FemandezCruz, E., A.M.
Femandez, C. Gunerrez, et al, 1988. Progressive cellular immune
impairment leading to development of AIDS: Two year prospective study of
HIV infection in drug addicts, Clin. Exp. Immunol. 72: 190195.
Fiala, M., L.A. Cone, C.M.
Chang & E.S. Mocarski. 1986. Cytomegalovirus viremia increases with
progressive immune deficiency in patients infected with HTLVIII. AIDS
Res. 2: 175181.
FribourgBlanc, A., 1988.
Deux observations d'annulation spontanee d'une seropositivite HIV.
Med. Mall Infect. 4: 216218.
Fumento, M., 1990. The Myth
of Heterosexual AIDS, New York, Harpers.
Garry, R.F., JJ. Kort, F.
KochNolte & G. Koch, 1991. Tatcontams a sequence related to snake
neurotoxins. AIDS. 5: 13811384.
Gibbons. J., J.M. Cory, I.K.
Hewlen, J.S. Epstein & M.E. Eyster, 1990. Silent infections with human
immunodeficiency virus type I are highly unlikely in multitransfused seronegative
hemophiliacs. Blood 76: 19241926.
Giesecke, J., G.R ScaliaTomba,
O. Berglund. E. Bemtorp, S. Schulman & L. Stigendal, 1988. Incidence
of symptoms and AIDS in 146 Swedish haemophiliacs and blood transfusion
recipients infected with human immunodeficiency virus. Br. Med. J. 297:
Goedert, J.J., C.M. Kessler,
L.M. Aledort, et al., 1989. A prospective study of human immunodeficiency
virus type I infection and the development of AIDS in subjects with hemophilia.
New Engl. J. Med.321: 11411148.
Golding. H., EA. Robey, ET.
Gates 111, W. Linder, et al., 1988. Indennfication of homologous
regions in human immunodeficiency virus I gp41 and human MHC class 11 beta
I domain. J. Exp. Med. 167, 914923.
Goldsmith, J.M., J. Deutsche,
M. Tang & D. Green, 1991. CD4 cells in HIVI infected hemophiliacs:
effect of Factor VIII concentrates. Thromb. Haemost. 66: 415419
Gonlieb, M.S., R.A. Zackin,
M. Fiala, D.H. Henry, A.J. Marcel., K.L. Combs, J. Vieira, et al, 1991.
Response to treatment with the leukocytederived immunomodulator IMREGI
in immunocompromised patients with AlDSrelated complex. Ann. Intem.
Gomperts, E.D., R. De Biasi
& R. De Vreker, 1992. The impact of cloning factor concentrates on
the immune system in individuals with hemophilia. Transfus. Med. Rev. 6:
Gougeon, M.L. &
L. Montagnier, 1993. Apoptosis and AIDS. Science260: 12961271.
Groenbladh, L. & L. Gunne,
1989. Methadoneassisted rehabilitation of Swedish heroin addicts.
Drug Alcohol Depend. 24: 3137.
Gurtler, L., J. Eberle &
E Deinhardt, 1989. Seroreversion in human immunodeficiencyvirus (HIV) infection.
Ann. Intem. Med. 110: 946948.
Hadden, J.W., 1991. Immunotherapy
of human immunodeficiency virus infection. Trends Pharmcol. Sci. 12: 1071
Halstead, S.B., 1988. Pathogenesis
of dengue: Challenges to molecular biology. Science 29: 476481.
Hamilton, J.R., J.C. Overall
& L.A. Glasgow. 1976. Synergistic effect on mortality in mice with
munne cytomegalovirus and Pseudomonas arrugionsa, Staphylococcus aureus,
or Candida albicans infections. Infect. Immunol.14: 928989.
Hardy, A.M., J.R. Allen,
W.M. Morgan & J.W. Curran, 1985. The incidence rate of acquired immune
deficiency syndrome in selected populations. JAMA 253: 215218.
