Perspectives in Biology and Medicine
Summer 1990, 33:480-500
DO WE KNOW THE CAUSE(S) OF AIDS?
ROBERT S. ROOTBERNSTEIN
Department of Physiology, Michigan State University, East
Lansing, Michigan 48824.
The reason for inventing a new theory is to drive us out of the hypotheses
in which we hitherto have taken refuge into the state of thoroughly conscious
ignorance which is the prelude to every real advance in science.
- J. C. MAXWELL
Some of the most interesting questions in science are those that appear
to have answers so obvious that no one thinks to ask them. Few people,
for example, would doubt at this moment in time that we know the cause
of the immunosuppression in AIDS. But do we? How do we know that we do?
While many people will consider such methodological questions pointless
(after all, virtual unanimity exists that HIV is the cause), it is nonetheless
true that data can be interpreted only in light of theory, and that the
same data may take on different meanings according to different theories.
For example, consider data showing that a beach ball falls more slowly
than a lead ball in earth's atmosphere at sea level. Aristotle would have
considered this observation to be evidence supporting the theory that heavy
objects fall faster than light ones. Galileo would have denied that Aristotle
was right and declared the experiment irrelevant to an understanding of
falling bodies because it was not performed in a vacuum. And a modern aeronautical
engineer trained within the Galilean tradition would nonetheless find the
experiment very informative - not about the law of falling bodies, but
about aerodynamics. Thus, data become facts only within certain theoretical
frameworks that predetermine what is to be observed and how it is to be
interpreted. In the case of AIDS, we must therefore understand that when
we say that HIV causes immunosuppression in AIDS, this statement presupposes
a whole series of theoretical and methodological assumptions about how
etiologies are established and what we mean by causation. In consequence,
data showing that HIV is highly correlated with AIDS and that it infects
a specific set of Tcells that are compromised in AIDS patients are
insufficient to prove that HIV causes the immunosuppression in AIDS if
these data can be shown to have a reasonable alternative meaning within
a different theoretical framework. The question is whether such an alternative
theoretical framework exists.
The history of science repeatedly demonstrates that the key to finding
such alternatives clearly lies in not accepting anything at face value.
Assumptions need to be questioned skeptically and systematically. We must
assure ourselves that our innate tendencies toward scientific positivism
have not misled us in our theorizing by focusing our attention on what
we observe rather than on what we expect to see and do not. Hypotheses
must be invented that can cause us to rethink the meaning of our data or
set new boundary conditions on the validity of our observations. We must
search for phenomena that we may be missing by prematurely accepting the
theory that HIV causes immunosuppression in AIDS.
In short, questions of methodology will be as important to defining
and solving the problem of AIDS as are clinical observation and laboratory
experiment. How do we know what we know? What are the limitations of that
knowledge? Many physicians and biologists may find this approach questionable.
Theory, after all, is not held in high esteem in the biomedical sciences.
And yet, to say that a disease agent causes a disease -that is to say,
to establish an etiology- is to work as a theoretician as much as to work
as an empiricist, and I believe that reference to the founders of modern
germ theory -Louis Pasteur, Robert Koch, and their peers- surely verifies
the point. It is, therefore, just as important to know how we justify the
conclusion that a disease agent causes disease as it is to discover new
Moreover, the adventure of searching for the unobvious and overlooked
aspects of AIDS surely has the potential benefit of allowing us to examine
how we know what we know about AIDS and how complete that knowledge is.
It also holds out the possibility of surprise. What if HIV cannot be demonstrated
convincingly to be the cause of AIDS? What if as yet untested alternatives
still exist despite the apparent confluence of scientific data and opinion?
Surely, given the threat of AIDS and the billions of dollars for research
being devoted to its cure, it is worth a skeptical look at the HIV theory.
We cannot afford -literally, in terms of human lives, research dollars,
and manpower investment- to be wrong. Unfortunately, we may be.
