CD8⁺ T cell cross-reactivity profiles and HIV-1 immune escape towards an HLA-B35-restricted immunodominant Nef epitope

Motozono, Chihiro, Miles, John J., Hasan, Zafrul, Gatanaga, Hiroyuki, Meribe, Stanley C., Price, David A., Oka, Shinichi, Sewell, Andrew K., and Ueno, Takamasa (2013) CD8⁺ T cell cross-reactivity profiles and HIV-1 immune escape towards an HLA-B35-restricted immunodominant Nef epitope. PLoS ONE, 8 (6). e66152. pp. 1-6.

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Antigen cross-reactivity is an inbuilt feature of the T cell compartment. However, little is known about the flexibility of T cell recognition in the context of genetically variable pathogens such as HIV-1. In this study, we used a combinatorial library containing 24 billion octamer peptides to characterize the cross-reactivity profiles of CD8⁺ T cells specific for the immunodominant HIV-1 subtype B Nef epitope VY8 (VPLRPMTY) presented by HLA-B*35∶01. In conjunction, we examined naturally occurring antigenic variations within the VY8 epitope. Sequence analysis of plasma viral RNA isolated from 336 HIV-1-infected individuals revealed variability at position (P) 3 and P8 of VY8; Phe at P8, but not Val at P3, was identified as an HLA-B*35∶01-associated polymorphism. VY8-specific T cells generated from several different HIV-1-infected patients showed unique and clonotype-dependent cross-reactivity footprints. Nonetheless, all T cells recognized both the index Leu and mutant Val at P3 equally well. In contrast, competitive titration assays revealed that the Tyr to Phe substitution at P8 reduced T cell recognition by 50–130 fold despite intact peptide binding to HLA-B*35∶01. These findings explain the preferential selection of Phe at the C-terminus of VY8 in HLA-B*35∶01⁺ individuals and demonstrate that HIV-1 can exploit the limitations of T cell recognition in vivo.

Item ID: 45107
Item Type: Article (Research - C1)
ISSN: 1932-6203
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© 2013 Motozono et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funders: Ministry of Education, Science, Sports, and Culture of Japan (MEXT), Ministry of Health, Labor, and Welfare of Japan (MHLW), National Health and Medical Research Council (NHMRC), Biotechnology and Biological Sciences Research Council (BBSRC)
Projects and Grants: MEXT Global COE Program, MEXT International Priority Graduate Programs, BBSRC Grant BB/H001085/1
Date Deposited: 16 Aug 2016 01:47
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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