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What Is the Evidence for the Existence of HIV?
by Valendar F. Turner
What Is the Evidence for the Existence of HIV?
By Dr. Valendar F. Turner
Department of Emergency Medicine<br>
Royal Perth Hospital<br>
Perth, Western Australia
The real purpose of scientific method is to make sure Nature hasn't
misled you into thinking something you don't actually know... One
logical slip and an entire scientific edifice comes tumbling down.
One false deduction about the machine and you can get hung up
indefinitely. <br>
-- Robert Pirsig, Zen and the Art of Motorcycle Maintenance
Does the currently available evidence prove beyond reasonable
doubt that a unique, exogenously acquired retrovirus has been
isolated from the tissues of AIDS patients? Perhaps. Perhaps not.
This is what I invite you to judge. And in case you are inclined to
be assaulted by the opinions of overwhelming majorities, you may
take comfort from a most venerated, international scientist who
said, "In Science the authority embodied in the opinion of
thousands is not worth a spark of reason in one man." I shall reward
you with his identity at the end of this talk.
A virus is two things. Number one: It's a microscopic particle of
certain size and form. Number two, such particles generate identical
progeny by parasitising chemical constituents and energy from a
living cell. This is what is actually meant by the term infectious. It
is this attribute which justifies a particle being called a virus. This
is the property which prevents our calling every particle we see a
virus. By definition, a retroviral particle is spherical in shape and
has a diameter of 100-120 Nm. On the outside is a shell studded
with outwardly projecting knobs, knobs obligatory to latch on to
and infect new cells. On the inside there is a core containing RNA
as well as some proteins, one of which is an enzyme called reverse
transcriptase. The latter gives retroviruses their name and its
function is to catalyse the transcription of viral RNA into DNA,
that is, to copy information contained in RNA in a direction
opposite the customary direction, DNA to RNA. According to
virologists, it is the DNA copy of the RNA blueprint, not the
original RNA, which hibernates inside the cell nucleus awaiting an
opportune time to orchestrate the production of new viruses.
To analyse their constituents and to prove they are truly viruses,
retroviral-like particles must first be purified. This is done by a
process called density gradient ultracentrifugation, something that
may sound complicated but which isn't. A test tube containing a
solution of sucrose, ordinary table sugar, is prepared light at the top
but gradually becoming heavier towards the bottom. A drop of fluid
from a cell culture is gently placed on top and the test-tube is
centrifuged for several hours at extremely high speeds. This
generates forces many thousands of times gravity and any tiny
particles present are gradually forced through the sugar solution
until they reach a point where their buoyancy prevents them
penetrating further. For retroviral particles, this occurs where the
density reaches 1.16 gm/ml, the point where the particles
concentrate or, to use virological jargon, band. The 1.16 band can
then be selectively extracted and photographed with an electron
microscope. So, to prove the existence of a retrovirus one is obliged
to:
1.Culture putatively infected cells.
2.Purify a sample in a sucrose density gradient.
3.Photograph the 1.16 band proving there are particles of the right
size and form, and there is no other material.
4.Extract and analyse the constituents of the particles and prove
they contain reverse transcriptase by showing they can make DNA
from RNA.
5.Culture purified particles with virgin cells demonstrating that a
new set of particles appears with the same morphology and
constituents as the originals.
Now I am going to discuss some of the data from four papers
published in Science in May 1984 by Dr. Robert Gallo and his
colleagues from the US National Cancer Institute. These papers do
not describe the original discovery of what the overwhelming
majority regard as HIV, that distinction falls a year earlier to
Professor Luc Montagnier and his colleagues from the Pasteur
Institute from where, it is important to say, samples were sent to the
Gallo laboratory and which later caused Gallo and his colleagues,
as well as the US government, quite a number of problems. Neither
are the Gallo papers the last word on HIV isolation but there is no
doubt they are most important because it was they that led to the
famous Washington press conference of April the 23rd 1984, two
weeks prior to publication, at which an anxious, waiting world was
told that the cause of AIDS had been identified. In fact, as one
scrutinises the vast AIDS literature, it is fair to say that of all the
papers published on HIV isolation, including the very latest, the
Gallo papers are the most rigorous by far. The problem is, are they
rigorous enough?