Most investigators believe that acquired immunodeficiency syndrome (AIDS)
is caused solely by human immunodeficiency virus (HIV) [1, 2]. However,
several puzzling facts cast doubt on this conclusion: about 5 percent of
AIDS patients tested for HIV seroconversion never display signs of HIV
infection, and less than 50 percent of all AIDS patients have been tested
for seroconversion ; seroconversion may not indicate active infection
but, rather, a successful immunological response to HIV, at least in some
cases ; a single Tlymphotropic virus cannot explain the simultaneous
immunosuppression of Tcells, natural killer cells, Bcells, and
macrophages that characterizes the immune system of AIDS patients ;
several other immunosuppressive viruses and bacteria are as highly correlated
with the syndrome as is HIV ; Koch's postulates have not been satisfied,
nor have chimpanzees infected with HIV displayed any of the typical symptoms
of AIDS ; and seroconversion following HIV exposure is so varied
(anything from seroconversion after a single, unprotected sexual contact
with an HIV carrier to no seroconversion after hundreds of unprotected
encounters) that even HIV proponents are admitting that there must exist
some "as yet unexplained biologic variation in transmissibility or
susceptibility" to HIV infection . Indeed, between 30 and 100 hemophiliacs
may use the same lot of clotting factor concentrates, and yet there are
no reported cases of more than one hemophiliac developing AIDS from an
AIDS-donorcontaminated lot .
Furthermore, there is a logical problem that is often overlooked by
uncritical HIV proponents: AIDS patients all die of previously identified
diseases, not of HIV infection per se. That is why AIDS is a syndrome,
not a distinct disease entity. Thus, the putative role of HIV is solely
to cause the immunosuppression that sets the stage for subsequent fatal
opportunistic infections. But before we can accept HIV as the sole cause
of immunosuppression characteristic of AIDS patients, it is necessary to
assure ourselves that alternative explanations of the data do not exist.
After all, theories, just like experiments, need controls; for just as
experimental artifacts are reproducible, so can a theory explain existing
data and yet, as Aristotle's theory of falling bodies demonstrates, still
not be the best explanation. In the present context we must, therefore,
before accepting HIV as the sole cause of the immunosuppression typifying
AIDS, demonstrate directly that HIV actually does cause immunosuppression
in animals or human beings and also assure ourselves that other immunosuppressive
agents cannot explain the etiology of AIDS. In other words, we must determine
that the HIV theory is necessary and sufficient to explain AIDS and that
no other theory is necessary or sufficient. Are there, for example, individuals
who are immunosuppressed whose sole infection is HIV? If so, then we can
assure ourselves that HIV is sufficient to cause immunosuppression. Do
AIDS patients in general have any identified immunosuppressive risks other
than HIV? If so, are these sufficient to explain the immunosuppression
associated with AIDS in the absence of HIV, or not?
Existing data do not, as yet, allow us to establish HIV as the unequivocal
cause of immunosuppression in AIDS. No nonhuman animal other than the chimpanzee
appears to be infected by HIV, and HIV-infected chimpanzees do not display
longterm immunological abnormalities [6, 7]. Moreover, all AIDS patients
do have multiple, wellestablished causes of immunosuppression prior to,
concomitant with, subsequent to, and sometimes in the absence of, HIV infection.
These immunosuppressive agents are of seven basic types: chronic or repeated
infectious diseases caused by immunosuppressive microorganisms; recreational
and addictive drugs; anesthetics; antibiotics; semen components; blood;
and malnutrition. While no AIDS patient is likely to encounter all of these
agents, all AIDS patients encounter several. Healthy heterosexuals and
lesbians rarely encounter more than one. Therefore, the conclusion that
HIV is the sole cause of immunosuppression in AIDS, and the sole factor
differentiating AIDS patients from nonAIDS patients, cannot be maintained,
and alternative hypotheses remain possible.
Begin by exploring a few immunological factors that have largely been
overlooked or ignored in the quest to conquer AIDS. The majority of AIDS
patients are gay or bisexual men . Many habits related to their sexual
preference translate into immunosuppressive risks. Receptive anal intercourse
and "fisting" with multiple partners are the most significant
identified risks . These forms of anal sex are often accompanied by
rectal bleeding, which probably allows semen to enter the bloodstream.
