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

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Abstract
Certain HIV-infected individuals, termed 'elite controllers', maintain extremely low viral loads over long time periods without therapy. A number of HLA class I alleles are enriched in these individuals, most prominently HLA-B57. The paper provides a model of how elite controllers might generate an effective immune response against HIV. According to the model, HLA-B57 binds fewer self-peptides, resulting in a T-cell repertoire with enhanced cross-reactivity and leading to a more effective T-cell response against the virus. This work may have implications for vaccination strategies. 'Elite controllers' are rare people who are infected with HIV but maintain low levels of HIV RNA without being treated, making it unlikely that they will develop AIDS. Certain HLA class I alleles, notably HLA-B57, are enriched in elite controllers. Here a model is proposed to explain how such elite controllers generate an effective immune response against HIV. In this model, HLA-B57 binds to fewer self-peptides, resulting in a T-cell repertoire with enhanced cross-reactivity and leading to a more effective T-cell response to the virus. 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 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we 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. Our 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, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.