HIV-1 adaptation to HLA-restricted immune responses

描述（由申请人提供）：HIV-1通过逃避由人白细胞抗原（HLA）识别介导的细胞毒性T淋巴细胞（CTL）应答，具有适应个体人类宿主的显著能力。虽然HLA类型是高度多态性的，并且病毒中存在位点特异性功能限制，但HIV-1似乎通过基因突变逃避HLA限制性CTL（可能还有CD 4 T辅助细胞）反应。在这里，研究人类白细胞抗原驱动的适应在人口水平上将被用来了解HIV-1感染者的HIV-1疾病严重程度的决定因素，并指导设计一种疫苗，最有效地克服HIV-1在人群中的适应性。具体目标是：1）在（宿主）群体水平表征HIV-I对HLA的适应，以在具有代表美国群体的HLA和病毒多样性的大型未用药队列中跨全长HIV-I序列鉴定免疫逃逸/适应; 2）将HLA驱动的适应与病毒载量相关联; 3）确定HLA驱动的适应和病毒载量的免疫学和病毒学决定因素。HLA相关选择的位点将标记出免疫应答的体内表位靶标，并且在这些位点处逃逸的病毒载量效应用作宿主免疫压力与对每种特定逃逸/适应所特有的突变的遗传屏障之间的平衡的定量测量。该信息将用于（i）将体内HLA I类选择效应与测定的离体CTL应答相关联（ii）定义新的CTL和CD 4 T辅助表位（ii）测量有利于或减轻特异性适应的T细胞的大小、表型和T细胞受体（TCR）特征，以及（iii）测量限制这些位点处的免疫选择的复制适应性成本; 4.设计一种“人群优化”的HIV-1疫苗。这些结果将用于确定给定疫苗诱导的免疫应答在多大程度上能够识别不同的、HLA适应的HIV-1毒株，这些毒株位于对研究队列的流行HLA类型最关键的表位。

DESCRIPTION (provided by applicant): HIV-1 has a remarkable capacity to adapt to individual human hosts by escaping cytotoxic T lymphocyte (CTL) responses mediated by human leukocyte antigen (HLA) recognition. Though HLA types are highly polymorphic, and there is site-specific functional constraint to change in the virus, HIV-1 appears to escape HLA-restricted CTL (and possibly CD4 T helper cell) responses by genetic mutation. Here, the study of HLA-driven adaptation at a population level will be used to understand determinants of HIV-1 disease severity in the HIV-1 infected individual and to guide design of a vaccine that would most effectively overcome the adaptability of HIV-1 in human populations. The specific aims are to: 1) Characterize HIV-1 adaptation to HLA at a (host) population level to identify immune escape/adaptations across full length HIV-1 sequences in a large drug-naive cohort that has HLA and viral diversity representative of populations in the US; 2) Correlate HLA-driven adaptation to viral load; 3) Determine immunological and virological determinants of HLA-driven adaptation and viral load. The sites of HLA-associated selection will mark out in vivo epitope targets of immune responses and the viral load effects of escape at these sites serve as a quantitative measure of the balance between host immune pressure and genetic barrier to mutation unique to every specific escape/adaptation. The information will be used to (i) correlate in-vivo HLA class I selection effects with assayed ex-vivo CTL responses (ii) define novel CTL and CD4 T helper epitopes (ii) measure magnitude, phenotype and T cell receptor (TCR) characteristics of T cells that favour or mitigate specific adaptations and (iii) measure the replicative fitness cost that constrains immune selection at these sites; 4) Design a 'population-optimised' HIV-1 vaccine. The results will be used to determine how well the immune responses induced by a given vaccine would recognise diverse, variably HLA-adapted HIV-1 strains at those epitopes most critical for the prevalent HLA types of the study cohort.