Thus, virtually all gay men who engage in receptive anal intercourse (but
not those who are exclusively sperm ''donors'') develop antibodies to semen
and sperm antigens [14, 15]. These antibodies have been shown to crossreact
with Tlymphocytes , which may cause gay men to develop an autoimmune
reaction against their own immune systems in which Bcells are pitted
against Tcells. Moreover, semen and sperm contain agents that are,
in and of themselves, immunosuppressive and act to protect sperm from vaginal
and cervical lymphocytes during heterosexual sex [17, 18]. Thus, immunological
contact with semen has multiple immunosuppressive effects.
Another immunosuppressive risk factor associated with gay men is abuse
of amyl and butyl nitrites as vasodilators and muscle relaxants in order
to facilitate anal intercourse and to increase sexual response . Subchronic
inhalations of extremely low doses of these volatile nitrites are not immunotoxic
but do cause degeneration of the thymus in experimental animals . Acute
high doses more akin to those encountered in human use cause natural killer
cell suppression and the abnormally low helper T-suppressor T ratio of
lymphocytes typical of AIDS patients . Since as much as tenthmillimolar
concentrations of nitrites have been observed in the blood of some abusers
, it is probable that the highdose results are more representative
of nitrite immunotoxicity in habitual and highdose acute users.
Many gay men, particularly promiscuous ones, also tend to abuse antibiotics,
apparently as a prophylactic or remedial measure against repeated sexually
transmitted diseases . Chronic treatment with most antibiotics causes
Tcell immunosuppression [24, 25], possibly by depleting trace elements
such as zinc, which is an essential cofactor for enzymes controlling lymphocyte
cloning . Gay men typically have unusually low zinc and selenium
serum levels and abnormally high copper levels as compared with heterosexual
men and women and lesbians [23, 29].
Antibiotics and nitrites taken together represent yet another risk:
nitrites convert virtually all commonly used antibiotics, including penicillin,
ampicillin, and tetracycline, into potent carcinogens  and produce
other mutagenic nitrosation products in blood . Given the high concentrations
of both compounds that may be present simultaneously, particularly in patients
being treated repeatedly for sexually transmitted diseases, the reactions
producing these carcinogens become likely. It has been suggested that nitrite
use is correlated with incidence of Kaposi's sarcoma in gay men ,
and perhaps the combination of nitrites with antibiotics is a causative
agent. (One recent study failed to find any evidence of HIV or hepatitis
B viral DNA in Kaposi's sarcoma tumors from AIDS patients and isolated
cytomegalovirus DNA from only two of 13 tumors. On the other hand, they
were able to demonstrate polyclonal karyotypic rearrangements within Kaposi's
cells, arguing for a nonviral mechanism of DNA disruption .) The same
mechanism would operate in heterosexuals who abuse nitrites and antibiotics
Another risk factor for AIDS that is common to most patients is the
presence of multiple, concurrent infections. Several viral diseases are
as highly correlated with AIDS as is HIV: hepatitis B virus, herpes simplex
virus (HSV), cytomegalovirus (CMV), and EpsteinBarr virus (EBV). Herpes
simplex virus, CMV, and EBV are all known to reduce the helper Tcell
(T4):suppressor Tcell (T8) ratio that typifies the AIDS patient's
immune system , and one type of herpes virus has been shown
to act symbiotically to increase the cytocidal effects of HIV . Both
hepatitis and cytomegalovirus were present in unusual proportions of highrisk
populations before the recognition of AIDS .
Chronic or repeated diseases carry other immunosuppressive risks both
in and of themselves or owing to chronic antibiotic treatment. Both acute
and chronic hepatitis infections have been shown to adversely affect cellmediated
immune functions . EpsteinBarr virus, CMV, influenza virus,
and various bacterial diseases including chronic syphilis and tuberculosis,
are known to adversely affect Bcell and macrophage function [38, 39,
46], and the World Health Organization lists genital ulcer disease caused
by HSV and Treponema pallidum as risk factors in AIDS . Homosexual
and bisexual men often suffer from repeated fungal and amoebal infections
of the lower intestine ("gay bowel"), which was recognized prior
to AIDS . Lymphadenopathy also increased significantly in gay
males in the decade before the recognition of AIDS . All of these phenomena
are evidence that multiple infections preceded the recognition of AIDS
in highrisk groups and led to observed immunological abnormalities.
