It has long been known that HIV can mutate in ways that allow it to evade HIV-specific CD8 T cell responses. This phenomenon is known as immune escape and it is loosely analogous to the development of drug resistance. Studies to date have generally found that the development of immune escape is associated with increased viral loads and disease progression. However, it's also known that there are some parts of HIV that cannot mutate easily because they are essential to viral replication; mutations in these areas can reduce the ability of HIV to replicate. In a new study, a group of researchers explore the question of whether effective CD8 T cell responses can drive the development of immune escape mutations that are disadvantageous to HIV.
The specific slices of HIV proteins (called epitopes) that can be targeted by CD8 T cells are dictated by a person's genes. Specifically, genes called class I HLA genes are responsible for manufacturing CD8 T cell receptors, which are docking bay-type structures that interact with HIV epitopes expressed on infected cells (allowing those cells to be recognized and killed by CD8 T cells). It is clear from the scientific literature that class I HLA genes can have a profound influence on the outcome of infections. In HIV, for example, HLA B57 is consistently associated with long-term non-progression.
For this study, the researchers took a close look at the HIV epitopes being targeted by people with class I HLA genes that have been associated with a better outcome in HIV infection. One possible reason that these class I HLA genes are beneficial could be that the HIV epitopes that they target do not mutate and escape from the CD8 T cell response. However, the researchers found the opposite: the beneficial effects of the class I HLA genes were significantly correlated with the number of mutations in the HIV epitopes being targeted. The researchers conclude that the clinical benefit associated with certain class I HLA genes is due to the strong selection pressure exerted on key HIV epitopes by the CD8 T cells in individuals possessing these "good" genes. In other words, the effectiveness of the HIV-specific CD8 T cell response in such individuals forces HIV to mutate in ways that appear to reduce its replicative capacity and pathogenicity. These findings demonstrate that immune escape is not necessarily always a bad thing, which may be good news for HIV vaccine candidates that aim to induce effective HIV-specific CD8 T cell responses.
Effective T cell Responses Select HIV-1 Mutants and Slow Disease Progression
A. J. Frater, H. Brown, A. Oxenius, H. F. Günthard, B. Hirschel, N. Robinson, A. J. Leslie, R. Payne, H. Crawford, A. Prendergast, C. Brander, P. Kiepiela, B. D. Walker, P. J. R. Goulder, A. McLean, R. E. Phillips, and the Swiss HIV-Cohort Study
The possession of some HLA Class I molecules is associated with delayed progression to AIDS. The mechanism behind this beneficial effect is unclear. We tested the idea that cytotoxic T cell responses restricted by advantageous HLA Class I molecules impose stronger selection pressures than those restricted by other HLA Class I alleles. As a measure of the selection pressure imposed by HLA Class I alleles, we determined the extent of HLA Class I-associated epitope variation in a cohort of European HIV+ve individuals (n=84). We validated our findings in a second, distinct cohort of African patients (n=516).
We found that key HIV epitopes restricted by advantageous HLA molecules (B27, B57, B51 in European patients and B5703, B5801 and B8101 in Africans) were more frequently mutated in individuals bearing the restricting HLA than in those who lacked the restricting HLA Class I molecule. HLA alleles associated with clinical benefit restricted certain epitopes for which the consensus peptides were frequently recognised by the immune response despite the circulating virus being highly polymorphic. We found a significant inverse correlation between the HLA-associated hazard of disease progression and the mean HLA-associated prevalence of mutations within epitopes (p = 0.028; R2 = 0.34).
We conclude that beneficial HLA Class I alleles impose strong selection at key epitopes. This is revealed by the frequent association between effective T cell responses and circulating viral escape mutants, and the rarity of these variants in patients who lack these favourable HLA Class I molecules, suggesting a significant pressure to revert.
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