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
Department of Paediatrics, University of Oxford, Oxford, United Kingdom
Harvard Medical School, Boston, Massachusetts, USA.
J Virol. 2017 Oct 27;91(22). doi: 10.1128/JVI.00544-17. Print 2017 Nov 15.
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-B14, which protects against HIV disease progression, but the immunodominant HLA-B14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B14-EL9). A subdominant HLA-B14-restricted response targets Gag (DRYFKTLRA, HLA-B14-DA9). Using HLA-B14/peptide-saporin-conjugated tetramers, we show that HLA-B14-EL9 is substantially more potent at inhibiting viral replication than HLA-B14-DA9. HLA-B14-EL9 also has significantly higher functional avidity ( < 0.0001) and drives stronger selection pressure on the virus than HLA-B14-DA9. However, these differences were HLA-B14 subtype specific, applying only to HLA-B14:02 and not to HLA-B14:01. Furthermore, the HLA-B14-associated protection against HIV disease progression is significantly greater for HLA-B14:02 than for HLA-B14:01, consistent with the superior antiviral efficacy of the HLA-B14-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. 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-B14, 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-B14-restricted activity is substantially more efficacious than the subdominant HLA-B14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B14:02, and not HLA-B14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B14:02. Finally, we show that HLA-B14:02 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.
人类免疫缺陷病毒1型（HIV）感染的免疫控制通常与有效的Gag特异性CD8 T细胞反应相关。我们在此聚焦于HLA - B14，它可预防HIV疾病进展，但免疫显性的HLA - B14限制性抗HIV反应是Env特异性的（ERYLKDQQL，HLA - B14 - EL9）。一种亚显性的HLA - B14限制性反应靶向Gag（DRYFKTLRA，HLA - B14 - DA9）。使用HLA - B14/肽 - 皂草素偶联四聚体，我们发现HLA - B14 - EL9在抑制病毒复制方面比HLA - B14 - DA9更有效。HLA - B14 - EL9的功能亲和力也显著更高（<0.0001），并且比HLA - B14 - DA9对病毒施加更强的选择压力。然而，这些差异是HLA - B14亚型特异性的，仅适用于HLA - B14:02而不适用于HLA - B14:01。此外，HLA - B14:02对HIV疾病进展的相关保护作用比对HLA - B14:01显著更大，这与HLA - B14 - EL9反应的卓越抗病毒功效一致。因此，尽管Gag特异性CD8 T细胞反应通常可能具有更大的抗HIV功效，但独立于蛋白质特异性的因素，包括个体反应的功能亲和力，对HIV的免疫控制也至关重要。在HIV感染中，尽管细胞毒性T淋巴细胞（CTL）在清除病毒储存库中可能发挥潜在关键作用，但构成有效反应的特征仍定义不清。我们聚焦于HLA - B14，在与HIV控制相关的HLA中它很独特，因为主要的CTL反应是Env特异性的，而非Gag特异性的。我们证明Env特异性的HLA - B14限制性活性比亚显性的HLA - B14限制性Gag反应更有效。仅在表达HLA - B14:02而非HLA - B*:01的受试者中观察到Env对Gag的免疫显性以及Env介导的对HIV的强大选择压力。这反映了Env反应相对于Gag反应功能亲和力的增加，对于HLA - B14:02更为显著。最后，我们表明HLA - B14:02与病毒血症控制的关联比HLA - B*14:01显著更强。这些发现表明，尽管Gag特异性CTL通常可能比Env反应具有更大的抗HIV功效，但独立于蛋白质特异性的因素，包括功能亲和力，在介导对HIV的有效控制中可能更具权重。