Intravenous drug abuse is the secondhighest risk factor associated
with AIDS. Intravenous drug abuse has been known to be immunosuppressive
since the early 1970s  and has been linked for at least 2 decades to
susceptibility to unusual infections and neoplasms , including CMV
infection  and multifocal, disseminated tuberculosis , both of
which are symptoms of AIDS . Moreover, heroin and morphine have been
demonstrated to cause immunosuppression of Tlymphocytes both by indirect,
brainmediated pathways [55, 56] and by direct action on the lymphocytes
themselves . One study of heroin addicts conducted in 1982 
found that all had significantly depressed Erosette formation, which
is highly correlated with clinical immunosuppression . The longer the
period of addiction, the greater the effect on Tlymphocyte activity.
Moreover, as of 1982, 24 percent had T4:T8 ratios typical of AIDS patients,
although retesting of these individuals in 1985 showed that only 12 percent
were HIV positive . It may be presumed that the incidence of HIV among
this group was significantly lower than 12 percent in 1982 and, therefore,
that profound immunosuppression preceded HIV infection. In the same vein,
clinicians have reported generalized lymphadenopathy, low-grade fevers,
night sweats, Roth spots, and other symptoms typical of AIDS and preAIDS
among heroin addicts for several decades .
Drug abusers also have other immunological risks. Like gay men, they
are very likely to transmit a wide variety of immunosuppressive disease
agents, including hepatitis, CMV , and EBV when they share needles.
They are very often malnourished [63, 64], and chronic malnourishment is
perhaps the oldest known and most frequent cause of immunosuppression [65,
66]. It is perhaps significant that the most frequent disease concomitant
of AIDS in drug abusers is Pneumocystis pneumonia and that all major outbreaks
of this pneumonia since World War 11 have been linked directly to malnutrition
[67, 68]. Also noteworthy is the fact that weight loss and anorexia are
frequent concomitants of AIDS in all risk groups, and that AIDS patients
in general display nutrient insufficiencies that are manifested in significantly
low levels of zinc and selenium [23, 29]. Deficiencies of each are known
to cause immunosuppression in man and experimental animals [2628,
Intravenous drug abusers also share an immunosuppressive risk factor
with hemophiliacs and blood transfusion recipients: they receive other
people's blood. I am unable to find any data concerning the immunological
effects of small doses of untyped blood such as drug abusers might
encounter repeatedly by sharing needles; however, it is a wellestablished
principle of immunology that repeated injections of very small amounts
of almost any antigen eventually result in suppression of the immune response
. (given that these small, repeated blood injections will include a
proportion of leukocytes, it is likely that immunosuppression to various
HLA types will eventually occur. This mechanism of immunosuppression has
previously been suggested for semen, which also contains small numbers
of leukocytes .
AntiHLA alloimmunization has already been observed in multiply
transfused patients [74, 75]. Repeated use of anticlotting factors results
in abnormal suppressor: helper Tcell ratios even among otherwise healthy
hemophiliacs and even in countries like Australia, in which HIV is virtually
nonexistent . Almost every hemophiliac also contracts hepatitis
 and presumably various other viral agents that are transmissible in
blood, such as CMV and EBV [80, 81]. Moreover, it has been established
that even properly typed blood causes profound immunosuppression [79, 8284].
Physicians have known for over a decade that blood transfusions depress
the immune response effectively enough to facilitate the acceptance of
organ transplants and to increase significantly the risk of death from
cancer . This immunosuppression is dose related, and it is therefore
significant that the average transfusionrelated AIDS patient receives
blood from 16 to 21 donors - five or more times that of the average surgery
patient (a statistically significant difference) [90, 91]. Although the
exact mechanism of transfusion induced immunosuppression is unknown, Tcells
are certainly a primary target, and Bcells and macrophages are also
involved. Thus, recent studies show that anyone receiving multiple transfusions
or bloodderived products such as clotting agents - hemophiliacs, those
with sicklecell anemia , trauma patients , and surgery patients
- are at high risk for developing the lymphadenopathy, low helper Tcell:
suppressor Tcell ratio, and low-grade fever associated with AlDSrelatedcomplex
(ARC,). These symptoms generally precede HIV seroconversion.
