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

描述(由申请人提供)： 人类免疫缺陷病毒(HLAI)类限制性CTL表位的杂乱呈现被认为是机体抵抗HIV感染的重要手段，许多HLAI等位基因与HIV疾病进展缓慢或快速相关。尽管在这一领域取得了一些重大进展，但人类白细胞抗原I类等位基因介导其有益或有害影响的机制仍不清楚，可能包括多种因素，如多肽结合、靶向病毒序列的可变性、抗原处理和病毒抗原表达的动力学。来自小鼠研究的最新数据也将T细胞受体(TCR)谱系的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，这些分析显示了不同的TCR谱系多样性，这取决于呈现目标表位的MHC等位基因，并表明TCR谱系较窄与功能亲和力低且无法控制病毒复制的CTL反应有关。基于这些最新报道和我们自己的大量初步最新数据，本提案旨在识别HIV编码的、混杂结合的CTL表位，这些表位可以由与HIV疾病进展不同的HLA等位基因呈现，并评估这些CTL反应的功能亲和力和TCR谱系多样性，这取决于呈现表位的等位基因。然后，将功能亲和力和TCR谱系多样性与CTL有效识别自然发生的病毒表位变异并推动病毒进化的能力联系起来，以响应免疫选择压力，免疫选择压力是由与枯萎的疾病进展快或慢相关的等位基因的表位呈现所介导的。将重点放在混杂结合的CTL表位上，在过去限制了类似分析的一些混杂影响的情况下，可以评估TCR谱系多样性、功能亲和力和艾滋病毒疾病进展率之间的潜在关联。新出现的数据将对艾滋病毒疫苗的开发具有重要意义，并有助于确定保护性艾滋病毒免疫的真正免疫相关因素。

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.