Searchlight Vol. 3, no. 1

Gone Insertion Treatment
Continued from page 1...
tor, inhibiting the infection of new CD4 cells; AZT,
ddl, ddC, D4T and TIBO are all believed to interfere with conversion of RNA to DNA, thus inhibiting
the actual integration of viral DNA into the cell's
genome after the viral particle has entered the cell.
Unfortunately, no patient has really been "cured"
using these modalities.
The popularity of the above hypothesis makes it
the standard by which other models for the pathophysiology of HIV are judged. Although many
physicians are dissatisfied with this model, its
weaknesses can, unfortunately, always be
explained away with the follow-up hypothesis that
current available medicines have not been able to
achieve the desired intervention-soluble CD4
does not really interfere with viral binding, and
Hypericin really doesn't destroy all viral surface
binding proteins, and AZT really doesn't stop all
virus from integrating into the host genome.
However, it would seem that medicine must eventually ask if this widely accepted model of the disease process of HIV needs to be reexamined.
An Alternative Hypothesis
There is another hypothesis concerning the pathophysiology of HIV, and like other mechanisms,
this one will require specific interventions to
assess its validity: "Without HIV viral particles you
do not have or achieve AIDS." HIV damages the
immune system through the production of constant viremia, 99.9% of which are not infectious.
Thus, it does most of its damage through a process
of antigen overload rather than through direct
infection. This hypothesis takes the emphasis off of
infectious HIV and places it on the protein/lipid
viral storm occurring in all the fluid compartments
of the body.
This is an important distinction, and an imaginary
experiment may help in understanding it: Suppose
one were to grow in a test tube a large number of
HIV viral particles, all of which started out being
infectious. Suppose further that this large quantity
of virus was then divided into two portions, half of
which was heated to 56o centigrade, and the other
half left alone (heating to this temperature renders
HIV non-infectious but does not destroy the viral
particle structure). Now if one were to take two
monkeys-both capable of developing an AIDSlike illness should they be infected-and infuse
them with these two different virus preparations,

our two hypotheses (HIV kills by infecting CD4
cells, and HIV kills by being an inherently toxic
protein) could be evaluated. If HIV kills by virtue
of infecting the CD4 cells, then one would expect
the monkey receiving the killed virus to remain

healthy, and the one receiving the live virus to
succumb. If, however, HIV killed by virtue of
being a protein toxin, then both monkeys would
fare poorly.
As one can see, different expectations are derived
from different interpretations on how the pathophysiology of HIV occurs. With this imaginary
experiment, one can see that it makes a great deal
of difference in the intervention one undertakes.

in this model sterile virus, as toxin, is as destructive as infectious virus. It follows that the use of
any of the above treatments would not be expected
to work, as none of these modalities stop the production of infectious or even non-infectious viral
particles (with the exception of chain terminators
which, as metabolic poisons, probably do slow
cellular production of the virus). If the virus particle is an inherent toxin, it really makes no difference whether or not it is infectious, or if you interfere with its binding to the CD4 receptor. To test
the validity of this "virus-as-toxin" model only
demands that production be stopped in those cells
which are making virus.
This hypothesis would redirect all interventions
away from virus-cell interaction to pre-viral
release from the infected cell. If it is correct, all
effective interventions in HIV have to be focused on
that portion of the viral life cycle prior to the
release of viral particles. Agents which fall into
this category are the TAT inhibitors, NAC, glutathione, and gene therapy.
Infectious Versus Non-Infectious HIV
It is rather amazing that we have only just become
able to measure viral particles in patients, infectious or not. A patient can generate more than one
million viral particles per milliliter of plasma, with
less than 5,000 of those being infectious. This is
not surprising in HIV, which thrives on mistakes or
mutations which are, by definition, not infectious.
As an analogy, most cars do not work if the engine
is taken out, torn apart and then put back together
in a haphazard fashion with either pieces missing
or the wrong pieces substituted. So it is with life: if
certain proteins are not produced according to
specification, life will not continue. If one randomly puts things together, one is more likely to
make a virus which doesn't work.
Again, we know that very few of the peripheral
blood cells are actually infected with HIV and most
of these infected cells are not actually producing
virus. So where is all of this defective virus coming
from? And how can we stop its production so as to
test the hypothesis "without HIV viral particles you
do not have or achieve AIDS"?
Testing the Virus-as-Toxin Hypothesis
The follicular dendritic cell found at the center of
the lymph node is a probable contender for the
title of virus producer. This cell is "permissive"
for virtually all HIV virus tested (that is, it is not
immediately killed by the infection but rather continues to produce virus). Therefore, the follicular

dendritic cell would be a likely candidate to test
for the efficacy of antiviral agents-not
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The Implications
This new hypothesis-"without HIV viral particles
you do not develop AIDS"-allows for the chronic
infection in cells as long as no viral particles are
produced. Most of the current strategies in HIV
focus on stages in the viral life cycle after the virus
has left the infected cell-that is, after the viral
particle has been produced. This is too late, even
if the particle is rendered non-infectious by antibodies, Hypericin, AZT, etc. The new theory flies
directly in the face of the commonly held one, for

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SEARCHLIGHT January/February,1993

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