Sketchy data also indicate that the rate of blood transfusions among
gay men is significantly higher than among heterosexual men and women and
lesbians . The cause is unknown. One possibility is that, since amyl
and butyl nitrites are known to cause methemoglobinemia (accounting for
between 20 and 70 percent of hemoglobin in some abusers ), and in some
cases it has been severe enough to warrant transfusion , they may be
the indirect cause. Fisting can also lead to complications requiring surgery
Patients who require multiple blood transfusions incur additional immunosuppressive
risks. They are on the operating table an unusually long time. Surgical
trauma is, itself, immunodepressive [94, 95]. So are anesthetics. The effects
of anesthetics are dose related; and some of their actions on Tcells,
Bcells, and macrophages can last for a month [97, 98]. Most major
surgical patients are given prophylactic doses of antibiotics and placed
on narcotic painkillers like morphine or one of its derivatives as well,
which are again immunosuppressive. If, on top of this, the blood they have
received is contaminated with any immunosuppressive viruses, such as EBV
or CMV, for which screening has only recently been initiated, further immunosuppression
may ensue. The more blood they receive, the more likely they are to incur
such an infection.
Thus far, every group at high risk for AIDS has been demonstrated to
have multiple immunosuppressive risks other than HIV-save for one group:
pediatric AIDS cases. These cases are of particular importance, since they
are often cited as some of the best evidence that HIV alone is sufficient
to cause AIDS. Anthony Fauci, for example, has disparaged lifestyle
theories of AIDS by asking what possible risky behaviors a newborn infant
could indulge in . Also, it is considered significant bv many investigators
that HlVinfected mothers who show no clinical symptoms of AIDS nonetheless
give birth to children who develop AIDS during the first years of life
. The inference that is often drawn from these data is that
HIV is the only immunosuppressive risk associated with these infants and
thus must be the sole cause of their immunosuppression. In fact, the mother
transfers all of her lifestyle risks to the fetus and newborn.
Of the 1,346 AIDS patients under the age of 13 years who were reported
to the CDC as of December 31, 1988, 78 percent acquired an HIV infection
perinatally, 13 percent from blood transfusions, and 6 percent from blood
products used to treat hemophilia. Four percent had no known risk. Sexual
abuse and intravenous drug abuse are thought to account for many of the
patients without known risk .
Among perinatally acquired cases, 73 percent of the mothers have intravenous
drug abuse as a risk factor, 7 percent are sexually active with an AIDS
or ARC patient, 2 percent acquired HIV infection through blood transfusion,
11 percent are from a country such as Haiti or Uganda in which heterosexual
transmission of AIDS (as well as malnutrition and multiple chronic infection)
is common, and no data are available for 7 percent . All mothers of
AIDS infants for whole immunological data are available have immunological
abnormalities , which undoubtedly put the infant at increased
risk for opportunistic infections during the 3 months during which its
own immune system becomes functional. In addition to passively acquired
immune abnormalities, the majority of infants contracting AIDS are of unusually
low birth weight and have unusually small head circumference; many suffer
from hepatosplenomegaly; most are premature; and like all very lowbirthweight,
microcephalic, and preterm babies, they are immunologically immature and
at higher risk for infections of all kinds [100102, 104].All of these
symptoms were found to be typical of infants of intravenous drug abusers
a decade or more before AIDS was first diagnosed .
Most AIDS infants not only have HIV infections but also must be treated
for one or more of the following: sexually transmitted diseases, CMV, hepatitis,
and a variety of other infectious diseases acquired from their mothers
[100 102, 104]. Moreover, each maternal risk factor translates into
an immunosuppressive risk for the child: the child, too, is immunosuppressed
by intravenous drug abuse; premature birth is highly correlated with multiple
or chronic maternal infections (often sexually transmitted diseases), causing
lymphocytes to release prostaglandins, which in turn stimulate uterine
contractions ; the highest correlate for lowbirthweight
infants and infants with small head circumference is malnutrition in the
mother, which often translates into malnutrition for the infant [105, 109,
110]; malnutrition and AIDS are both correlated with unusually low levels
of serum selenium and zinc which lead to immunosuppression [2629,
111112]; and maternal zincaemia can also result in failure of immune
development in breastfed infants who acquired a nutritional zinc deficit
through the milk . Thus, maternal immunodeficiencies, malnutrition,
drug abuse, and infections can all play a role in determining the immune
status of the infant: AIDS infants, like all other AIDS patients, therefore
have multiple sources of immunosuppression.
