Are HIV Vaccines Fighting Fire with Gasoline?

FALLOUT DATA

Experiments have not tested whether promoting a lentiviral- (HIV, simian immunodeficiency virus [SIV], or feline immunodeficiency virus [FIV]) specific T_h response by vaccination leads to greater incidence or severity of AIDS. Rather, data thus far have been the fallout of other research.

Staprans' team presented data last year showing that macaques vaccinated against and then challenged with SIV showed higher SIV replication levels, and faster T_h depletion and disease progression relative to control animals.² In this small study, the vaccine elicited no neutralizing antibodies and little CTL activity, leaving open the possibility that either might control the additional replication taking place in the HIV-specific T_h compartment.

Hamer has been presenting data that HIV preferentially evolves in HIV-specific T_h cells, even in individuals who initiated antiretroviral treatment shortly after infection. The abstract, coauthored with Douek, Dominik Wodarz, a theoretical biologist at the University of California, Irvine, and others, concludes that the ability ofHIV-specific T_h cells to serve as a reservoir for HIV growth and variation suggests that treatments such as vaccination (and by implication, cytokine therapy) aimed at augmenting HIV-specific CD4⁺ T-cell responses "should be undertaken with caution."³

Such findings are not unprecedented. Reports from at least as far back as 1992 state that cats immunized against FIV displayed enhanced susceptibility to viremia after challenge.⁴ David Schwartz at Johns Hopkins University later hypothesized that inducing a strong lentiviral-specific T_h response might provide a pool of highly susceptible targets.⁵ More recently, FIV and other lentiviral model systems have yielded similar results, prompting the conclusion that "immune activation may thus be a confounding factor in vaccination against lentivirus infection."⁶

STIMULATING SIMULATION

Wodarz asks, "Under which circumstances [does] boosting CD4 cells [make] the immune response react stronger and get an upper hand over the virus; and which makes the virus grow better and overcome the immune response better?" The answer, he says, requires mathematical modeling. "There are a lot of things that interact with each other in a very complex way, and you can't really figure it out by just drawing diagrams or thinking about it."

Wodarz' model is based on general processes, turned into a system of equations: A population of T_h cells proliferates in response to virus; the virus can infect and grow in the T_h cells; they also make CTL expansion more efficient. To apply the model, however, requires values for the half-life of infected cells, replication rates, and other parameters, including some unknowns. "That makes it difficult to apply it to a specific system to make quantitative predictions," he continues.

But by making certain assumptions – that CD4⁺ cells are both good for the virus and for the CD8⁺-cell response – Wodarz says it is possible to "get a qualitative feel, and to ask ... What are the possible outcomes? What are the main determinants of the outcomes? Which parameter shifts the outcome ... if you change it from one extreme to the other?"

Wodarz' model predicts "a definite parameter region" in which aboost in the T_h response benefits the host, and another that promotes virus replication. But, he says, immunization will be beneficial only if infection takes place soon after – where a low virus load would meet a large number of activated CTLs. If memory CTLs have to be activated from a resting state, however, the virus has a chance to grow unopposed for a time. "If there are high numbers of CD4 cells, the virus grows much, much, much, much faster, and if it's so much faster, it will delete the population of the specific CD4 cells very quickly," he continues. With no functional T_h cells, the CD8⁺ cell response is at a disadvantage.

The question of how much of a delay is too much is one that "we can't answer," notes Wodarz, "because the parameter value is not specifically known." But he does cite a real-world example: a robust CTL response is known to protect some sex-workers against infection; their CD8⁺ cells are kept in an active state by the continual presence of HIV antigen. If they take a half-year sabbatical, they are likely to develop AIDS when they return to work.⁷

A LIVELY DISCUSSION

"I do not see any good evidence that having such viral-specific CD4 cells can be harmful," asserts virologist Ronald Desrosier, director of Harvard's New England Primate Research Center. He is familiar with the data that virus replicates in HIV-specific CD4⁺ T cells. "That doesn't say you're worse off having [a high HIV-specific T_h response]," he says. In fact, he adds, that's exactly what researchers should strive for in vaccines.

Andrew McMichael, of the University of Oxford, attended a recent talk where Hamer discussed his work and Wodarz' simulations. The issue of whether a strong T_h response is better for the patient or the virus, McMichael remarked, was the subject of "lively discussion," the consensus being that the issue is a legitimate one that must be tested.

Feinberg says the case has not yet been made: "Models are models." His group, as wells as Douek's, have been contemplating ways of testing the theory. It would be necessary to compare vaccines using the same antigen yet elicit different balances of CD4⁺ and CD8⁺ cells. One challenge is to elicit a strong CTL response without a strong T_h response, which Douek calls "a kind of Catch-22 situation." Picking a model system is not straightforward, notes Feinberg, and there is no consensus on the relevance of extrapolating animal results to humans. Staprans laments the difficulty of gaining access to the various vaccine candidates that might have that differential ability, because "nobody wants their vaccine to look bad."

But researchers doubt that developers are tilting at windmills. McMichael says, "I get the feeling [HIV's use of T_h cells as a factory is] just another obstacle in front of us on this incredibly rocky road we actually go down to try and get a vaccine."

Josh P. Roberts tcwriter@msn.com is a freelance writer in Minneapolis, Minn.