Hassen, J., G.E Gjerset,
J.W. Mosley, M.A. Fletcher, et al., 1993. Effect on Lymphocyte subsets
of cloning factor therapy in human immunodeficiency virus I negative
congenital cloning disorders. Blood 82: 13511357.
Haverkos, H.W., 1988. Kaposi's
sarcoma and nitrite inhalants. In: T.R Bndge (ed.) Psychological, Neuropsychiatric,
and Substance Abuse Aspeas of AIDS. New York: Raven Rress, 165 172.
Hay, C.R.. R McEvoy &
M. DugganKeen, 1990. Inhibitions of Lymphocyte IL2receptor expression
by factor VIII concentrate: a possible cause of immune suppression in haemophiliacs.
Br. J. Haematol. 75: 278281.
Hendricks, J.C., G.E Medley,
G.J. Van Griensven, R.A. Coutinho, et al, 1993. The treatmentfree
incubation period of A'DS in a cohort of homosexual men. AIDS 7: 231239.
Henrard, D.R.Y. Laurian,
W.E Mehaffey & J.R Allain, 1993. Lack of detection of human immunodeficiency
virus type I DNA by
polymerase chain reaction
in the plasma and Lymphocytes of seronegative exposed hemophiliacs. Transfusion
Higgins, J.A. & A.H.
Goodall, 1991. Immune pctivation in HIVseronegative hemophiliacs: Is this
related to infection with hep atitis C virus? Thromb. Haemost.65: 1163
Hilgartner, M.W., J.D. Buckley,
E.A. Operskalsi, M.C. Pike & J.W. Mosely, 1993. Purity of factor VIII
concentrates and serial CD4 counts. Lancet 341: 1373 1374.
Hoff, C. & R.D.A. Peterson,
1989. Does exposure to HLA alloantigens trigger immunoregulatory
mechanisms operative in both pregnancy and AIDS? Life Sci. 45: iiiix.
Hoff, C., W.C. James, R.B.
Hester, R Nolan & R.D.A. Peterson, 1991. Signs of cellular immunosuppression
correlate w ith HLADR phenotypes in healthy HlVnegative homosexuals:
preliminary findings. Human Biology 63: 129135.
Holman, R.C., RH. Rodes,
T.L. Chorba & B.L. Evan, 1992. Survival of hemophiliac males with acquired
immunodeficiency syndrome with and without risk factors for AIDS other
than hemophilia. Am. J. Hematol. 39: 275282.
Hoover, D.R., AJ. Saah, H.
Bacellar, et al, 1993. Clinical manifestation of AIDS in the era
of pneumocystis prophylaxis. New Engl. J. Med.329: 19221926.
Horsburgh, C.R., Jr., C.Y.
Ou, J. Jason, et, al, 1990. Concordance of polymerase chain reaction
with human immunodeficiency virus antibody detection. J. Infect. Dis. 162:
Huang, S.W. & R.
Hong, 1973. Lymphopenia and multiple viral infections. IAMA 225: 11201121.
Huang, S.W., D.B. Lados,
D.B. Nelson, K. Reb & R. Hong, 1973. Antibodyassociated lymphotoxin
in acute infection. J. Clin. Invest. 52: 10331040.
Hughes, M D., D.S. Stein.
H.M. Gundacker, ET. Valentine, J.R Phair & PA. Volberding, 1994. Withinsubject
variation in CD4 lymphocyte count in asymptomatic human immunodeficiency
virus infection: Implications for patient monitoring. J. Infect Dis. 169:
Imagawa, D. & R. Detels,
1991. HIVI in seronegativehomosexual men. NEJM 325:12501251.
Jaffe, H.W., RM. Feorino,
W.W. Darrow, es aL, 1985. Persistent infection with human Tlymphotropic
virus type III/lymphadenopathyassociated virus in apparently healthy
homosexual men. Ann. Intern. Med. 102:627.
Judson, EN., 1990. The relationship
of HIV infections to infections with pathogenic Neisseria in homosexual
men. Med. Clin. North. Am. 74: 13531366.
