CORRELATES OF ELITE CONTROL OF SIV

精英控制 SIV 的相关性

• 批准号: 8173110
• 负责人: Thomas C. Friedrich
• 金额: $ 5.16万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173110
• 关键词: Accounting; Alleles; Animals; Biological Assay; CD8B1 gene; Cells; Coculture Techniques; Computer Retrieval of Information on Scientific Projects Database; Containment; Defect; Epitopes; Funding; Genetic Services; Grant; Growth; HIV; HIV Infections; Human; Immune; Immune response; Immunology; Individual; Institution; Intravenous; MHC Class I Genes; Macaca; Manuscripts; Mutation; Peptides; Play; Preparation; Proteins; Research; Research Personnel; Resources; Role; SIV; Series; Services; Source; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; United States National Institutes of Health; Vaccinated; Viral; Viremia; Virus; cohort; cost; fitness; interest; mutant; novel; superinfection; virology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To understand the "correlates of control" in macaque elite controllers (ECs). The "correlates of protection," i.e., the immune responses which will protect vaccinated individuals against HIV infection, are unknown. Because of this, there is intense interest in studying "elite controllers" (ECs), rare individuals who spontaneously control HIV replication. Over the past few years we have assembled a cohort of elite controller macaques that resemble human ECs in several important respects. This project is aimed at understanding the "correlates of control" in these macaque ECs. Previously we showed that elite control in our macaque cohort was associated with expression of particular MHC class I (MHC-I) alleles, Mamu-B*17 and Mamu-B*08. Strikingly, all macaque elite controllers in our cohort express at least one of these alleles. These proteins present peptide "epitopes" derived from SIV proteins to CD8+ T cells, "flagging" infected cells for destruction. Since Mamu-B*17 and B*08 play a role in the cellular immune response, we therefore hypothesized that the specific CD8+ T cell responses made by animals expressing these proteins made it possible for them to become ECs. This project has therefore probed the contribution of CD8+ T cell responses, particularly those "restricted" by Mamu-B*17 and B*08, to immune containment of SIV in macaque ECs. To our surprise, we recently found no apparent differences in either the strength of immune responses or number of viral epitopes recognized in ECs and progressors. To determine more directly whether particular CD8+ T cell responses enable Mamu-B*17-positive ECs to control SIV replication, we constructed a series of SIVmac239 derivatives bearing mutations in combinations of Mamu-B*17-restricted epitopes. We reasoned that one or more of these mutant viruses would cause breakthrough viremia in Mamu-B*17-positive ECs after intravenous inoculation. Again to our surprise, we found that ECs resisted superinfection, even with a virus bearing mutations in all 5 CD8+ T cell epitopes that constitute the Mamu-B*17-restricted repertoire. We devised a novel competing coculture assay to test the replicative capacity of these mutant viruses, which showed that the epitope mutations exact negligible costs to viral fitness, suggesting that growth defects cannot account for the ability of ECs to control the epitope mutant viruses. A manuscript describing these results is currently in preparation. This research used WNPRC Animal Services, Genetics Services, and Immunology & Virology Services.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目的：了解猕猴精英控制器（EC）中的“控制相关性”。 “保护的相关性”，即保护疫苗接种个体免受艾滋病毒感染的免疫反应是未知的。 因此，对研究“精英控制者”（EC），自发控制艾滋病毒复制的罕见个体有强烈的兴趣。 在过去的几年中，我们组装了一系列精英控制器猕猴，在几个重要方面都与人类EC相似。 该项目旨在了解这些猕猴EC中的“控制相关性”。 以前我们表明，猕猴队列中的精英控制与特定MHC I类（MHC-I）等位基因，Mamu-B*17和Mamu-B*08的表达有关。 令人惊讶的是，我们同类中的所有猕猴精英控制器至少表达这些等位基因之一。 这些蛋白质呈现从SIV蛋白到CD8+ T细胞的肽“表位”，它标记为“感染”细胞进行破坏。 由于MAMU-B*17和B*08在细胞免疫反应中起作用，因此我们假设表达这些蛋白质的动物产生的特定CD8+ T细胞反应使它们成为可能成为EC。 因此，该项目探讨了CD8+ T细胞反应的贡献，尤其是Mamu-B*17和B*08的“限制”对猕猴EC中SIV的免疫遏制的贡献。 令我们惊讶的是，最近我们发现在EC和进步者中识别的免疫反应强度或病毒表位数量上没有明显的差异。 为了更直接地确定特定的CD8+ T细胞反应是否使MAMU-B*17阳性EC可以控制SIV复制，我们在MAMU-B*17量限制的表位中构建了一系列具有轴承突变的SIVMAC239衍生物。 我们认为，这些突变病毒中的一种或多种将在静脉内接种后MAMU-B*17阳性EC中引起突破性的病毒性。 再次令我们惊讶的是，我们发现ECS抵抗了超级感染，即使在构成Mamu-B*17限制曲目的所有5个CD8+ T细胞表位中都有病毒轴承突变。 我们设计了一种新型的竞争性共培养测定法，以测试这些突变病毒的复制能力，这表明表位突变对病毒适应性的成本确切可忽略不计，这表明生长缺陷无法解释ECS控制表位垂体突变体病毒的能力。 目前正在准备描述这些结果的手稿。 这项研究使用了WNPRC动物服务，遗传学服务以及免疫学和病毒学服务。