The first paper begins with cultures made of T-lymphocyte cells
from AIDS patients. These cells were chosen because, included
amongst their numbers, are the putatively infected cells, a subgroup
known as T4 lymphocytes. It is these that are often diminished in
AIDS, the hypothesis being that the yet to be discovered retrovirus
was infecting and killing them. After an unspecified time,
concentrated fluids from these T-cell cultures were subcultured
with cells of a stock, leukaemic T-cell line known as HT. In these
secondary cultures the Gallo team reported particles in electron
microscopic examination of gross, unrefined culture fluids and
measured reverse transcriptase activity in both these and banded
specimens but without evidence that retroviral-like particles or
indeed any particles were present at 1.16 gm/ml. They also reported
reactions were seen between culture proteins and some antibodies
present in human and animal sera. From these data, the Gallo team
claimed to have isolated a new retrovirus, HIV, as well as inducing
it to grow in the HT cell line in large enough quantities for use in
analysis and diagnosis. In a subsequent third paper, from banded
culture fluids obtained from a disrupted HT cell clone, two
proteins, and for no other reason than they reacted with antibodies
present in human AIDS sera, were deemed to be the HIV proteins.
Subsequent papers, published after the Gallo four, using the same
logic, increased the number of such proteins to about ten.
Reading these data it is obvious that Gallo and his colleagues had
abandoned the traditional method of retrovirus isolation. This is
enigmatic when one realises that in 1976, Gallo himself had
stressed that the detection of particles and reverse transcriptase,
even reverse transcriptase inside particles, are not proof of the
existence of retrovirus because, no matter how remarkably such
particles may resemble retrovirus, many such particles are not
viruses because they totally lack the ability to replicate (Gallo et
al., 1976). You must appreciate the magnitude of the particle
problem. Cell cultures contain many and many kinds of particles,
some viral-like and some not. The viral-like include retroviral-like.
In the 1970s, retroviral-like particles were frequently observed in
human leukaemia tissues (Gallo et al., 1976), cultures of embryonic
tissues and "in the majority if not all, human placentas." (Panem,
1979) One genus of retroviral-like particles, the type-C particle and
the one into which Gallo classified his newly discovered retrovirus
HIV, is found in "fish, snakes, worms, pheasant, quail, partridge,
turkey, tree mouse and agouti" (Grafe, 1991) as well as in
"tapeworms, insects...and mammals." (Frank, 1987) This being the
case, there seems to be no way of avoiding the rules developed over
the decades of research into animal retroviruses, rules that enabled
a scientists to sort out this clutter. And there are two more
complicating factors. The first is that reverse transcription is not
only a property of retroviruses. Normal cells contain enzymes
which reverse transcribe RNA and so does hepatitis B virus, a virus
that infects T-cells as well as liver cells and is present in a
considerable number of AIDS patients. The second is the choice of
the HT cell line. It was long known that leukaemic cells theselves
can reverse transcribe and, strange as it may seem, although Dr.
Gallo was about to look for reverse transcription as a sign of a new
retrovirus, the HT cell line originated from a patient who, according
to Dr. Gallo, had a disease caused by a retrovirus he discovered
called HTLV-I. In fact, in 1983, Gallo reported that the HT parental
cell line contained HTLV-I genetic sequences. On this basis alone
one would expect to find evidence of reverse transcription in the
HT cell line. Given all these data, one would imagine it was
impossible for the Gallo team to abandon the need to follow the
traditional method and isolate and characterise infectious particles
but abandon it they did. By what reasoning then did the Gallo team
claim to have proven the existence of a new retrovirus from AIDS
patients?
For their 1984 papers they reiterated the limitations of particles and
reverse transcriptase and made three assumptions which, taken
together, constitute a precept known as specific reactivity (Gallo et
al., 1986). The first assumption was that AIDS patients are infected
with a replicating retroviral particle, a virus which could be grown
in cell cultures to yield unique, virus-specific proteins. Second,
being foreign the virus would stimulate the production of a number
of distinctive antibodies directed against the viral proteins. Third,
the proteins and the antibodies react specifically, that is, only with
each other and with no other agent. Let us take a very careful look
at this paradigm. First, when the Gallo team began their
experiments, the existence of specific viral proteins as constituents
of a replicating viral particle which could infect humans was
entirely hypothesis, not fact. Second, antibodies and proteins are
not monogamous, even the purest of each take on other partners.