Kallenius, G., S.E. Hoffner
& S.B. Svenson, 1989. Does vaccination with bacille CalmetteGuerin
protect against AIDS? Rev. Infect. Dis. 11:349351.
Keay, S., C.O Tacket, J.R.
Murphy & B.S. Handv.erger, 1992. AntiCD4 antiidiotype antibodies
in volunteers immunized with rgpl60 or HIVI or infected with HIVI.
AIDS Res. Human Retroviruses8: 10911098.
Kion, T.A. & G.W. Hoffmann,
1991. AntiHIV and antiantiMHC antibodies in alloimmune and
autoimmune mice. Science 253: 11381140.
Klenk, H.D. & R. Rott,
1988. The molecular biology of influenza virus pathogenicity. Adv. Virus
Res. 34: 247281.
Kliks, S.C., A. Nisalak,
W.E. Brandt, et aL, 1989. Antibodydependentenhancementofdenguevirusgrowthinhumanmono
cytes as a risk factor for dengue hemorrhagic fever. Am. J. Trop. Med.
Hyg. 40: 444451.
KnuverHopf, J., H. Heinze,
B. Lambrecht, H. Mohr, J. Beyer & H. Schmitt, 1993. Blood donations
indeterminate in HIVI Western blot analysed by IgM immunoblot and
polymerase chain reaction. Vox Sang. 64: 8993.
KopecSchrader, E., B.
Tindall, J. Learmont, B. Wylie & J.M. Kaldor, 1993. Developmentof AIDS
in people with transfusionacquired HIV infection. AIDS 7: 10091013.
Krasinski. K., W. Borkowsky
& R.S. Holzman, 1989. Prognosis of human immunodeficiency virus infection
in children and adolescents. Pediatr. Infect. Dis. J. 8: 216220.
Lafeuillade, A. & R.
Quilichine, 1992. HIV cofactors in the course of AIDS. Presse Med. 21:
Lang, Ph., R Niaudet, and
the Groupe Cooperatif de Transplantation de l'lle de France, 1991. Update
and outcome of renal transplant patients with human immunodeficiency virus.
Transplantation Proc.23: 13521353.
Laurence, J., 1993. Tcell
subsets in health, infectious disease, and idiopathic CD4+ T Lymphocytopenia.
Ann. Intem. Med. 119: 5562.
Levy, J., 1988. The transmission
of AIDS: the case of the infected cell. JAMA 259: 30373038.
Littlefield. J.W., 1992.
Possible supplemental mechanisms in the pathogenesis of AIDS. Clin. Immunol.
Immunopathol. 65: 85q7
Lo, S.H., S. Tsai, J.R.
Benish, et aL, 1991 . Enhancement of HIVI cytocidal effects
in CD4+ Lymphocytes by the AlDSassociated mycoplasma. Science 251:
Lorenzo, 11., R. Molina &
J.A. Aznar, 1993. Evolution of CD4 and CD8 Lymphocyte subsets in HIV seronegative
and seropositive hemophiliacs. Sangre Barc. 38: 511.
Ludlum, C.A., J. Tucker,
C.M. Steel, et aL, 1985. Human Tlymphotropic virus type 111 (HTLV111)
infection in seronegative hemophiliacs affertransfusions offactorVIII.
Lancet ii: 233236.
Lui, K.J., D.N. Lawrence,
W.M. Morgan, T.A. Peterman, H.W. Haverkos & D.J. Bregman, 1986. A model
based approach for estimating the mean incubation period of transfusionassociated
acquired immunodeficiency syndrome. Proc. Natl. Acad. Sci. U.S.A. 83: 301305.
Lusso, R. R. Ensoli, RD.
Markham, et uL, 1989. Productive dual infection of human CD4+ T
Lymphocytes by HIV I and HHV6. Nature (Lond.), 337: 370373.
Lusso, P., E Lori & R.C.
Gallo, 1990. CD4independent infection by human immunodeficiency virus
type I aher phenotypic mixing with human Tcell leukemia viruses. J.
Virol. 64: 63416344.
