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

描述（由申请人提供）： 目前候选的 HIV-1 疫苗诱导的 T 细胞 (i) 宽度有限；即仅识别几个不同的表位； (ii) 主要针对 HIV-1 的可变区域。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HIV-1表位的T细胞的个体更快地患病。这些数据支持以下观点：有效的基于 T 细胞的免疫原将仅包含 HIV-1 的保守区域（保守免疫原方法）。另一种方法（嵌合免疫原方法）是设计包含多种变体的免疫原。这种方法基于这样的理论：包含多个变体将能够对更广泛的循环变体做出反应，并可以启动免疫系统对抗常见的逃逸突变体。该提案旨在检验以下假设：与疫苗诱导 T 细胞反应的有效性相关的是保守性（通过保守性评分衡量），而不是针对非保守表位的反应多样性。这一假设将在以下三个具体目标中得到解决：1) 评估 T 细胞靶向保守与可变 HIV-1 表位以抑制体外病毒复制的有效性，2) 确定使用保守或嵌合免疫原诱导的 T 细胞是否会在自然 HIV-1 感染的情况下被激活，并评估其控制病毒复制的能力； 3) 确定 HIV 免疫原的片段化是否会通过增加源自缺陷核糖体产物 (DRiP) 的表位库来增加诱导 T 细胞反应的广度。该提案将利用一种新型体外引发测定来预测候选疫苗接种后诱导 T 细胞将识别的表位特异性。该测定可用作其他候选 T 细胞免疫原的首次筛选，仅允许那些最有希望进入更昂贵的人体临床试验的候选者。拟议的研究对于基于 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 细胞反应是否是由于 (i) 增加了已识别的 HIV-1 变体的数量或 (ii) 增加了特异性，从而仅针对 HIV-1 的保守区域（或两者兼而有之），这也将对开发针对具有高突变率的其他传染性生物体的疫苗产生影响。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).