MHC analogy and T-cell activation in SIV infection

描述（由申请人提供）：我们已经在人类和恒河猴中鉴定了一组类似的MHC分子。我们现在建议扩大这些分析，包括一个队列的中国恒河猴感染猴免疫缺陷病毒（SIV）。这些动物代表了一种独特的艾滋病感染模型，其中一部分受感染动物显示出长期非进展者（LTNP）的特征，类似于HIV感染的人类。我们建议评估这些动物是否表达影响疾病进展的等位基因，类似于HIV感染的人类。这些等位基因改变疾病进程的机制还有待确定。如果我们能够描述一个非人猕猴模型，模仿人类HIV感染中的HLA效应，我们可能能够对这些现象有一些了解。我们还将确定这些SIV感染的猕猴的T细胞活化概况，这在人类中也被证明对艾滋病的发展或阻碍其发展的能力有影响。因此，我们提出以下具体目标：具体目标1。为了确定在SIV感染中国恒河猴的背景下是否存在功能类似的MHC分子，我们将测试冷冻保存的或新鲜的外周血单核细胞对MHC分子的人类应答，这些MHC分子已被证明对AIDS的进展有影响。对这些表位具有应答的动物将具有其MHC等位基因序列，并进一步表征其作为类似MHC分子的潜力。具体目标2。使用细胞内抗体鉴定这些猕猴的T细胞活化特征。磷酸化状态通常是蛋白质的活化水平或状态的标志。了解这些级联如何受到SIV感染的影响，比较人类HIV-1感染的细胞与猕猴SIV感染的细胞的效果，更重要的是，为了这项资助的目的，比较LTNP，短期进展者和正常细胞的细胞，可以揭示疾病进展或/和易感性的重要步骤。这些研究将首次深入了解为什么有些动物比其他动物更快地发展为艾滋病，类似于艾滋病毒感染的人类。从这个模型中获得的信息将允许开发可能影响人类艾滋病进展的干预措施。项目叙述我们建议研究一组非人类灵长类动物，恒河猴，这已感染了猿猴免疫缺陷病毒（SIV）。这些动物代表了独特的AIDS感染模型，因为感染动物的子集显示出与HIV感染的人相似的长期非进展者（LTNP）的特征。我们建议评估这些动物是否表达影响疾病进展的免疫标志物。

DESCRIPTION (provided by applicant): We have identified sets of analogous MHC molecules in humans and rhesus macaques. We now propose to expand these analyses to include a cohort of Chinese rhesus macaques infected with Simian Immunodeficiency Virus (SIV). These animals represent a unique model of AIDS infection in that a subset of the infected animals displays characteristics of long-term non-progressors (LTNP), similar to HIV-infected humans. We propose to assess whether these animals express alleles which influence disease progression, similar to HIV- infected humans. It has yet to be determined the mechanism by which these alleles alter disease course. If we can characterize a non-human macaque model which mimics the HLA effect in human HIV infection, we may be able to gain some insight into these phenomena. We will also determine the T-cell activation profiles of these SIV-infected macaques, which in humans has also been shown to have an affect on the ability to progress or hinder the development of AIDS. Accordingly, we propose the following specific aims: Specific Aim 1. To determine whether functionally analogous MHC molecules exist in the context of SIV infection of Chinese rhesus macaques We will test cryopreserved or fresh peripheral blood mononuclear cells for human responses against MHC molecules which have been shown to have an impact on the progression to AIDS. The animals which have responses against these epitopes will have their MHC alleles sequences and characterized further for their potential to serve as analogous MHC molecules. Specific Aim 2. To identify the T-cell activation profile of these macaques using intracellular antibodies. The phosphorylation status is generally a signature of the activation level or status of the protein. Understanding how those cascades are affected by SIV infection, comparing the effect of human HIV-1-infected- versus macaque-SIV-infected cells, and more importantly for the aim of this grant, comparing cells from LTNPs, short-term progressors and normal cells, can reveal important steps in progression or/and susceptibility to disease. These studies will provide the first insight into why some animals progress to AIDS more rapidly than others, similar to HIV-infected humans. Information obtained from this model will allow for the development of interventions which may affect the progression to AIDS in humans. Project Narrative We propose to study a group of non-human primates, rhesus macaques, which have been infected with Simian Immunodeficiency Virus (SIV). These animals represent a unique model of AIDS infection in that a subset of the infected animals displays characteristics of long- term non-progressors (LTNP), similar to HIV-infected humans. We propose to assess whether these animals express immune markers which influence disease progression.