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.

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。我们在这里重点关注 HLA-B*14，它可以防止 HIV 疾病进展，但免疫显性 HLA-B*14 限制性抗 HIV 反应是 Env 特异性的（ERYLKDQQL、HLA-B*14-EL9）。次显性 HLA-B*14 限制性反应以 Gag（DRYFKTLRA、HLA-B*14-DA9）为目标。使用 HLA-B*14/肽皂草素缀合的四聚体，我们表明 HLA-B*14-EL9 在抑制病毒复制方面比 HLA-B*14-DA9 更有效。 HLA-B*14-EL9 还具有显着更高的功能亲和力 ( P < 0.0001)，并且比 HLA-B*14-DA9 对病毒产生更强的选择压力。然而，这些差异是 HLA-B*14 亚型特异性的，仅适用于 HLA-B*14:02，不适用于 HLA-B*14:01。此外，HLA-B*14:02 与 HLA-B*14 相关的针对 HIV 疾病进展的保护作用显着高于 HLA-B*14:01，这与 HLA-B*14- 的卓越抗病毒功效一致。 EL9 响应。因此，虽然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，对于HIV的免疫控制也至关重要。

重要性在 HIV 感染中，尽管细胞毒性 T 淋巴细胞 (CTL) 在根除病毒储库方面发挥着潜在的关键作用，但构成有效反应的特征仍然不明确。我们重点关注 HLA-B*14，它在与 HIV 控制相关的 HLA 中是独一无二的，因为主要的 CTL 反应是 Env 特异性的，而不是 Gag 特异性的。我们证明 Env 特异性 HLA-B*14 限制性活性比次显性 HLA-B*14 限制性 Gag 反应更有效。仅在表达 HLA-B*14:02 的受试者中观察到 Env 相对于 Gag 的免疫优势以及 Env 介导的对 HIV 的强烈选择压力，而不是在表达 HLA-B*14:01 的受试者中观察到。这反映了 Env 反应的功能亲合力比 Gag 更高，对于 HLA-B*14:02 来说更为明显。最后，我们发现 HLA-B*14:02 与病毒血症控制的相关性明显强于 HLA-B*14:01。这些发现表明，虽然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，可能在介导有效控制HIV方面发挥更大的作用。