HIV-1 adaptation to HLA-restricted immune responses

描述（由申请人提供）：HIV-1具有通过逃避人类白细胞抗原（HLA）识别介导的细胞毒性T淋巴细胞（CTL）反应来适应个体人类宿主的显著能力。尽管HLA类型是高度多态性的，并且在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CD4 T辅助细胞）的反应。在这里，在人群水平上对hla驱动的适应的研究将用于了解HIV-1感染个体中HIV-1疾病严重程度的决定因素，并指导设计最有效地克服HIV-1在人群中的适应性的疫苗。具体目标是：1)在（宿主）群体水平上表征HIV-1对HLA的适应，以在具有代表美国人群的HLA和病毒多样性的大型药物初始队列中识别全长HIV-1序列的免疫逃逸/适应；2)将hla驱动的适应与病毒载量相关联；3)确定hla驱动适应和病毒载量的免疫学和病毒学决定因素。hla相关选择位点将标记出免疫应答的体内表位靶标，这些位点上逃逸的病毒载量效应可作为衡量宿主免疫压力和每一特定逃逸/适应所特有的突变遗传屏障之间平衡的定量指标。这些信息将用于(i)将体内HLA i类选择效应与体外CTL反应相关联（ii）定义新的CTL和CD4 T辅助表位（ii）测量有利于或减轻特定适应性的T细胞的大小、表型和T细胞受体（TCR）特征（iii）测量限制这些位点免疫选择的复制适应性成本；4)设计“人群优化”的HIV-1疫苗。这些结果将用于确定由一种给定疫苗诱导的免疫反应如何识别在那些对研究队列中流行的HLA类型最关键的表位上的不同的、可变的HLA适应的HIV-1毒株。

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.