Functional genomic analysis of the CD8 T cell response to HIV vaccines in

描述（由申请人提供）：开发有效的艾滋病毒疫苗是全球最大的健康挑战之一。然而，尽管经过几十年的研究，还没有疫苗能够引起对艾滋病毒的保护性免疫。最近，开发针对HIV的疫苗的努力集中在优化T细胞对疫苗接种的应答，因为T细胞免疫与HIV中的病毒控制之间存在关联。然而，最佳CD 8 T细胞对疫苗接种的反应的分子相关性仍不清楚。本研究将使用功能基因组学、细胞免疫学和动物模型来确定疫苗接种后最佳CD 8 T细胞功能的分子特征。 在目标1中，我们将产生目前临床开发的三种HIV疫苗引起的四聚体分选的HIV特异性CD 8 T细胞的全基因组表达谱。我们将比较这些HIV特异性CD 8特征与抗原特异性CD 8 T细胞对牛痘病毒（VV）疫苗的反应-这是有史以来最成功的疫苗之一。我们将确定每种疫苗所特有的基因模式和这些疫苗所共有的特征，如VV，诱导高功能的CD 8 T细胞。将使用详细的计算分析来鉴定赋予每种疫苗诱导的CD 8 T细胞应答不同功能属性的候选机制。这将是疫苗诱导的抗原特异性CD 8 T细胞的第一次全面的转录分析，并将鉴定高功能CD 8 T细胞的新分子相关物。 越来越多的数据表明，腺病毒（Ad 5）载体的疫苗诱导的CD 8 T细胞的功能有限。在目标2中，我们将检验以下假设：在CD 8 T细胞中响应于Ad 5载体免疫原的基因上调有助于其次优功能。基于我们在小鼠模型中的研究，并补充来自Aim 1的新数据，我们将使用功能基因组方法评估多达96个候选调节基因在Ad 5/HIV诱导的CD 8 T细胞中的作用。一系列高度平行的过表达研究和RNAi介导的敲低实验将验证候选基因在人CD 8 T细胞和Ad 5疫苗接种的小鼠模型中作为抑制分子的作用。拟议的研究将通过发现最佳疫苗诱导的T细胞免疫的新相关性，并确定疫苗接种后控制CD 8 T细胞功能的机制，加速HIV疫苗的开发。

DESCRIPTION (provided by applicant): The development of an effective HIV vaccine is one of the greatest global health challenges. However despite decades of research, no vaccine has yet been able to elicit protective immunity to HIV. Recently, efforts to develop vaccines against HIV have focused on optimizing the T cell response to vaccination because of the association between T cell immunity and viral control in HIV. However, the molecular correlates of an optimal CD8 T cell response to vaccination remain unclear. This investigation will identify the molecular characteristics of optimal CD8 T cell function after vaccination, using functional genomics, cellular immunology and animal models. In Aim 1, we will generate genome-wide expression profiles of tetramer-sorted HIV-specific CD8 T cells elicited by three HIV vaccines in current clinical development. We will compare these HIV-specific CD8 profiles to antigen-specific CD8 T cells responding to vaccines against vaccinia virus (VV) - one of the most successful vaccines ever developed. We will identify patterns of genes that are unique to each type of vaccine and signatures that are common to those vaccines, such VV, that induce highly functional CD8 T cells. Candidate mechanisms that confer different functional attributes to each vaccine-induced CD8 T cell response will be identified using detailed computational analyses. This will be the first comprehensive transcriptional analysis of vaccine-induced antigen-specific CD8 T cells, and will identify new molecular correlates of highly functional CD8 T cells. Increasing data suggest that adenovirus (Ad5) vectored vaccines elicit CD8 T cells with limited functionality. In Aim 2 we will test the hypothesis that genes upregulated in CD8 T cells responding to Ad5-vectored immunogens contribute to their sub-optimal function. Based on our studies in a mouse model, and supplemented with new data from Aim 1, we will evaluate the role of up to 96 candidate regulator genes that are increased in Ad5/HIV-induced CD8 T cells using functional genomic approaches. A series of highly parallel over-expression studies and RNAi-mediated knockdown experiments will validate the role of candidate genes as inhibitory molecules in human CD8 T cells and in a mouse model of Ad5 vaccination. The proposed studies will accelerate HIV vaccine development by discovering new correlates of optimal vaccine-induced T cell immunity, and identifying the mechanisms that govern CD8 T cell function after vaccination.