Macon, W.R., S.C. Lo,
B.J. Poisz, D.C. Monefiori, et al., 1993. Acquired immunodeficiencysyndromelike
illness associated with systemic Mycoplasma fermentans infection
in a human immunodeficiency virusnegative homosexual man. Human Pathol
Madhok, R., J.A. Gracie,
J. Smith, G.D. Lowe & C.D. Forbes, 1990. Capacity to produce interleukin
2 is impaired in haemophilia in the absence and presence of HIV I infection.
Br. J. Haematol.76: 7074.
Madhok, R., J. Smith, A.
Jenkins & G.D.O. Lowe, 1991. Tcell sensitization to factor Vlll
in haemophilia A? Br. J. Haematol. 79: 235238.
Mannucci, RM., A. Gringeri,
R. De Biasi, E Baudo, M. Morfini & N. Ciavarella, 1992. Immune status
of asymptomatic HlVinfected haemophiliacs: randomized, prospective,
twoyear comparison of treatment with highpunty or an intermediatepunty
factor Vlll (FVIII). Thromb. Haemost.67: 31~313.
Mares, M., M.T. Sartori &
A. Girolami, 1992. Prevalence of bleeding as cause of death in HlVseropositive
patients with congenital cloning disorders. Vox Sang. 63: 7778.
Mathe, G., 1992. Is the AIDS
virus responsible for the disease? Biomed. Pharmacother. 46: 1 2.
McClean, A.R. & M.A.
Nowak, 1992. Models of interactions between HIV and other pathogens. J.
Theor. Biol. 155: 6986.
McDougal, J.S., M. Hubbard,
J.K.A. Nicholson, et al., 1985. Immune complexes in the acquired
immunodeficiency syndrome (AIDS): relanonship to disease manifestation,
nsk group, and immunologic defect. J. Clin. Immunol.5: 130.
Medawar, RB., 1967. The art
of the soluble. London: Methuen.
Medley, G.E, R.M. Anderson,
D.R. Cox & L. Billard, 1987. Incubation period of AIDS in patients
infected via blood transfusion. Nature 328: 719721.
Mills, L.B., 1986. Stimulation
of Tcellular immunity by cutaneous application of dinitrochlorobenzene.
J. Am. Acad. Dermatol. 14: 10891090.
Minkoff, H., D. Nanda, R.
Menez & S. Flkrig, 1987. Pregnancies resulting in infants with acquired
immunodeficiency syndrome or AlDSrelated complex: followup of
mothers, children, and subsequently born siblings. Obstet. Gynecol. 69:
Montagnier, L., D. Berriman,
D. Guetard, A. Blanchard, et al., 1990. Inhibition de l'infectiosite
de souches prototype du VIH par des anticorps diriges contre une sequence
peptideque de mycoplasme. Comptes rendus Acad. Sci. Paris 311: 425430.
Montaner, J.S., L M. Lawson,
A. Gervais, et al., 1991. Aerosol pentamidine for secondary prophylaxis
of AlDSrelated PneumfJCystis cariniipneumonia. A randomized,
placebocontrolled study. Ann. Intern. Med. 114: 948953.
Moreni, M.L., 1992. Specific
behavioural factors among intravenous drug users have been shown to influence
HIV seroconversion . . . J. InterAm. Med. Health. Assoc. 1: 18.
Morrow, W.J.W,, D.A. Isenberg,
R.E. Sobol, R.B. Stricker & T. KeiberEmmons, 1991. AIDS virus
infection and autoimmunity: A perspective on the clinical, immunological,
and molecular origins of the autoallergic pathologies associated with HIV
disease Clin. Immunol. Immunopathol. 58, 163180.
Msellati, R. M. Dupon, R
Morlat, D. Lacoste, er al., 1990. A cohort study of 89 HIV I infected
adult patients contaminated by blood products: Bordeaux 19811989.
AIDS 4: 1 1051 109.
Munoz, A., V. Carey, A.J.
