Less Can Be More

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Science  11 Jun 2010:
Vol. 328, Issue 5984, pp. 1328
DOI: 10.1126/science.328.5984.1328-b

“Elite controllers” are HIV-infected individuals who manage to maintain low levels of viremia without therapy and who rarely progress to AIDS. They disproportionately express certain major histocompatibility complex (MHC) class I alleles, such as HLA-B57, which are strongly associated with viral control. HLA molecules present viral fragments (peptides) to CD8+ T cells, which can then go on to recognize and kill infected cells; however, how the expression of HLA-B57 contributes to enhanced viral control is not well understood.

Košmrlj et al. are now able to address this question by using computational modeling to demonstrate that the expression of HLA-B57 affects T cell development in a way that results in elevated frequencies of virus-specific T cells that are more cross-reactive. Compared to non-protective HLA molecules, HLA-B57 binds to substantially fewer peptides derived from oneself in the thymus. This is important because the spectrum of specificities of the developing T cells is determined by interactions with MHC proteins that bind to self peptides in the thymus. The authors find that when T cells encounter fewer self peptides in the thymus, T cells that recognize viral peptides on the basis of a small number of important contacts develop with higher frequency. The resulting cells are more cross-reactive, which means that they can also recognize viral peptides containing point mutations, a situation that often arises as HIV attempts to evade immune detection by mutating its proteins. These computational predictions were supported by comparative data from HLA-typed cohorts of controllers versus noncontrollers. Control of infection was associated with HLA molecules binding fewer self peptides. The number of self peptides bound by HLA molecules may mediate a general enhancement in viral surveillance because HLA-B57 is also associated with control of hepatitis C virus.

Nature 465, 350 (2010).

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