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出几组类似的MHC分子。我们现在建议将这些分析扩大到包括一组感染了猿猴免疫缺陷病毒(SIV)的中国恒河猴。这些动物代表了艾滋病感染的一种独特模式，因为受感染动物的一部分表现出长期非进展性(LTNP)的特征，类似于感染艾滋病毒的人类。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，类似于感染艾滋病毒的人类。这些等位基因改变病程的机制尚未确定。如果我们能够描述一个非人类猕猴模型，它模仿了人类HIV感染中的HLA效应，我们或许能够对这些现象有一些了解。我们还将确定这些感染SIV的猕猴的T细胞激活情况，这在人类中也被证明对艾滋病的进展或阻碍发展的能力有影响。因此，我们提出以下特定目标：特定目标1.为了确定在中国猕猴SIV感染的背景下是否存在功能相似的MHC分子，我们将测试冷冻保存的或新鲜的外周血单个核细胞对MHC分子的反应，这些分子已被证明对艾滋病的进展有影响。对这些表位有反应的动物将获得它们的MHC等位基因序列，并进一步表征它们作为类似MHC分子的潜力。具体目的2.使用细胞内抗体鉴定这些猕猴的T细胞激活模式。磷酸化状态通常是蛋白质激活程度或状态的标志。了解SIV感染是如何影响这些级联反应的，比较人类HIV-1感染细胞和猕猴SIV感染细胞的影响，更重要的是，为了这笔赠款的目的，比较来自LTNPs的细胞、短期进展者和正常细胞，可以揭示疾病进展或/和易感性的重要步骤。这些研究将提供第一个洞察，了解为什么一些动物比其他动物更快地发展为艾滋病，类似于感染艾滋病毒的人类。从该模型获得的信息将允许开发可能影响人类发展为艾滋病的干预措施。项目简介我们计划研究一组感染了猿猴免疫缺陷病毒(SIV)的非人灵长类动物--恒河猴。这些动物代表了艾滋病感染的一种独特模式，因为受感染动物的一部分表现出长期非进展性(LTNP)的特征，类似于感染艾滋病毒的人类。我们建议评估这些动物是否表达影响疾病进展的免疫标记物。

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.