DEFINING THE IMPORTANCE OF CD8+ T CELL BREADTH IN SIV/HIV PROTECTIVE IMMUNITY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目的：了解宽度在CD 8 + T细胞抗HIV和SIV免疫中的重要性。大量证据表明，CD 8 + T细胞在SIV/HIV的控制中是重要的。 STEP Trail疫苗旨在诱导HIV特异性CD 8 + T细胞;然而，该试验在2007年因未能预防HIV感染而停止。这种疫苗的失败可能部分是由于不能引起CD 8 + T细胞的广泛特异性。我们正在用SIVmac 239挑战纯合子和杂合子动物，并密切关注这些动物中的SIV发病机制，以确定CD 8 + T细胞宽度是否是HIV控制的重要组成部分。在具体的目标1中，我们将检查是否两个常见的MHC单倍型杂合的猕猴将控制SIV更有效地比动物纯合的单倍型。为了完成这一目标，将用SIVmac 239感染18只动物，每种遗传背景6只。在具体目标2中，我们将通过用一种缺乏来自单倍型之一的表位的病毒感染动物来检查降低潜在的CD 8 + T细胞应答的宽度是否增加SIV的致病性。在具体目标3中，我们将定义CD 8 + T细胞宽度对减毒活疫苗通过用具体目标2的病毒攻击接种动物而提供的保护的影响。我们目前正在完成具体目标1。我们用SIVmac 239感染了18只动物，并监测这些动物的病毒载量，CD 4计数以及CD 8 T细胞反应的大小和焦点的差异。目前正在利用目前收集的数据编写两份可能的手稿。我们还启动了具体目标2，开始工作，创造将用于该目标的病毒。这项研究使用了WNPRC动物服务，免疫学和病毒学服务，研究计算和遗传学服务。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To understand the importance of breadth in CD8+ T cell immunity against HIV and SIV. Numerous lines of evidence suggest CD8+ T cells are important in the control of SIV/HIV. The STEP Trail vaccine was designed to elicit HIV-specific CD8+ T cells; however this trial was halted in 2007 after a failure to protect against HIV infection. It is possible that the failure of this vaccine is due, in part, to an inability to elicit a broad specificity of CD8+ T cells. We are challenging homozygous and heterozygous animals with SIVmac239 and closely following SIV-pathogenesis in these animals in order to determine whether CD8+ T cell breadth is an important component of HIV control. In specific aim 1 we will examine whether Mauritian cynomolgus macaques heterozygous for two common MHC haplotypes will control SIV more effectively than animals homozygous for either of the haplotypes. In order to complete this aim, 18 animals, six of each genetic background, will be infected with SIVmac239. In specific aim 2 we will examine whether reducing the breadth of potential CD8+ T cell responses increases the pathogenicity of SIV by infected animals with a virus that is depleted of epitopes from one of the haplotypes. In specific aim 3 we will define the impact of CD8+ T cell breadth to the protection afforded by live attenuated vaccines by challenging vaccinated animals with the virus from specific aim 2. We are currently in the process of completing specific aim 1. We have infected 18 animals with SIVmac239 and are monitoring these animals for differences in viral loads, CD4 counts, and the size and focus of their CD8 T cell response. Two potential manuscripts are being prepared with currently gathered data. We have also initiated specific aim 2 by beginning work to create the virus that will be used in that aim. This research used WNPRC Animal Services, Immunology & Virology Services, Research computing and Genetics Services.