Saah, et al., 1988. Predictors of decline in CD4 lymphocytes in
a cohort of homosexual men infected with human immunodeficiency virus.
1. Acquir. Immune. Defic. Syn. 1:396.
National Research Council.
1990. AIDS: The Second Decade National Academy of Sciences, Washington,
Naz, R.K., M. Ellauri, T.M.
Phillips & J. Hall, 1990. Antisperm antibodies in human immunodeficiency
virus infection: Effects on fertilization and embryonic development. Biol.
Reprod. 42: 859868.
Odell, T.W. & J.A. Green,
1990. Prolonged zidovudine therapy: confounded by Pneumocysitis carinii
prophylaxis? JAMA 263: 1 635.
Oehen, S., H. Henganner &
R.M. Zinkemagel, 1991. Vaccination for disease. Science 251: 195198.
Ozturk, G.E., RE Kohler,
C.R. Horsburgh & C.H. Kirkpatrick, 1987. The significance of antilymphocyte
antibodies in patients with acquired immune deficiency syndrome (AIDS)
and their sexual pawners. J. Clin. Immunol. 7: 130133.
Padian, N.S., S.C. Shiboski
& N.R Jewell, 1990. The effect of number of exposures on the risk of
heterosexual HIV transmission. J. Infect. Dis. 161: 883887.
Palestine, A.G., M.A. Polis,
M.D. De Smet, et al., 1991. A randomized, controlled trial of foscarnet
in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann.
Intem. Med. 115: 665671.
E., 1988. Reappraisal of AIDS. Is the oxidation induced by the risk factors
the primary cause? Med. Hypotheses25: 151162.
Perrin, L.H., R. Zubler,
B. Hirschel, J.L. Manin, D. Salomon, J.H. Sauret & O. Fryc, 1988. Negativation
d'une serologic positive pour le virus dtimmunodefience humaine (VIH).
A propos de deux observations. Schweiz. Med. Wochenschn. 118/45: 16411644.
Peterman, T.A., R.L. Stoneburner,
J.R. Allen, H.W. Jaffe & J.W. Curran. 1988. Risk of human immunodeficiency
virus transmission from heterosexual adults with transfusionassocinted
infections. JAMA 259: 5558.
Pifer, L.W., Y.F. Wang, T.M.
Chiang, R. Ahokas, D.R. Woods & R.E. Joyner, 1987. Borderline immunodeficiency
in male homosexuals: Is lifestyle contributory? South. Med. J. 80: 687697.
Popper, K., 1962. Conjectures
and refutations. The growth of scientific knowledge. New York: Basic Books.
Ponerfield, J.S., 1986. Antibodydependent
enhancement of viral activity. Adv. Virus. Res. 31: 335353.
Rahman, M.A., L.A. Kingsley,
M.K. Berinig, et aL, 1989. Reactivation of EpsteinBarr virus
during early infection with human immunodeficiency virus. J. Clin. Microbiol.
Ribot, S. & H.H. Eslami,
1992. HIV infection in kidney transplant recipients. N. J. Med. 89: 597599.
Rinaldo. C.R. Jr., L.A. Kingsley,
D.W. Lyter, et al., 1986. Association of HTLVII I with EpsteinBarr
virus infection and abnormalities of T Lymphocytes in homosexual men. J.
Infect. Dis. 154: 556561.
Rinaldo, C.R., Jr., L.A.
Kingsley, M. Ho, J.A. Armstrong & S.Y.J. Zhou, 1992. Enhanced shedding
of cytomegalovirus in semen of human immunodeficiency virusseropositive
homosexual men. J. Clin. Microbiol. 30: 11481155.
Riner, M., 1994. AIDS raises
death rate for hemophilia. Associated Press release based on CDC press
conference, 3 Feb. 1994.
Roithmann, S., J.M. Tourani,
J.A. Gastaut, R Brice, er al., 1993. Hodgkin's disease associated
with HIV infection: clinical charactenstics and development. Bull. Cancer.
Paris. 79: 873882.