Third, even if they were monogamous, we know that AIDS patients
contain antibodies to many different agents, many with which they
are infected, for example hepatitis B and cytomegalic inclusion
viruses, mycoplasma, fungi and mycobacteria. Unless Gallo further
hypothesised that all these agents or parts of them, or their
respective antibodies, disappear from cultures or sera, when blood
from an AIDS patient is mixed with cell cultures of the same or
another AIDS patient, how can anyone tell what is reacting with
what, let alone define precisely where each of the reactants
originated? As far as the reactions are concerned, it's no different
from mixing up milk from six species of animals, adding a mixture
of a dozen different acids and claiming to know which acid is
curdling which milk. So, although the term specific HIV proteins
conjures up visions of proteins being extracted from retroviral-like
particles proven to be a unique virus, this is not how it was done. It
was done by breaking up cells of the HT cell line, not a virus
particle, and observing unknown proteins reacting with unknown
antibodies. From these data both the proteins and the antibodies
were deemed viral, and not just any virus, but HIV. That's all. Logic
or magic? And as an aside, similar to the proteins, the origin of
what is called the HIV genome, the HIV RNA, is also based on
circumstance, not on purification and dissection of particles proven
to be infectious. The Gallo team may have claimed isolation of a
new retrovirus but what they actually did was weave a nexus
between reverse transcriptase, particles and certain proteins under
the dubious imprimatur of specific reactivity. Is this virus isolation?
Is this even virus detection?
There are also a number of unsolved mysteries in the Gallo papers.
Mystery number one:
Reading the first paper one gets the impression that the HT cell line
was cultured with individual AIDS patient cultures. However, the
National Institutes of Health enquiry instigated after allegations of
misappropriation of the French specimens found that the HT cell
line was cultured with concentrated fluids pooled initially from
individual cultures of three patients and ultimately from the
individual cultures of ten patients. (Maddox, 1992) In evidence
given to the enquiry the reason given was because none of the
individual cultures "was producing high concentrations of reverse
transcriptase." That means not enough to convince the Gallo team
of scientists or anybody else there actually was a virus in any of the
individual specimens in the first place. The fact that pooled
specimens produced reverse transcription is not proof of a
retrovirus. The conditions may have merely changed in favour of
the action of one of the cellular enzymes that performs the same
trick. Or it could have been due to the HT cell line, unaided or at
the behest of its HTLV-I retrovirus. The Gallo investigation found
the pooling of specimens "of dubious scientific rigor." One
scientist described the procedure as "really crazy." In essence it is
no different from investigating an outbreak of pneumonia by having
all patients spit in separate pots and, when nothing turns up, getting
them all to spit in the same pot.
Mystery number two:
The method of specific reactivity required a source of antibodies to
the putative viral proteins. To logical place to obtain these was
from AIDS patients, after all, that is what the hypothesis required.
The antibodies reported in the first paper appeared from two
sources, a haemophiliac patient known as E.T. who had pre-AIDS
and rabbits. Yes, rabbits. What precisely constituted E.T's pre-
AIDS we are not told, but pre-AIDS is often generalised
enlargement of the lymph nodes, a condition not invariably
followed by AIDS and which is not AIDS. Thus, according to the
paradigm of specific reactivity, we cannot be sure that E.T. actually
had the right kind of antibodies. Rabbits do not develop AIDS and
if specific antibodies to a retrovirus were to exist they could only
be produced by immunising rabbits with pure virus or, as the first
Gallo group paper reported, from rabbits infected repeatedly with
disrupted HIV. I hope you are beginning to see the problem. To
make antibodies just to HIV one has to inject rabbits with pure
HIV. Pure virus means isolated virus and if rabbits were injected
with pure virus, why should it be necessary to produce antibodies
to define the isolation of virus that had already been isolated?