It is also important to note that two caveats are in order in evaluating
the data concerning infant AIDS. The most recent reports indicate that
HIV seropositivity should not be used uncritically (as it has been in the
past) as a marker for infant AIDS, since many HlVseropositive infants
have been shown to acquire seropositivity lasting up to 24 months through
their mothers' milk and in the absence of either pre or perinatal
HIV infection . Thus, some previously reported cases of infant AIDS
might not now qualify as AIDS cases. This is very important since a significant
number of HIVseropositive mothers have given birth to healthy children,
and some HlVseropositive children never develop any symptoms of ARC
or AIDS [100102, 104]. Both observations argue against HIV as a sufficient
cause of AIDS.
Much is also made by some investigators of the fact that many HIVinfected
mothers of AIDS infants do not, themselves, show AIDSrelated symptomatology
during pregnancy. It is important to stress that all do show immunological
abnormalities, and the majority do go on to develop AIDS or ARC [100
102]. It should therefore be considered whether pregnancy has some shortterm
prophylactic action on AIDS development similar to the delay in immunological
response to fetal antigens such as Rh factor. This observation could be
of use in developing a treatment for AIDS if the effect is real and if
its cause can be isolated.
So, it appears that acquired immunosuppression can be acquired in many
ways, and that HIV is, at best, only one of many immunosuppressive factors
encountered by all AIDS patients. Moreover, some of these immunosuppressive
factors may help to explain aspects of AIDS that the HIV theory leaves
murky. Unlike HIV, which in vitro has very specific effects only on a particular
subset of Tlymphocytes, most of the immunosuppressive factors just
listed affect the T4:T8 ratio and other Tcell subsets, Bcells,
and macrophages. These broader immunosuppressive effects explain the clinical
and immunological picture of AIDS in ways in which retroviral infection
of a single set of Tcells cannot . since AIDS patients eventually
display abnormalities of virtually all lymphocyte activities. Moreover,
all AIDS patients encounter these nonHIV immunosuppressive factors
repeatedly before, during, and after HIV infection and, notably, sometimes
in the absence of HIV infection. The greater the number of these immunosuppressive
factors encountered by a patient, and the more prolonged their exposure
to them, the greater the risk of developing AIDS. Logically, then, HIV
cannot be singled out as the sole cause of acquired immunosuppression in
At this point, we must, it seems to me, elaborate possibilities and
determine how they can be compared and tested. Several alternative hypotheses
for AIDS etiology must therefore be considered: HIV may cause AIDS only
in people previously, concomitantly, or subsequently immunosuppressed by
other agents; HIV may not cause AIDS at all but be merely another, difficulttoacquire,
opportunistic organism that accompanies AIDS (this would make HIV no more
than a marker infection indicating previous immunosuppression ); AIDS
may have several distinct etiologies and HIV may or may not be one; or
HIV may be necessary to development of AIDS, but these other immunosuppressive
agents determine the time course and specific disease symptoms that an
individual patient displays.
The last hypothesis bears particular consideration, since one of the
characteristics of AIDS that cannot be explained by an exclusive HIV etiology
is the fact that different risk groups contract different opportunistic
diseases: Kaposi's sarcoma and chronic candidiasis are largely limited
to gay men, whereas drug abusers have a significantly higher incidence
of Pneumocystis pneumonia . While basic immunology leads one to expect
that different immunosuppressive agents will result in the suppression
of different Iymphocyte specificities, thus exposing individuals in different
risk groups to different opportunistic diseases, a single immunosuppressive
agent as HIV cannot explain why AIDS has different manifestations in different
The possibility that HIV is not sufficient to induce AIDS is further
supported by data on the incidence of AIDS among healthcare workers
and laboratory researchers who handle HlVcontaminated material. The
CDC figures show that, of several thousand reported cases of needle sticks,
cuts, and other contaminations, only 5 percent have developed HIV seropositivity;
and of these, only one individual lacking other identified risk factors
has thus far developed AIDS [116, 117]. Since identification of risk requires
personal testimony, we can never be sure that a lack of identified risk
does not mean simply a lack of candor on the part of the patient, so that
this one case may or may not be significant. Certainly it is significant
that so few healthcare and laboratory workers having subcutaneous
contact with HIV have even developed antibody. One possible interpretation
of these data are that people with healthy immune systems are as safe from
HIV as from the other opportunistic diseases, such as Kaposi's sarcoma
or Pneumocystis pneumonia, that characterize AIDS.
