class I-associated control of HIV infection.AA

Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection.

Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57. Because HLA molecules present viral peptides that activate CD8(+) T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here the authors describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Their calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, Kosmrlj and colleagues’ experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. These results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.

The human leukocyte antigen (HLA) system is composed of a large number of genes related to immune system function in humans. It was first recognised as a result of reactions to organ transplantation. Organ transplants are less likely to be rejected if the donor and recipient have similar HLA profiles. People expressing HLA-B8 have a rapid progression to HIV disease while those expressing HLA-B57 tend to have a lower HIV viral setpoint and a slower HIV disease progression. This research suggests that this difference is related to the diversity of peptides presented in the thymus during T-cell development. Individuals with HLA-B57 tend to have a more cross-reactive repertoire because their T-cells encounter fewer self-peptides during development – this also makes such individuals more likely to have autoimmune diseases and hypersensitivity reactions. Although rarer, cross-reactive T-cells are found in people with other HLA alleles so the challenge for a T-cell vaccine will be to activate these cells in everyone to enable robust immune responses.