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Diversity Threshold: New Model of Immune Defense
to HIV Shows How Nature of
Response Might Determine
Eventual Outcome
Sloppy RT, Bane of All

August 1995

A provocative research paper initially published in the international weekly science journal Nature ("Antigenic oscillations and shifting immunodominance in HIV-1 infections," Nowak M.A. et al. Nature 375:606-11) has been reworked into a more readable exposition--wonderfully illustrated--for the August issue of Scientific American ("How HIV Defeats the Immune System"). The mathematical model simulates the raging battle between a tactically disadvantaged immune system and an ever-evolving population of HIV viral variants, and suggests considerations for vaccine design, antiretroviral strategies, and immunotherapy alike.

The Scientific American piece might have been more aptly titled, "A Hypothetical Modeling of the CTL Response to--and Ultimate Defeat by--HIV Infection" (although they'd admittedly sell fewer copies); it's really just one possible explanation for this immunological war of attrition between HIV and the cellular arm of the immune system. And although the authors casually mention that this same type of mathematical simulation could be applied to the antibody response to HIV infection, their paper treats the cellular (in particular, the CTL) immune response to HIV more or less in isolation.

By way of background, it is useful to remember that a typical antigen contains several epitopes that can be recognized by CD8+ (or "T-8") killer cells called cytotoxic T lymphocytes (CTLs). In a characteristic antiviral immune response in vivo , CTLs generally recognize only a small number of the total epitopes on any given antigen--and sometimes only one . This phenomenon is called "immunodominance" because the dominant immune response is focused on the epitopes most easily "seen" by the body's immune system, in this case, the CTLs. Through one or more mutations which alter the immunogenicity of these epitopes (and thus make them more difficult for the immune system to "recognize"), HIV (and other highly mutable viruses) is believed to escape the immune attack. This so-called "antigenic escape" is believed to be responsible for the persistence of HIV. In the other arm of the immune response, the humoral (or antibody) component, it is generally accepted that variants resistant to neutralization by antibodies also appear during infection, but the importance of these to the actual course of infection is uncertain.

Even more uncertain is how cytotoxic T cells (CTLs) generated in the cellular immune response contribute to controlling infection and forcing antigenic diversity. In HIV infection, the CTL response is strong and directed at several epitopes. Mounting evidence suggests that CTLs are important in controlling the virus, although others challenge this notion. (Most notably, researchers at the New Mexico-based CytoDyn company, working via Search Alliance , with a mouse antibody (Cytolin, or S6F1) that blocks CD8+ cells.)

Recent observations that virus and infected cells are turning over much more rapidly than previously thought (with a half-life of about 2.5 days for the virus and some 7-8 days for the CD4+ T cells) have brought these issues into sharp focus by removing the misconception of HIV infection as a relatively indolent process. With the knowledge that the virus is replicating constantly at all stages of infection, and that it is transmitted from one infected cell to another every one to two days, researchers are forced to confront the mystery of how the infection is kept under such firm control for so long. Although this initial simulation by Nowak and colleagues does not exactly answer these important questions, it does provide a stepping stone for getting there.

The study consists of two parts: observations of the CTL response to selected HIV epitopes in infected individuals and the development of a mathematical model to simulate these responses. The model is based on the differing CTL responses of two HIV-infected hemophiliacs observed over nearly five years (55 months). In the patient who remained well over the follow-up period, only a single reactive epitope could be detected in the virus-infected cells. By contrast, the patient who progressed to AIDS in 8 years (and died) during the observation period, displayed activity against three epitopes of the virus in a fluctuating pattern over time.

The virus in the first patient appeared bonded to a single epitope (HLA-B27-restricted gag ), which the authors claim is suggestive of the immunodominant model in which competitively successful escape mutants cannot rise. A weak response to the HIV pol gene was found on one occasion and no CTL responses were seen to the nef or env genes, nor to any other epitope in gag .

By contrast, the second patient displayed the complex pattern (variation within three HLA-B8-restricted gag epitopes that are not seen at some time points by the patient's CTL) which is suggestive of shifting immunodominance in the face of emerging and disappearing variant viruses. The authors propose that the slower course of disease progression in the first patient reflects the more successful response against a relatively unchangeable epitope.

The model, of course, is limited by the fact that it analyzes only two epitopes and that it requires sometimes arbitrary assignment of values to some fourteen biological parameters. All in all, though, it represents an important step toward trying to understand much of the complexity of viral escape from CTL responses.

It is perhaps short of revolutionary to suggest that HIV evades the immune response by virtue of its constant mutation, but by taking this proposition a step further the authors suggest that patients who recognize fewer epitopes of the virus may have a more stable CTL response and thus control the virus more effectively. The implication for vaccine development means that a vaccine which induces a narrow response to a relatively conserved epitope of HIV would be more desirable than a product which elicits a broad cellular immune response. An immunotherapeutic approach in HIV-infected individuals might include boosting the CTL response to single conserved epitopes in hope of inducing a stable pattern of immunological recognition. There's no guarantee, however, that even these more conserved epitopes won't mutate, once more selective pressure against them is in force.




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