Countervailing Selective Forces Shape HIV

April 9, 2013

It's well documented that T-cell immune responses targeting HIV can cause selection of viral variants that evade recognition (immune escape). But some studies have reported that, surprisingly, HIV variability in regions targeted by T cells is lower compared to other locations in the genome, a phenomenon not seen with other RNA viruses. In a paper published last week in PLoS Biology, Rafael Sanjuán and colleagues offer a potential explanation. Based on mathematical modeling studies, they suggest that selection may favor the conservation of parts of HIV that efficiently activate CD4 T cells, because this provides the virus with target cells in which to replicate. This suggestion is consistent with evidence that HIV itself is often a major driver of immune activation (e.g., activation precipitously declines when HIV replication is suppressed by therapy), and with the finding that HIV preferentially infects HIV-specific CD4 T cells. The theory also fits with recent data showing that SIV can cause immune activation and progression to simian AIDS in the absence of any contribution from microbial translocation.

The overall message is that while effective CD8 T-cell responses can drive the development of immune escape mutations and thus promote viral variation, HIV's need to activate CD4 T-cell targets may act as a countervailing force selecting for conservation. The strength of the selective pressure favoring conservation, Sanjuán and colleagues note, will depend on the extent to which other stimuli -- such as co-infections and/or microbial translocation -- are contributing to immune activation (the greater their contribution, the less HIV needs to activate CD4 T cells itself).

One implication of the study, the researchers argue, is that vaccines that induce HIV-specific CD4 T-cell responses might create conditions favorable to viral replication. They suggest that in order to provide the CD4 T-cell help required to generate functional CD8 T-cell responses, non-HIV antigens that activate CD4 T cells should be included in vaccines. However, the model does not distinguish between the different types of CD4 T cell that may respond to HIV antigens (e.g., naive or the many possible types of memory cells) and an alternative solution to this conundrum may be to try to design vaccines that create HIV-specific memory CD4 T cells that are relatively resistant to infection. Evidence that CMV-specific specific memory CD4 T cells are highly resistant to HIV suggests that this might be possible.

Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.

This article was provided by Treatment Action Group. It is a part of the publication Michael Palm HIV Basic Science, Vaccines & Cure Project.

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