Other data seem to support this interpretation. Of four women identified
as having been artificially inseminated with HIVcontaminated semen
before 1984, all are currently healthy, as are their children and spouses
. These data suggest that contact with HIV, and even outright HIV
infection, is insufficient to induce AIDS in some (if not most) cases [6,
7, 63, 115].
Alternative hypotheses must therefore be entertained and seriously investigated.
These alternative hypotheses may be differentiated on the basis of several
sorts of experimental tests. Animals may be pretreated with repeated small
doses of untyped blood, multiple transfusions, drugs, anesthetics, antibiotics,
semen components, malnutrition, and chronic infections, either singly or
in various combinations and over varying periods of time, and then exposed
to the various infectious agents that typify AIDS: CMV, Pneumocystis carinii,
and so forth. Since most healthy animals have already been shown to be
resistant to these disease agents unless previously chemically immunosuppressed
[67, 119122]-that is, after all, why they are known as opportunistic-
infection would indicate the sort of profound immunosuppression characteristic
of AIDS; HIV would then be demonstrated to be unnecessary for AIDS induction.
The possibility that the time course of AIDS is affected by nonHIV
immunosuppressive agents, or that HIV is necessary to AIDS induction but
requires concomitant immunosuppression to become pathogenic, can be tested
in chimpanzees with the same strategy but combining the immunosuppressive
regimens with prior, concomitant, or postHIV infection. The success
of any of these experiments would suffice to produce a natural animal model
for the various marker diseases characteristic of AIDS, thus satisfying
Koch's postulates. Success of any experimental protocol would also provide
strong support for one or more of the hypotheses suggested above, while
their constant failure could bolster the notion that AIDS is caused solely
by HIV or indicate that still further hypotheses are needed.
We must also consider some of the possible implications of these various
hypotheses. These implications can aid hypothesis testing. If HIV is not
the sole cause of immunosuppression in AIDS, then it follows that HIV seroconversion
may not be, in and of itself, an indicator of incipient AIDS. Only in the
ongoing presence of the other immunosuppressive agents listed above would
HIV positivity indicate incipient AIDS. Alternatively, the rate at which
HIV infection develops into AIDS may be determined by the degree to which
individuals are acted upon by these other agents. Seropositive individuals
who lack these other risk factors, or who alter their behavior to eliminate
these ongoing immunosuppressive factors from their lifestyle, may
have a much higher probability of remaining healthy, or remain healthy
longer, than those individuals who repeatedly engage in risky behaviors.
Retrospective or prospective studies of existing cases might be able to
validate or falsify this possibility. Certainly, such a hypothesis would
allow the huge variation in HIV infectivity and the everincreasing
period from HIV seroconversion to active AIDS to be explained. If so, behavior
modification techniques such as those used to treat alcohol and nicotine
addiction might be of benefit for those patients at high risk for AIDS.
Nutritional counseling, alternative drug regimens, and nonsurgical approaches
to disease treatment may turn out to be as effective as antiviral drugs
Another implication of the hypotheses elaborated above is that new types
of information will have to be gathered in new ways if they are to be tested
adequately. What you discover is determined by how and when you look. Thus,
physicians will need to alter the way in which they gather information
from AIDS patients and the types of questions they ask. We can no longer
rely on the pediatrician to evaluate the newborn infant infected with HIV-we
must collaborate with the obstetrician infant family practitioner to gather
a complete picture of the previous health care and habits of the entire
AIDS family if we are to reveal the risk factors that may have brought
about the infant's immunosuppression. It will no longer be sufficient to
collect merely a sexual history of each patient-drug use, eating habits,
and a complete medical history will he essential, including a history of
all medications and hospital procedures. Nor can we rely on verbal questions
and answers to identify risks. Tests for drug use, zinc and copper levels,
anemia, vitamin deficiencies, proteincalorie deprivation, and other
measures of nutritional and drugrelated metabolic imbalances will
have to become more common and our understanding of their affects on the
immune system broadened and applied more cogently to discussions of AIDS.
