A Hypothetical Disease Of The Immune System That May Bear Some Relation To The Acquired Immune Deficiency Syndrome, (1994), Kary B. Mullis

Genetica 95: 195-197, 1995. (~) 1995 Kluwer Academic Publishers. Printed in the Netherlands.

195

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 likelihood 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 perpetually generating new immunogens. As the frequency of infection increased such an immune chain reaction would be progressively more debilitating for the stability 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 average would result in the release of more than one new viremia. Such a situation would generate an exponentially increasing number of independent immune stimuli 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 environment 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 significantly. 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 publicized that in the so-called "bath house cultures" of some metropolitan gay communities, intimate exposure to hundreds of individuals per year was unexceptional until very recently when viral infection became a serious issue. The potential for collecting a vast number of diverse latent viruses through intimate exposure to hundreds of different human beings per year is increased enormously if those humans are also being

196 exposed to hundreds of different humans per year. Thus 300 contacts with people having themselves 300 contacts 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 spreading 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 efficiently 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 association with an individual harboring a sufficient number of diverse viruses as to be suffering from immune dysfunction 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 technological developments in this century have raised the potential for multiple modes of accelerated transmission for infectious organisms and this has resulted in the catastrophic accumulation of an evolutionarily 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 presence 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 disproportionately 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 incorporated viruses could somehow be removed or permanently 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 infection, 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 laboratory animals by infecting them at a low multiplicity 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 geographically 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 single human AIDS patient should be capable of transferring 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

197 able to produce AIDS-like immune dysfunction in any one of them. According to this hypothesis there is not a single organism that is the cause of AIDS, and there should exist AIDS patients who do not test positive for HIV. It is an overwhelming number of distinct organisms which causes the immune dysfunction. These may individually be harmless.

Acknowledgements The author is grateful for more than a little help from Stephen H. Judd and Andrew E. Dizon in clarifying his thoughts and rendering his prose more intelligible.