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HLA-B*14:02-RESTRICTED ENV-SPECIFIC CD8+ T-CELL ACTIVITY HAS HIGHLY POTENT ANTIVIRAL EFFICACY ASSOCIATED WITH IMMUNE CONTROL OF HIV INFECTION.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Leitman Ellen M, Willberg Christian B, Tsai Ming-Han, Chen Huabiao, Buus Søren, Chen Fabian, Riddell Lynn, Haas David, Fellay Jacques, Goedert James J, Piechocka-Trocha Alicja, Walker Bruce D, Martin Jeffrey, Deeks Steven, Wolinsky Steven M, Martinson Jeremy, Martin Maureen, Qi Ying, Sáez-Cirión Asier, Yang Otto O, Matthews Philippa C, Carrington Mary, Goulder Philip J R,
Project Swiss HIV Cohort Study (SHCS)
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Original article (peer-reviewed)

Journal Journal of virology
Page(s) 1 - 1
Title of proceedings Journal of virology
DOI 10.1128/jvi.00544-17

Open Access

Abstract

Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, that protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env-specific (ERYLKDQQL, 'HLA-B*14-EL9'). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, 'HLA-B*14-DA9'). Using HLA-B*14/peptide-saporin conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (p<0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype-specific, applying only to HLA-B*14:02 and not HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although CTL play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLA associated with control of HIV in that the dominant CTL response is Env-specific, not Gag. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag, and strong Env-mediated selection pressure on HIV, are only observed in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects increased functional avidity of Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viraemic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.
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