TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection

Huabiao Chen, Zaza M. Ndhlovu, Dongfang Liu, Lindsay C. Porter, Justin W. Fang, Sam Darko, Mark A. Brockman, Toshiyuki Miura, Zabrina L. Brumme, Arne Schneidewind, Alicja Piechocka-Trocha, Kevin T. Cesa, Jennifer Sela, Thai D. Cung, Ildiko Toth, Florencia Pereyra, Xu G. Yu, Daniel C. Douek, Daniel E. Kaufmann, Todd M. AllenBruce D. Walker

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

Abstract

The human leukocyte antigens HLA-B*27 and HLA-B*57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B*27 and HLA-B*57 are unable to control HIV-1. Here we found that HLA-B*27-restricted CD8 + T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B*57- restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.

Original languageEnglish (US)
Pages (from-to)691-700
Number of pages10
JournalNature Immunology
Volume13
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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