Promiscuous presentation of HLA class I restricted, HIV derived CTL epitopes

描述（由申请人提供）： CTL介导的细胞免疫被认为是宿主防御HIV感染的重要手段，并且许多HLA I类等位基因与缓慢或快速的HIV疾病进展相关。尽管在该领域取得了一些重大进展，但HLA I类等位基因介导其有益或有害作用的机制仍不清楚，可能包括多种因素，如肽结合、靶向病毒序列的变异性、抗原加工和病毒抗原表达的动力学。最近的鼠研究数据也将T细胞受体（TCR）库多样性与病毒感染的相对控制联系起来。比较呈现相同表位的密切相关的MHC分子，这些分析揭示了不同的TCR库多样性，这取决于哪个MHC等位基因呈现靶向表位，并表明窄的TCR库与低功能亲合力和不能控制病毒复制的CTL应答相关。基于这些最近的报告和我们自己的，广泛的初步最近的数据，本提案的目的是确定HIV编码的，混杂结合的CTL表位，可以提出的HLA等位基因差异与HIV疾病的进展，并评估这些CTL反应的功能亲合力和TCR库的多样性，这取决于哪个等位基因的表位。然后将功能亲合力和TCR库多样性与CTL有效识别天然存在的病毒表位变体的能力以及响应于由与枯萎快速或缓慢疾病进展相关的等位基因上的表位呈递介导的免疫选择压力而驱动病毒进化的能力相关联。聚焦于混杂结合的CTL表位，TCR库多样性、功能亲合力和HIV疾病进展速率之间的潜在关联可以在不存在许多混淆效应的情况下进行评估，这些混淆效应限制了过去的类似分析。新出现的数据将对HIV疫苗开发具有重要意义，并有助于识别保护性HIV免疫的真正免疫相关性。

DESCRIPTION (provided by applicant): Promiscuous presentation of HLA class I restricted, HIV derived CTL epitopes CTL mediated cellular immunity is considered an important arm of the host defense against HIV infection and a number of HLA class I alleles have been associated with slow or fast HIV disease progression. Despite some significant advances in the field, the mechanisms by which HLA class I alleles mediate their beneficial or detrimental effects, are still unclear and may include multiple factors such as peptide binding, variability of targeted viral sequences, antigen processing and the kinetics of viral antigen expression. Recent data from murine studies have also linked T-cell receptor (TCR) repertoire diversity with relative control of viral infections. Comparing closely related MHC molecules presenting the identical epitope, these analyses revealed different TCR repertoire diversity depending on which MHC allele presented the targeted epitope and indicated that a narrow TCR repertoire was associated with CTL responses of low functional avidity and inability to control viral replication. Based on these recent reports and our own, extensive preliminary recent data, the present proposal aims to identify HIV encoded, promiscuously binding CTL epitopes that can be presented by HLA alleles differentially associated with HIV disease progression and to assess the functional avidity and TCR repertoire diversity of these CTL responses, depending on which allele the epitope is presented. Functional avidity and TCR repertoire diversity are then put in relation with the CTL's ability to efficiently recognize naturally occurring viral epitope variants and to drive viral evolution in response to immune selection pressure mediated by epitope presentation on alleles associated with wither fast or slow disease progression. Focusing on promiscuously binding CTL epitopes, the potential association between TCR repertoire diversity, functional avidity and rate of HIV disease progression can be assessed in the absence of a number of confounding effects that have limited similar analyses in the past. The emerging data will be of significant importance for HIV vaccine development and help the identification of true immune correlates of protective HIV immunity.