Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes

Author:

Yu Xu G.1,Lichterfeld Mathias1,Chetty Senica2,Williams Katie L.1,Mui Stanley K.1,Miura Toshiyuki1,Frahm Nicole1,Feeney Margaret E.1,Tang Yanhua1,Pereyra Florencia1,LaBute Montiago X.3,Pfafferott Katja4,Leslie Alisdair4,Crawford Hayley4,Allgaier Rachel1,Hildebrand William5,Kaslow Richard6,Brander Christian1,Allen Todd M.1,Rosenberg Eric S.1,Kiepiela Photini2,Vajpayee Madhu7,Goepfert Paul A.6,Altfeld Marcus1,Goulder Philip J. R.124,Walker Bruce D.128

Affiliation:

1. Partners AIDS Research Center, Massachusetts General Hospital and Harvard University Center for AIDS Research, Boston, Massachusetts

2. HIV Pathogenesis Program, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa

3. Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico

4. Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom

5. University of Oklahoma Health Science Center, Oklahoma City, Oklahoma

6. University of Alabama at Birmingham, Birmingham, Alabama

7. All India Institute for Medical Sciences, New Delhi, India

8. Howard Hughes Medical Institute, Chevy Chase, Maryland

Abstract

ABSTRACT The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8 + T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR β-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703 + individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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