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