Mystery number three:
In the second paper the Gallo team attempted what they called HIV
isolation from 72 AIDS patients. Again, they cultured cells and
detected particles and reverse transcriptase in unrefined culture
fluids, and observed some protein/antibody reactions, but also
added a fourth category, transmission, by which was meant finding
particles or reverse transcriptase in bone marrow and other cells
cultured with fluids, but not purified banded, photographed fluids,
from one of the 72 starting cultures. What is enigmatic about the
second paper is that HIV isolation was defined merely as detecting
at least two of any of these four phenomena. The same criticism
applies as in the first paper. Nothing was isolated and detection of
unspecific phenomena is not surrogate isolation of a retrovirus.
Even it were, this peculiar definition leads to some rather bizarre
possibilities, for example, instances of virus isolation without the
need to see particles or measure reverse transcriptase, for a
retrovirus about as convincing as trying to sell a car without a body
and an engine. Even so, loose as these criteria were, isolation was
successful in only 26 of the 72 patients, that is, in only 36%. And,
in case you think things have improved, there is a recent,
international cooperative study reported by the World Health
Organisation. In this study, by HIV isolation was meant detection
of a single protein, p24, in culture fluids using a single antibody.
Not only is p24 not specific for HIV (Agbalika et al., 1992;
Mortimer et al., 1992) but from 224 HIV positive individuals, the
success rate was a mere 37%, not significantly better than Gallo's
figures a decade earlier. (WHO, 1994)
Even if the Gallo team had proved the existence of a new retrovirus,
on what basis did they claim it was the cause of AIDS? Even if
virus had been isolated from all patients and all patients had
antibodies, which they didn't because in the fourth paper, the data
showed only 88% of AIDS patients had antibodies (and on a single
ELISA test which no one now regards as specific), is this sufficient
proof that HIV causes AIDS? If the bank manager and his constant,
faithful offsider are present at the bank robbery, is this proof that
the manager robbed the bank? The Gallo papers provide no
evidence whatsoever that HIV kills T4-cells or that low numbers of
T4-cells is necessary and sufficient for the development of the
AIDS infections and cancers and, I might add, there is still no such
evidence.
Let me finish by summarising the problem. The method of
retrovirus isolation presented at the beginning flows logically from
the definition of a virus. It is model of intelligibility, it is the only
method and was used for decades of research into animal
retroviruses. (Sinoussi et al., 1973; Toplin, 1973) The problem is
that to date, nobody in the world has reported use of this method in
AIDS patients. Without it, for example, how can one resolve the
dilemma imposed by the numerous particles of stunning
morphological variability present in cell cultures of AIDS patients.
Even so, although some particles are the right diameter, there are no
particles with the right diameter AND the projecting knobs, both
integral to the definition of a retroviral particle and the latter
essential to infect new cells. (Gelderblom et al., 1988; Layne et al.,
1992; Levy, 1996) Yet, as I speak, there is still not even one
published electron micrograph from a density gradient to tell us
which, if any constituents of this zoo of particles, presents itself to
be proved an infectious retrovirus. Perhaps, if someone were to
look, there might not be any. Reading the literature, it is obvious
that scientists everywhere have abandoned the traditional method of
isolation and, under the assumed aegis of specific reactivity,
claimed that two unknowns, antibodies and proteins, interact in
specific pairs simultaneously betraying each other's genesis from a
virus. In other words, what is the guts of what is called HIV
isolation is actually no more than a chemical reaction, an antibody
test, and from an antibody test, one cannot claim proof of isolation
of anything. If an antibody test is isolation of a virus then the
pregnancy test, which uses an antibody to detect the placental
hormone beta HCG, must be regarded as placental isolation. Of
course there may be instances of specific reactivity involving viral
proteins and antibodies but the only way to prove this is to compare
reactions in the test-tube with the virus of interest. Nature would
then reveal specific reactivity by the fact that reactions, the
virological equivalent of curdling milk, show up only when there is
virus and never if there is no virus. This is crux of the matter and
where the evidence for the existence of HIV begins to fall apart. To
prove specific reactivity one must first isolate the virus for use as a
gold standard for comparison. One cannot adopt specific reactivity
as a premise to prove the existence of a virus if one must first
isolate the virus to prove the premise upon which isolation is
contingent. Try as you will but the cart does not go before the horse
and the Gallo argument is reductio ad absurdum.
