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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：了解猕猴精英控制者（EC）的控制相关因素。 “保护的相关因素”，即，保护接种个体免受HIV感染的免疫应答是未知的。 正因为如此，人们对研究“精英控制者”（EC）产生了浓厚的兴趣，这些人是自发控制HIV复制的罕见个体。 在过去的几年里，我们已经聚集了一批精英控制器猕猴，在几个重要方面类似于人类EC。 本项目旨在了解这些猕猴EC中的“控制相关物”。 先前我们表明，猕猴组群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的表达相关。 引人注目的是，我们这一组中所有的猕猴精英控制者都表达至少一种这些等位基因。 这些蛋白质将来自SIV蛋白的肽“表位”呈递给CD 8 + T细胞，“标记”受感染的细胞以进行破坏。 由于Mamu-B *17和B*08在细胞免疫应答中起作用，因此我们假设表达这些蛋白质的动物产生的特异性CD 8 + T细胞应答使它们成为EC成为可能。 因此，本项目探索了CD 8 + T细胞应答，特别是那些受Mamu-B *17和B*08“限制”的T细胞应答，对猕猴EC中SIV的免疫遏制的贡献。 令我们惊讶的是，我们最近发现EC和进展者中识别的免疫应答强度或病毒表位数量没有明显差异。 为了更直接地确定特定的CD 8 + T细胞应答是否使Mamu-B*17阳性EC能够控制SIV复制，我们构建了一系列在Mamu-B*17限制性表位的组合中携带突变的SIVmac 239衍生物。 我们推断这些突变病毒中的一种或多种在静脉接种后会导致Mamu-B*17阳性EC的突破性病毒血症。 再次令我们惊讶的是，我们发现EC抵抗重复感染，即使是在构成Mamu-B*17限制性库的所有5个CD 8 + T细胞表位中携带突变的病毒。 我们设计了一种新的竞争共培养试验来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可以忽略不计，这表明生长缺陷不能解释EC控制表位突变病毒的能力。 目前正在编写一份介绍这些结果的手稿。 这项研究使用了WNPRC动物服务，遗传学服务和免疫学和病毒学服务。