HIV-1 adaptation to HLA-restricted immune responses

描述(申请人提供)：HIV-1通过逃避人类白细胞抗原(HL A)识别介导的细胞毒性T淋巴细胞(CTL)反应，具有显著的适应单个人类宿主的能力。虽然人类白细胞抗原类型具有高度的多态，并且病毒有特定部位的功能改变，但HIV-1似乎通过基因突变逃脱了人类白细胞抗原限制的CTL(以及可能的CD4T辅助细胞)反应。在这里，人类白细胞抗原在人群水平上的适应性研究将被用来了解HIV-1感染者中HIV-1疾病严重程度的决定因素，并指导疫苗的设计，以最有效地克服HIV-1在人类人群中的适应性。其具体目的是：1)在(宿主)人群水平上表征HIV-1对人类白细胞抗原的适应，以确定在具有代表美国人群的人类白细胞抗原和病毒多样性的大型药物初治队列中，全长艾滋病毒-1序列的免疫逃逸/适应；2)将人类白细胞抗原驱动的适应与病毒载量联系起来；3)确定人类白细胞抗原驱动的适应和病毒载量的免疫学和病毒学决定因素。人类白细胞抗原相关的选择位点将标记出体内免疫反应的表位靶点，这些位点上逃逸的病毒载量效应可定量衡量宿主免疫压力和对每个特定逃逸/适应所特有的突变的遗传屏障之间的平衡。这些信息将被用来(I)将体内HLAI类选择效应与检测的体外CTL反应相关联(Ii)定义新的CTL和CD4T辅助表位(Ii)测量有利于或减轻特定适应的T细胞的大小、表型和T细胞受体(TCR)特征，以及(Iii)测量限制这些部位免疫选择的复制适应性成本；4)设计一种“种群优化的”HIV-1疫苗。这些结果将被用来确定给定疫苗诱导的免疫反应在多大程度上识别对研究队列中流行的HLA型最关键的表位上不同的、不同的、适应于HLA1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.