One final set of implications must also be explored (although space
does not permit a full discussion of them here), and these concern why
AIDS has emerged as an apparently new phenomenon during the 1980s when
the immunosuppressive factors listed have existed, in some cases, for centuries.
Suffice it to say that a significant number of cases fitting the preHIV
definition of AIDS (1987) do exist in the literature for at least 100 years
before 1980 (a few of which have been cited here [53, 54, 123, 124]); intravenous
drug abuse, nitrite use, and promiscuous homosexual activity all increased
dramatically during the 1970s; and techniques of diagnosis for many rare,
opportunistic diseases, such as Pneumocystis pneumonia, in living patients
became available only during the 1970s. Finally, the likelihood of infection
with the rare opportunistic diseases that constitute AIDS has become probable
only since the widespread use of antibiotics and vaccines in the past few
decades has allowed immunosuppressed patients to survive previously more
prevalent diseases (tuberculosis, smallpox, typhus, typhoid, etc.) that
undoubtedly killed such patients in the past. The evidence for these assertions
will form the basis of a forthcoming paper.
Let me be clear, in concluding, about just what I am and am not arguing.
I am arguing that premature closure of inquiry lays us open to the risk
of making a colossal blunder by assuming that the first reasonable answer
we achieve is in fact the best answer. It may be; then again, it may not.
I am arguing further that, because the standard criteria for establishing
etiologies have not been satisfied for AIDS, it is premature to conclude
that HIV is "the" cause of immunosuppression in AIDS [57,
63, 115, 125]. Correlations between HIV and AIDS are not sufficient to
establish the etiology of AIDS because too many other immunosuppressive
agents are also correlated with AIDS and because no AIDS patient has only
HIV as his or her sole risk factor. Koch's postulates must be met or some
other direct form of experimental proof of disease causation provided.
I am not arguing that HIV cannot cause immunosuppression in AIDS-it
may, and some of the experiments suggested above may help to prove that-but
the assertion that HIV is the sole or even the primary cause of the immunosuppression
in AIDS needs to be demonstrated by direct experiment, not argued by correlation
or assumption. And I am not arguing that we should abandon research on
HIV-only that we should investigate other possible modes of immunosuppression
that are associated with AIDS as possible causative factors or potentiating
agents until such time as these have been demonstrated conclusively either
to influence the course of AIDS or not.
And if it turns out that all of the tests of alternative theories of
AIDS etiology are negative, then what? Nothing could be more important,
for then we will have a much firmer basis upon which to conclude that HIV
is the sole cause of AIDS-something that we do not have now. These alternative
theories will become the controls for the HIV theory, tested, elaborated,
and, if the data so dictate, discarded. Yet the process of testing these
alternatives is far from useless. It is in the nature of research that,
for every correct theory, dozens of others must be tried and abandoned
along the way. For, just as in the evolution of new species by natural
selection of random genetic variations, these abandoned theories are a
necessary part of the process without which there would be no way to know
that the most adaptive possibility was selected . Alternatives-especially
unlikely alternatives that cause us to question assumptions and to rethink
dogmatic assertions-need to be propounded and tested before we can be sure
that our preconceptions have not blinded us to the unexpected. Nature is
full of surprises. and the purpose of doing research is to search for them
Thus, the question of AIDS etiology must be kept open a bit longer while
we assure ourselves that no surprises still await us. I therefore ask,
and ask quite seriously, "Do we know the cause(s) of AIDS?" I
believe that we all stand to gain new insights and deeper knowledge of
AIDS if we take the question of causation seriously and realize that theory
and methodology will be as important to understanding this syndrome as
data. We must therefore heed not only what fits our cherished beliefs about
AIDS, but data that do not , and alternative hypotheses  that
challenge our assumptions. These are the crucibles of science.*
This research was not funded. The author expresses gratitude
to Peter Duesberg, Scott Gilbert, Walter Gilbert, Mott Greene, Jonas Salk,
Fred C. Westall, Michele RootBernstein, and Arnold Seid for their
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