MHC analogy and T-cell activation in SIV infection

SIV 感染中的 MHC 类比和 T 细胞激活

• 批准号: 7494893
• 负责人: Bianca Romina Mothe
• 金额: $ 23.45万
• 依托单位: CALIFORNIA STATE UNIVERSITY SAN MARCOS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494893
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Alleles; Animals; Antibodies; Binding; Biological Assay; California; Cells; Characteristics; Chinese People; Data; Development; Disease; Disease Progression; Epitopes; Freezing; Grant; HIV; HIV Infections; Human; Immune response; Immunologic Markers; In Vitro; Infection; Influenza; Length; Macaca; Macaca mulatta; Major Histocompatibility Complex; Modeling; Normal Cell; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Phosphorylation; Predisposition; Primates; Proteins; Research; SIV; Sampling; Scientist; Signal Transduction; Specimen; Students; T-Cell Activation; T-Lymphocyte; Testing; Universities; Virus Diseases; Work; base; cohort; cross reactivity; insight; nonhuman primate; response; therapy development

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.

描述（由申请人提供）：我们已经确定了人类和恒河猴中类似的MHC分子。我们现在建议将这些分析扩展到感染猴免疫缺陷病毒（SIV）的中国恒河猴队列。这些动物代表了一种独特的艾滋病感染模型，因为受感染动物的一个子集表现出长期不进展（LTNP）的特征，类似于艾滋病毒感染者。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HIV的人类。这些等位基因改变疾病进程的机制尚未确定。如果我们能够描述一种非人类猕猴模型的特征，这种模型模仿人类HIV感染中的HLA效应，我们可能能够对这些现象有一些深入的了解。我们还将确定这些siv感染的猕猴的t细胞激活谱，这在人类中也被证明对艾滋病进展或阻碍发展的能力有影响。为此，我们提出以下具体目标：为了确定中国恒河猴SIV感染中是否存在功能类似的MHC分子，我们将测试冷冻保存或新鲜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具有它们的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。具体目标2。利用细胞内抗体鉴定这些猕猴的t细胞活化谱。磷酸化状态通常是蛋白质激活水平或状态的标志。了解这些级联如何受到SIV感染的影响，比较人类hiv -1感染细胞与猕猴SIV感染细胞的影响，以及更重要的是，比较ltnp细胞、短期进展细胞和正常细胞，可以揭示疾病进展或/和易感性的重要步骤。这些研究将首次揭示为什么有些动物比其他动物更快地患上艾滋病，就像感染艾滋病毒的人类一样。从该模型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。我们拟研究一组感染猴免疫缺陷病毒（SIV）的非人类灵长类动物恒河猴。这些动物代表了一种独特的艾滋病感染模型，因为受感染动物的一个子集表现出长期不进展（LTNP）的特征，类似于hiv感染者。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。