1989. Discovering, Inventing and solving problems at the frontiers of knowledge.
Cambridge, MA: Harvard University Press.
1990a. Do we know the cause(s) of AIDS? Persp. Biol. Med. 33: 480500.
1990b. Multipleantigenmediated autoimmunity (MAMA) in AIDS: a
possible model for postinfectious autoimmune complications. Res. Immunol.141:
1990c. NonHIV immunosuppressive agents in AIDS: a multifactorial,
synergistic theory of AIDS aetiology. Res. Immunol. 141: 815838.
1991. Self, nonself, and the paradoxes of autoimmuniry. In: All. Tauber,
ed. Organism and the Development of Self. Kluwer Academic, pp.159209.
1992a.HIV and immunosuppressivecofactors in AIDS. EOS. Rev. Immunol. Immunopharm.12:
1992b. AIDS is more than HIV. Genetic Engineenng News 12 no. 13: 46;
12 no. 14: 45.
1993. Rethinking AIDS. The Tragic Cost of Premature Concensus. New York:
1994. Preliminary evidence of idiotypeantiidiotype immune complexes crossreactive
w ith Lymphocyte antigens resulting from pairs of infectious agents associated
with AIDS and lupus. Med. Hypoth. In press.
RootBemstein, R.S. &
S.H. Hobbs. 1991. Homologies between mycoplasmaadhesion pepetide, CD4,
and class 11 MHC proteins: a possible mechanism for HlVmycoplasma
synergism in AIDS. Res. Immunol.142:519523.
RootBemstein, R.S. &
S.H. Hobbs, 1993. Does HIV 'piggyback'on CD4like surface proteins
of sperm, viruses, and bactena? Implications for cotransmission, cellular
tropism and the induction of autoimmunity in AIDS. J. Theor. Biol. 160:
RootBemstein, R.S. &
S.H. DeWitt, 1994. CD4 similarity to proteins of infectious agents in AIDS,
and autoimmunity. Med. Hypoth. In press.
Rosendaal, EC., C. Smit &
E. Briet, 199 B Hemophilia treatment in historical perspective: a review
of medical and social developments. Ann. Hematol. 62: 525.
Roy, M.J., JJ. Damato &
D.S. Burke, 1993. Absence of true seroreversion of HIVI antibody in
seroreactive individuals. JAMA 269: 28762879.
Rubenstein, A., M. Sicklick,
A. Gupta, L. Bemstein, N. Klein, et al., 1983. Acquired immunodeficiency
with reversed T4/T8 ratios in infants bom to promiscuous and drugaddicted
mothers. IAMA 249: 23502356.
Rubin, H., 1988. Etiology
of AIDS. Science 214: 13891390.
of AIDS vaccines. Science 251: 1161.
Sabin,C.,A. Phillips, J.
Elford. R Griffiths, G. Janossay & C. Lee, 1993. Prcrgression of HIV
disease in a haemophiliac cohort followed for 12 years. Br. J. Haemoatol.83:
Salk, I.P.A. Bretscher, RL.
Salk, M. Clerici & G.M. Shearer, 1993. A strategy for prophylactic
vaccination against HIV. Science 260: 12701272.
Schinaia, N., A. Ghirardini,
E Chiaroni, A. Gringeri, PM. Mannucci, et al, 1991. Progression
of AIDS among Italian HIVseropositive haemophiliacs. AIDS 5/4: 385391.
Schulman. S., 1991. Effects
of factor VIII concentrates on the immune system of hemophiliac patients.
Ann. Hematol.63; 145151.
Schwarz. A., G. Offerman,
E Keller, 1. Bennhold, J. L'ageStehr, RH. Krause & M.J. Mihatsch,
1993. The effect of cyclosporine on the progression of human immunodeficiency
virus type I infection transmitted by transplantation data on four cases
and review of the literature. Transplantation 55: 95103.
Shearer, G.M. & R.B.
Levy. 1984. Noninfectious cofactors in susceptibility to AIDS: possible
contributions of semen, HLA alloantigens, and lack of natural resistance.
