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. naïve 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.
PLoS Biol 11(4): e1001523. doi:10.1371/journal.pbio.1001523
Rafael Sanjuán, Miguel R. Nebot, Joan B. Peris, José Alcamí
The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4+ helper T lymphocytes (TH cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when THcell infection is concomitant to epitope recognition (trans-infection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved TH epitopes may be counterproductive.
PLoS Biol 11(4): e1001521. doi:10.1371/journal.pbio.1001521
Roland G. Roberts
Viruses are locked into an adaptive arms race with the host immune system: the immune system adapts to recognize the virus, the virus adapts to evade the immune system, the cycle repeats. But in the case of HIV, it seems, sometimes it's good to be recognized.