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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.

HLA-B*14:02-Restricted Env-Specific CD8(+) T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection.
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Leitman EM, Willberg CB, Tsai MH, Chen H, Buus S, Chen F, Riddell L, Haas D, Fellay J, Goedert JJ, Piechocka-Trocha A, Walker BD, Martin J, Deeks S, Wolinsky SM, Martinson J, Martin M, Qi Y, Sáez-Cirión A, Yang OO, Matthews PC, Carrington M, Goulder PJR,


Leitman EM, Willberg CB, Tsai MH, Chen H, Buus S, Chen F, Riddell L, Haas D, Fellay J, Goedert JJ, Piechocka-Trocha A, Walker BD, Martin J, Deeks S, Wolinsky SM, Martinson J, Martin M, Qi Y, Sáez-Cirión A, Yang OO, Matthews PC, Carrington M, Goulder PJR, (click to view)

Leitman EM, Willberg CB, Tsai MH, Chen H, Buus S, Chen F, Riddell L, Haas D, Fellay J, Goedert JJ, Piechocka-Trocha A, Walker BD, Martin J, Deeks S, Wolinsky SM, Martinson J, Martin M, Qi Y, Sáez-Cirión A, Yang OO, Matthews PC, Carrington M, Goulder PJR,

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Journal of virology 2017 10 2791(22) pii 10.1128/JVI.00544-17

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, which 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 to 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 cytotoxic T lymphocytes (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 HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. 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 observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the 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 viremic 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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