Ann. N. Y. Acad. Sci. 437: 4957.
Shope, E., 1931. Swine influenza,
111. Filtration experiments and etiology. J. Exp. Med.54: 373385.
Sonnabend. I.A., 1989. AIDS:
An explanation for its occurrence in homosexual men. In: AIDS and Opportunistic
Infections of Homosexual Men, R Ma and D. Armstrong, eds. Bunerworth Publishers,
Stoneham. MA, pp. 450460.
Sonnabend. J.A. & S.
Saadoun, 1984. The acquired immunodeficiency syndrome: A discussion of
etiologic hypothesis. AIDS Res. 1: 107120.
Sonnabend, J.A., S.S. Witkin
& D.T. Portillo, 1984. A multifactorial model for the development of
AIDS in homosexual men. Ann. N. Y. Acad. Sciences 437: 177182.
Sorice, E. A. Ghirardini,
P. Martino, D. Pasqualeni, et aL, 1989. Spectrum of HIV infection
and AIDS in a cohort of Italian hemophiliacs. Haemotologica74: 149154.
StehrGreen, J.K., J.M.
Jason, B.L. Evan, R.C. Holman, et aL, 1989. Geographic variability
of hemophiliaassociated AIDS in the United States: Effect of population
characteristics. Am. J. Hematol.32: 178183.
Ston, E.J., 1991. Anticell
antibody in macaques. Nature 353: 393395.
Stricker, R.B.. T.M. McHugh,
DJ. Moody, W.J.M. Morrow, D.R Stites, M.A. Shuman & J.A. Levy, 1987a.
An AlDSrelated cytotoxic antoantibody reacts with a specific antigen
on stimulated CD4+ cells. Nature 327: 710713.
Stricker, R.B.. T.M. McHugh,
RA. Marx, W. J.M. Morrow, J.A. Levy, M.A. Shuman, D.R Stites & RD.
Nyeman,1987b. Prevalence of an AlDSrelated autoantibody against CD4+
Tcells in humans and monkeys. Blood 70: 127A.
Stricker, R.B., B.E Elswood
& D.l. Abrams, 1991. Dendritic cells and dinitrochlorobenzene (DNCB):
a new treatment approach to AIDS. Immunol.Len.29: 191196.
Stricker, R.B., B.E Elswood,
D.l. Abrams, et aL, 1993. Pilot study of topicaJ dinitrochlorobenzene
(DNCB) in human immunodeficiency virus infection. Immunol. Len. 36: 16.
Sullivan, J.L.. EE. Brewster,
D.B. Brettler, ctaL, 1986. Hemophiliac immunodeficiency: Influence
of exposure to factor Vlil concentrate, LAVHTLV111, and herpes
viruses. J. Pediatr. 108: 504510.
Sumaya, C.V., R.N. Boswell,
Y. Ench, et aL, 1985. Enhanced serological and virological findings
of EpsteinBarr virus in patients with AIDS and AIDS related complex.
J. Infect Dis. 154: 864.
Susal, C., M. Krdpelin, V.
Daniel & G. Opeiz, 1993. Molecular mimicry between HIVI and antigen
receptor molecules: a clue to the pathogenesis of AIDS. Vox Sang. 65: 1017.
Tanenbaum, S.A., R.E Garry,
H. LuoZhang, S.S. Alexander & C.A. Leissinger, 1993. Humoral and
cellular responses against HIV in multitransfused HIV seronegative hemophiliacs.
Absts Ist National Conf. Human Retroviruses. Abst. #86, p. 71.
Tanenbaum, S.A., C.A. Leissinger
& R.E Garry. 1993. Absence of seroconversion of HIVI antibody
in seroreactive individuals. JAMA 270:2178.
Taylor, J.M., J.M. Duo &
R. Detels, 1991.1s the incubation period of AIDS lengthening? J. Acquir.
Immune. Defic. Syndr. 4 6975.