This leaves us in a perilous quandary. What are these unknown
antibodies to unknown proteins which we call being HIV positive?
They could represent a virus, but that remains to be proven by
isolating a retroviral-like particle and proving it is a retrovirus. It is
certainly not cogent to argue that the conjunction of a number of
unspecific phenomena makes one possibility a definite outcome
any more than claiming that ten men, all dressed in white, hitting a
ball around a paddock, must be playing cricket. They might just as
well be Ku Klux Klaners playing baseball. If not a virus, then what?
If someone tests positive, is this proof that a virus has been
transmitted? Or is it something altogether different? Whatever these
reactions mean, they do seem to be a marker for AIDS in the high
risk groups but are they just as significant in those at low or at no
risk? Does just knowing you're HIV positive affect your health?
Does your doctor knowing you're positive lead to treatments for a
virus you may not have? Could such treatments themselves cause
harm? We now know that antibodies to the germs that cause the
diseases present in 90% of AIDS patients also react with the so
called HIV proteins. (Muller et al., 1991; Kashala et al., 1994) Are
we being fooled by antibodies that have nothing to do with a
retrovirus? Are we seeing curdle from a different milk? Why, in one
study, did 10% of 1300 individuals at low risk for AIDS including
blood donors have antibodies to a sufficient number of HIV
proteins to deem them HIV infected by the most stringent United
States criteria? (Lundberg, 1988) Why do 30% of individuals
transfused with HIV negative blood develop antibodies to the same
p24 protein nearly every HIV researcher uses to "isolate" HIV?
(Genesca et al., 1989) Why do 50% of dogs have antibodies to one
or more of these same proteins? (Strandstrom et al., 1990) How
come healthy, non-HIV-infected mice injected with blood from
similar mice, or mice injected with extracts of a common human
bowel bacterium, develop some of the same antibodies? Why does
transfusion of one's own, irradiated blood produce the same
antibodies? (Kozhemiakin & Bondarenko, 1992) If these data do
not mean that HIV antibodies are non-specific then there must be
some completely unknown as well as very peculiar ways for men,
dogs and mice to acquire HIV infection. On the other hand, if some
humans, injected with their own or someone else's blood, or mice
injected with foreign cells and foreign proteins develop "HIV
antibodies" but are not infected with HIV, why should gay men, IV
drug users and haemophiliacs, who are all exposed to foreign cells
and/or foreign proteins, not also develop "HIV antibodies" and not
be infected with HIV? Is it possible that we been misled by non-
retroviral phenomena altogether? This would not be the first time.
Over the mid to late 1970s, Gallo and his colleagues claimed to
have isolated the first human retrovirus, HL23V, from patients with
various types of leukaemia and their evidence included a picture
from a density gradient. (Gallagher & Gallo, 1975; Gallo et al.,
1976) Soon enough antibodies to the HL23V proteins were found
to be widespread, even amongst normal people and there was great
excitement that a cause of leukaemic was at last in the offing.
However, two groups of researchers then found that the antibodies
were in reality directed against a wide range of naturally occurring
substances, thus destroying that particular notion of specific
reactivity. (Barbacid et al., 1980; Snyder & Fleissner, 1980)
Overnight, HL23V vanished from the scientific literature, so much
so that Gallo now never mentions it. Does a similar fate await HIV?
Neville Hodgkinson (Hodgkinson, 1996), the former science and
medical correspondent for the London Sunday Times has suggested
that HIV is the greatest scientific blunder of the twentieth century.
If so, there are alternative theories and therapies for AIDS we
would do well to consider.
Now, are you ready for that scientist? His name is Galileo Galilei, a
man no stranger to heresy. Perhaps we should heed his counsel and
begin to trust our own sparks. I say the sooner the better.
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Dr. Valendar F. Turner is affiliated with the Department of
Emergency Medicine at the Royal Perth Hospital, Perth, Western
Australia. He can be reached via email at:
vturner@cyllene.uwa.edu.au
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