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Effects of thymic selection of the T-cell repertoire on HLA class?I-associated control of HIV infection
Andrej Ko?mrlj1,2,9, Elizabeth L. Read1,3,4,9, Ying Qi5, Todd M. Allen1, Marcus Altfeld1, Steven G. Deeks6, Florencia Pereyra1, Mary Carrington1,5, Bruce D. Walker1,7 & Arup K. Chakraborty1,3,4,8
1Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA
2Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
4Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
5Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA
6University of California, San Francisco, California 94110, USA
7Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
8Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
9These authors contributed equally to this work.
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.