Tzakis, A.G., M.H. Cooper,
J.S. Dummer, M. Ragni, J.W. Ward & T.E. Starzl, 1990. Transplantation
in HIV+ patients. Transplantation 49: 354358.
Umovitzj H.B.. M. Clerici,
G.M. Shearer, T.D. Gonfned, D.J. Robinson, L.l. Lutwick, L. Montagnier
& D.V. Landers, 1993. HIVI antibody serum negativity with urine
positivity. Lancet 342: 14581459.
Vamvakas, E. & H.S. Kaplan,
1993. Early transfusion and length of survival in acquired immune deficiency
syndrome: experience with a population receiving medical care at a public
hospital. Transfusion 33: 111118.
Vandenbroucke, J.R &
V.RA.M. Pardoel, 1989. An autopsy on epidemiologic methods: the case of
'poppers' in the early epidemic of the acquired immunodeficiency syndrome
(AIDS). Am. J. Epidem. 129:455457.
Van Griensven, G.J., E.M.
de Vroom, J. Goodsmit & R.A. Coutinho, 1989. Changes in sexual behaviour
and the fall in incidence of HIV infection among homosexual men. Br. Med.
J.298: 2 18221.
Vega, M.A., R. Guigo &
T.F. Smith, 1990. Autoimmune response in AIDS. Nature 345:26.
Wang, M.C. & L.C. See,
1992. Nestimation from retrospectively
as certained events with
application to AIDS. Biometrics48: 129141.
Wang, R.Y., J.\V. Shih, T.
Grandineni, RE Pierce, M.M. Hayes, D.J. Wear, H.J. Alter & S.C. Lo,
1992. High frequency of antibodies to Mycoplasma penetrans in HlVinfected
patients. Lancet 340: 13121316.
Ward, J.W., T.J. Bush, H.A.
Perkins, et aL, 1989. The natural history of transfusionassociated
infection with human immunodeficiency virus. New Engl. J. Med. 321: 947952.
Watson, H.G. & C.A. Ludlum,
1992. Immunological abnormalities in haemophiliacs. Blood Rev. 6: 2633.
Weber, R., W. Ledergerber,
M. Opravil, W. Siegenthaler & R. Luthy, 1990. Progression of HIV infection
in misusers of injected drugs who stop injecting or follow a programme
of maintenance treatment with methadone. Br. Med. J. 301: 1361 1365.
Webster, A., C.A. Lee, D.G.
Cook, J.E. Grundy, et al., 1989. Cytomegalovirus infection and pregression
towards AIDS in haemophiliacs with human immunodeficiency virus infection.
Lancet ii: 6366.
Weiss, R.A., 1993. How does
HIV cause AIDS? Science 260: 12731279.
Weyer, J. & H.J. Eggers,
1990. On the structure of the epidemic spread of AIDS: the influence of
an infectious coagent. Int. J. Med. Microbiol.273: 5267.
Winkelstein, \V. Jr, J.A.
Wiley, N.S. Padian, M. Samuel, S. Shiboski, M.S. Ascher & J.A. Levy.1988.
The San Francisco Men's Health Study: Continued decline in HIV seroconversion
rates among homosexual/bisexual men. Am. J. Public Health 78: 14721474.
Witebsky, E., N.R. Rose,
K. Terplan, J.R. Pain & R.W. Egan, 1957. Chronic thyroiditis and autoimmunization.
JAMA 164: 1439
Zarling, I.M., J.A. Ledbetter,
J. Sias, P. Fultz, J. Eichberg, G. Gjerset & RA. Moran, 1990. HlVinfeeted
humans but not chimpanzees, have circulating cytotoxie T Lymphoeytes that
Lyse uninfected CD4+ cells J. Immunol. 144. 29922998.
Ziegler, J.L. & D.P.
Stites, 1986. Hypothesis: AIDS is an autoimmune disease directed at the
immune system and triggered by a Lymphotropie retrovirus. Clin. Immunol.
Immunopathol. 41: 305.
Zuck, T.F., 1988. Silent
sequences and the safety of blood transfusion Ann Inter. Med. 108