Immune pressure on HIV
Richard Jefferys, TAG
Several recent papers offer insights into the role of the immune response in shaping the genetic make-up of HIV. In a well-publicised, open access paper by Vincent Dahirela, Karthik Shekhara and colleagues, a complex statistical approach called random matrix theory is used to analyse published HIV sequences and look for groups of sites that evolve collectively. 
The method allows the researchers to uncover a region of the Gag protein they dub “sector 3” that is far more constrained in its ability to mutate than surrounding areas. Additional analyses reveal this constraint is likely due to an important role in the formation of the viral capsid. In collaboration with Bruce Walker’s group at the Ragon Institute, the researchers show that HIV-specific CD8 T cell responses in elite controllers preferentially target sector 3 of Gag, consistent with prior studies indicating that immune responses in these individuals work partly by compromising viral fitness. The findings suggest that vaccines should attempt to induce T cells against this potentially vulnerable region of HIV. The researchers also recommend using their technique to search for other “multidimensionally constrained” parts of viral proteins.
In a paper published in Blood, Tao Dong and colleagues describe the impact of CD8 T cell responses on HIV diversity in a population of Chinese individuals who were infected with genetically homogenous viruses as a result of plasma donation. 
Because of the similarity of the infecting viruses, the cohort offers a unique window into how individual variability in the parts of HIV targeted by CD8 T cells shapes viral evolution, by selecting variants able to escape recognition. Based on analyses of four HIV proteins?Gag, Reverse Transciptase, Integrase and Nef?the researchers find evidence that 24-56% of variable sites were subject to selection by CD8 T cell responses (over approximately 10-12 years since the time of infection). The results offer strong and unusually direct evidence for the key role of virus-specific immune responses in driving HIV diversity.
In a separate paper by the same authors, involving individuals from the same cohort possessing the beneficial HLA B51 immune response gene, CD8 T cell responses targeting specific epitopes from HIV Gag and Pol proteins are investigated in detail. 
The researchers show that mutations in these epitopes that abrogate CD8 T cell recognition are associated with higher viral loads and lower CD4 counts, whereas individuals in whom the epitopes are unmutated had higher CD4 T cell counts and lower viral loads. The findings add to the evidence that the beneficial effect of certain HLA genes in HIV infection is mediated by CD8 T cell responses targeting vulnerable parts of the virus.
Lastly, Ingrid Schellens and colleagues compare two groups of HIV-positive individuals who seroconverted in 1985 and 2005/6, respectively, to investigate whether CD8 T cell responses are altering the make-up of circulating HIV over time. 
The researchers report that certain HIV epitopes have become significantly less common, and these are epitopes known to be targeted by people with HLA-B alleles associated with slower HIV disease progression (such as HLA B27, B51 and B57). The implication is that HIV is adapting at the population level to avoid the most effective CD8 T cell responses, so HLA alleles that have been shown to be “protective” against disease progression in the past may not always show this association. As a possible example, the authors note that individuals with HLA B57 who seroconverted in 1985 had significantly lower viral loads than individuals lacking this allele, but this was not the case among the 2005/6 cohort.
Source: TAG basic science blog (05 Jul 2011).
- Dahirel V et al. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. Proc Natl Acad Sci U S A. 2011 Jun 20. [Epub ahead of print]
- Dong T et al. Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China. Blood. 2011 May 11. [Epub ahead of print]
- Zhang Y et al. Multilayered Defense in HLA-B51-Associated HIV Viral Control. J Immunol. 2011 Jun 13. [Epub ahead of print]
- Schellens IM et al. Loss of HIV-1 derived CTL epitopes restricted by protective HLA-B alleles during the HIV-1 epidemic. AIDS. 2011 Jun 15. [Epub ahead of print]