Genetica 95: 195-197, 1995.

195
(~) 1995 Kluwer Academic Publishers. Printed in the Netherlands.

A hypothetical disease of the immune system that may bear some relation to
the Acquired Immune Deficiency Syndrome

K a r y B. M u l l i s
6767 Neptune Place, Apt. 5, La Jolla, CA 92037, USA

Received 12 April 1994 Accepted 14 June 1994

Abstract

The cells of an individual immune system could be so highly infected with latent viruses that were immunologically
distinct from one another as to result in an immune dysfunction resembling the Acquired Immune Deficiency
Syndrome.

There is a population of cells in a particular individual
from which sub-populations are chosen by immune
mechanisms to undergo clonal expansion in the course
of normal immune function. The number of individual
cells in such a sub-population in any particular episode
of immune function is dependent on a variety of factors
that are incompletely understood.
1. Call this number of cells R.
2. Assume that in this population of cells at least one
cell in R is latently infected by at least one virus
capable of expressing a new and distinct epitope.
3. Now, every episode of immune function involving
the promotion to clonality of R cells will result in
the clonal expansion of at least one latently infected
cell.
4. And during the course of clonal expansion the like-
lihood for expression of a latent virus from one or
more members of the growing infected clone would
be expected to grow in proportion to the number of
cells in the clone.
5. Because expression of a previously latent virus
with a distinct epitope would tend to provoke a
new immune response, every immune response
would tend to provoke at least one further immune
response.
6. AIDS may be the result of such a chain reaction.
The immune system so infected would be perpetu-
ally generating new immunogens. As the frequency
of infection increased such an immune chain reaction
would be progressively more debilitating for the sta-
bility and effectiveness of immune function. At a level
of infection where more than one latent viral species
existed in R cells, a single immune response on aver-
age would result in the release of more than one new
viremia. Such a situation would generate an exponen-
tially increasing number of independent immune stim-
uli and, unless somehow controlled, would certainly
be fatal.
It is difficult to imagine a control mechanism that
would not seriously compromise immune function.
Mechanisms for such control may not have evolved
because selection pressures for the evolution of such
mechanisms would only have existed if there were a
sufficient diversity of viruses available in the environ-
ment capable of latently infecting mammalian immune
cells to a level near 1/R.
However, in the past century humans have come to
constitute a greater and greater proportion of their own
environment, and therefore the availability of diverse
and infectious human viruses may have risen signifi-
cantly. Certainly the increase in speed of transportation
has dramatically increased the number of other human
beings any one individual wilLencounter during the
course of a lifetime. /,~
Certain life styles have been in the vanguard of this
development. For instance, it has been widely pub-
licized that in the so-called "bath house cultures" of
some metropolitan gay communities, intimate expo-
sure to hundreds of individuals per year was unexcep-
tional until very recently when viral infection became a
serious issue. The potential for collecting a vast num-
ber of diverse latent viruses through intimate expo-
sure to hundreds of different human beings per year is
increased enormously if those humans are also being
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exposed to hundreds of different humans per year. Thus
300 contacts with people having themselves 300 con-
tacts at a first approximation yields an exposure level
90,000-fold higher than that incurred by contact with a
stably pair-bonded individual. Going out in the spread-
ing pyramid of exposure one step further generates a
relative risk factor of 27 million. The particular social
dynamic of the metropolitan, international, gay, bath
house community could not have been more efficient-
ly organized if maximum exposure by individuals to
the world's supply of diverse viruses had been actively
sought.
Other modes for unprecedented accumulation of
diverse viral infections can be envisioned. Transfusion
of blood from one or more highly infected individuals
could transfer a sufficiently large number of viruses
to cause immune dysfunction. Or long term associa-
tion with an individual harboring a sufficient number
of diverse viruses as to be suffering from immune dys-
function could transfer a sufficient number of them to
an otherwise unexposed individual. It would not be
expected that a casual or brief encounter with such an
infected individual would be sufficient to transfer a
lethal diversity of viruses. At a given time most viral
infections in an individual are latent.
For the purposes of this hypothesis, the absolute
levels of infection are not critical. Social and tech-
nological developments in this century have raised
the potential for multiple modes of accelerated trans-
mission for infectious organisms and this has resulted
in the catastrophic accumulation of an evolutionari-
ly unprecedented burden of latent infections in some
humans. This is all that the present hypothesis assumes.
If this mechanism is causal for AIDS, then the pres-
ence of any particular virus would not be necessary or
sufficient for the development of that disease, although
someone so afflicted might be expected to have a far
greater than average chance of being infected by any
particular virus, for instance HIV, than someone not
afflicted.
This hypothesis is not inconsistent with the notion
that one or more species of virus may be dispropor-
tionately effective in achieving a highly diverse state
of immune cell infection. Some viruses, for example,
might be far more effective than others at spreading
significantly mutated copies of themselves throughout
the population and throughout the immune system of
an infected individual. The high rate of mutation in
the Retroviridae and their capacity for latent infection
make them ideal candidates for such a role. HIV might
be a significant species, but absent any evidence for
this there is no reason to suspect it over any other
virus, most of which, it can be easily argued, are not
presently detectable.
Such a mechanism would predict that any drug that
could prevent the growth of latent viruses would be
beneficial, unless of course it were poisonous to the
patient. However, unless latent chromosomally incor-
porated viruses could somehow be removed or per-
manently prevented from expressing new epitopes, no
cure would be expected.
This hypothesis predicts that a vaccine against any
specific virus would be ineffective against AIDS.
This hypothesis is consistent with a disease of
slow onset with a steadily more rapid progression.
Progression of the disease would be accelerated by
any immune activity whether it be elicited by infec-
tion, environmental immunogens, immune reactions
to drugs, etc. Progression of such a disease would
also be enhanced by the rapid growth of any infected
cells that were capable of producing infective viruses,
particularly if these infective viruses were capable of
infecting immune cells.
Usefully, this hypothesis is subject to experimental
verification or denial. If correct, then an experimental
animal model of AIDS should be induced in labora-
tory animals by infecting them at a low multiplici-
ty with a very large number of diverse viruses. One
way of doing this would involve collecting the blood
from a large number of wild mice from geographical-
ly distant locations, mixing it together and injecting it
into healthy mice. The number of mice that would be
required to produce such a lethal injection or series of
injections is not predicted by this hypothesis, although
from the numbers suggested by the behavior patterns of
the human victims of AIDS the number of individuals
whose viruses must be pooled could be quite high.
The hypothesis suggests that some level of diverse
infection would cause AIDS-like malfunction of the
immune system to appear rapidly, and that this could
not be reproduced by simply isolating a particular
infectious species and infecting similar animals with
only this species.
The hypothesis also suggests that blood from a sin-
gle human AIDS patient should be capable of trans-
ferring the appropriate level of diversity of infection
to another organism, given that the recipient organism
contains a functional human immune system.
The hypothesis suggests further that aliquots of an
appropriate dilution of the blood from a single AIDS
patient injected into a large number of experimental
animals with a human immune system would not be
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able to produce AIDS-like immune dysfunction in any Acknowledgements

one of them.
According to this hypothesis there is not a single The author is grateful for more than a little help from
organism that is the cause of AIDS, and there should Stephen H. Judd and Andrew E. Dizon in clarifying
exist AIDS patients who do not test positive for HIV. his thoughts and rendering his prose more intelligible.
It is an overwhelming number of distinct organisms
which causes the immune dysfunction. These may
individually be harmless.