Identifying, Characterizing and Inducing Effective Anti-HIV T Cell Responses

描述(由申请人提供)： 目前的候选HIV-1疫苗诱导的T细胞(I)具有有限的广度；即仅识别少数不同的表位；以及(Ii)主要针对HIV-1的可变区。此外，在急性HIV-1感染期间，拥有针对可变HIV-1表位的T细胞的个体比拥有针对保守的HIV-1表位的T细胞的个体进展得更快。这些数据支持这样的观点，即有效的基于T细胞的免疫原将只包含HIV-1的保守区域(保守的免疫原方法)。另一种方法(马赛克免疫原法)是设计包括多种变种的免疫原。这种方法的理论基础是，包括多个变异体将使人们能够对更广泛的循环变异体产生反应，并使免疫系统能够抵御常见的逃逸突变。这一建议试图检验这样一种假设，即保守性(由保守性分数衡量)而不是对非保守性表位的反应多样性与疫苗诱导的T细胞反应的有效性相关。这一假说将在以下三个具体目标中得到解决：1)评估针对保守的和可变的HIV-1表位在体外抑制病毒复制的T细胞的有效性；2)确定使用保守或镶嵌免疫原诱导的T细胞在自然HIV-1感染的背景下是否会被激活，并评估它们控制病毒复制的能力；以及3)确定HIV免疫原的片段化是否会通过增加缺陷核糖体产物(DIP)的表位池来增加诱导的T细胞反应的广度。这项建议将利用一种新的体外启动试验来预测候选疫苗接种后诱导T细胞将识别的表位特异性。这种试验可以作为其他候选T细胞免疫原的第一次筛选，只允许那些表现出最有希望的候选进入更昂贵的人类临床试验。拟议的研究对基于T细胞的HIV疫苗的设计具有深远的影响。确定疫苗接种诱导的有效抗病毒T细胞反应是由于(I)增加了被识别的HIV-1变异体的数量，还是(Ii)增加了特异性，使得只针对HIV-1的保守区域(或两者兼而有之)，这也将对开发针对其他高变异率的传染病的疫苗，如丙型肝炎病毒(HCV)。

DESCRIPTION (provided by applicant): Current candidate HIV-1 vaccines induce T cells that (i) possess restricted breadth; i.e. recognize only a few different epitopes; and (ii) predominantly target variable regions of HIV-1. Furthermore, during acute HIV-1 infection individuals who possess T cells targeting variable HIV-1 epitopes progress to disease faster than individuals possessing T cells targeting conserved HIV-1 epitopes. These data support the views that an effective T cell-based immunogen will contain only conserved regions of HIV-1 (the conserved immunogen approach). An alternative approach (the mosaic immunogen approach) has been to design immunogens to include multiple variants. This approach is based upon the theory that inclusion of multiple variants would enable responses to a broader range of circulating variants and could prime the immune system against common escape mutants. This proposal seeks to test the hypothesis that the conservation (as measured by conservation score) rather than the diversity of response against non-conserved epitopes correlates with effectiveness of vaccine-induced T cell responses. This hypothesis will be addressed in the following three Specific Aims: 1) To assess the effectiveness of T cells targeting conserved vs. variable HIV-1 epitopes to suppress viral replication in vitro, 2) To determine if T cells induced using conserved or mosaic immunogens will be activated in the context of natural HIV-1 infection and assess their ability to control viral replication; and 3) To determine if fragmentation of HIV immunogens will increase breadth of induced T cell response by increasing the pool of epitopes derived from defective ribosomal products (DRiPs). This proposal will utilize a novel in vitro priming assay to predict the epitope specificities that will be recognized by induced T cells upon vaccination with candidate vaccines. This assay could be used as a first screen of other candidate T cell based immunogens allowing only those candidates that show the most promise to move forward into more costly human clinical trials. The proposed studies have far reaching implications for design of T cell-based HIV vaccines. Determining whether effective anti-viral T cell responses induced by vaccination are due to (i) increasing the number of HIV-1 variants that are recognized or (ii) increasing specificity such that only conserved regions of HIV-1 are targeted (or both) will also have implications for the development of vaccines for other infectious organisms with high mutation rates e.g. Hepatitis C Virus (HCV).