High-Functional-Avidity Cytotoxic T Lymphocyte Responses to HLA-B-Restricted Gag-Derived Epitopes Associated with Relative HIV Control
High-Functional-Avidity Cytotoxic T Lymphocyte Responses to HLA-B-Restricted Gag-Derived Epitopes Associated with Relative HIV Control
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DOI：
10.1128/jvi.00460-11
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Brander, Christian
中科院分区：
文献类型：
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作者：
Berger, Christoph T.;Frahm, Nicole;Brander, Christian
具有高水平功能亲合力的病毒特异性细胞毒性T淋巴细胞（CTL）与丙型肝炎病毒感染中的病毒清除以及动物模型中增强的抗病毒保护性免疫相关。然而，功能亲合力作为HIV特异性CTL疗效的决定因素的作用仍有待评估。在这里，我们测量了HIV特异性CTL反应的功能亲和力，靶向20个不同的，最佳定义的CTL表位限制13个不同的HLA I类等位基因在一个队列中，包括44个HIV控制器和68个HIV非控制器。受HLA-B等位基因限制的应答和靶向位于HIV Gag中的表位的应答表现出显著高于受HLA-A或HLA-C分子限制的应答（P = 0.0003）或靶向Gag外部表位的应答（P < 0.0001）的功能亲合力。HIV控制者的GAG特异性和HLA-B限制性反应的功能亲和力高于非控制者（P = 0.014和P = 0.018），并且在启动抗逆转录病毒治疗的HIV非控制者中没有恢复。T细胞受体（TCR）分析显示，高亲和力CTL群体中的TCR谱系较窄，这些群体由HIV控制者中的公共TCR序列主导。总之，这些数据链接的存在下，高亲合力GAG特异性和HLA-B限制性CTL反应与体内病毒抑制，并提供了新的见解免疫参数介导的HIV感染的自发控制。
Virus-specific cytotoxic T lymphocytes (CTL) with high levels of functional avidity have been associated with viral clearance in hepatitis C virus infection and with enhanced antiviral protective immunity in animal models. However, the role of functional avidity as a determinant of HIV-specific CTL efficacy remains to be assessed. Here we measured the functional avidities of HIV-specific CTL responses targeting 20 different, optimally defined CTL epitopes restricted by 13 different HLA class I alleles in a cohort comprising 44 HIV controllers and 68 HIV noncontrollers. Responses restricted by HLA-B alleles and responses targeting epitopes located in HIV Gag exhibited significantly higher functional avidities than responses restricted by HLA-A or HLA-C molecules (P = 0.0003) or responses targeting epitopes outside Gag (P < 0.0001). The functional avidities of Gag-specific and HLA-B-restricted responses were higher in HIV controllers than in noncontrollers (P = 0.014 and P = 0.018) and were not restored in HIV noncontrollers initiating antiretroviral therapy. T-cell receptor (TCR) analyses revealed narrower TCR repertoires in higher-avidity CTL populations, which were dominated by public TCR sequences in HIV controllers. Together, these data link the presence of high-avidity Gag-specific and HLA-B-restricted CTL responses with viral suppression in vivo and provide new insights into the immune parameters that mediate spontaneous control of HIV infection.