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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：了解广度在CD8+T细胞抗HIV和SIV免疫中的重要性。大量证据表明，CD8+T细胞在SIV/HIV的控制中起着重要作用。 Step Trail疫苗旨在诱导HIV特异性CD8+T细胞；然而，由于未能预防HIV感染，这项试验于2007年停止。这种疫苗的失败可能部分是由于无法诱导CD8+T细胞的广泛特异性。我们正在用SIVmac239挑战纯合子和杂合子动物，并密切关注这些动物的SIV发病机制，以确定CD8+T细胞宽度是否是HIV控制的重要组成部分。在具体目标1中，我们将研究两种常见MHC单倍型杂合的毛里求斯食蟹猴是否会比任何一种单倍型纯合的毛里求斯食蟹猴更有效地控制SIV。为了完成这一目标，18只动物，每种遗传背景6只，将感染SIVmac239。在特定目标2中，我们将研究减少潜在CD8+T细胞反应的广度是否会增加感染SIV的动物的致病性，这种病毒缺乏其中一种单倍型的表位。在特定目标3中，我们将确定CD8+T细胞的广度对减毒活疫苗提供的保护的影响，方法是从特定目标2用病毒攻击接种的动物。我们目前正在完成特定目标1的过程。我们已经感染了18只动物SIVmac239，并正在监测这些动物在病毒载量、CD4计数以及CD8 T细胞反应的大小和焦点方面的差异。目前正在用目前收集的数据准备两份潜在的手稿。我们还启动了具体目标2，开始创建将用于这一目标的病毒。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.