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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：了解猕猴精英控制者(ECs)的“控制相关因素”。 “保护的相关性”，即保护接种疫苗的人免受艾滋病毒感染的免疫反应，是未知的。正因为如此，人们对研究“精英控制者”(ECs)产生了浓厚的兴趣，“精英控制者”是一种罕见的自发控制艾滋病毒复制的人。在过去的几年里，我们聚集了一群精英控制器猕猴，它们在几个重要方面与人类ECs相似。这个项目旨在了解这些猕猴ECs中的“控制相关因素”。 此前，我们发现猕猴群体中的精英控制与特定的MHC-I类(MHC-I)等位基因MAMU-B*17和MAMU-B*08的表达有关。引人注目的是，我们队列中的所有猕猴精英控制者都至少表达这些等位基因中的一个。这些蛋白质向CD8+T细胞呈递来自SIV蛋白的多肽“表位”，“标记”受感染的细胞进行破坏。由于MAMU-B*17和B*08在细胞免疫反应中发挥作用，因此我们推测，表达这些蛋白的动物产生的特异性CD8+T细胞反应使它们有可能成为ECs。因此，该项目探索了CD8+T细胞反应，特别是那些被Mamu-B*17和B*08“限制”的反应，对猕猴内皮细胞中SIV的免疫抑制作用。 令我们惊讶的是，我们最近发现在免疫反应的强度或ECs和进展者中识别的病毒表位的数量方面都没有明显的差异。为了更直接地确定特定的CD8+T细胞反应是否使Mamu-B*17阳性的ECs能够控制SIV复制，我们构建了一系列SIVmac239衍生物，携带Mamu-B*17限制性表位组合的突变。我们推测，这些突变病毒中的一个或多个在静脉接种后会在Mamu-B*17阳性的ECs中引起突破性病毒血症。再次令我们惊讶的是，我们发现ECs抵抗重叠感染，即使病毒携带构成Mamu-B*17限制性谱系的所有5个CD8+T细胞表位的突变。我们设计了一种新的竞争共培养方法来测试这些突变病毒的复制能力，结果表明，表位突变对病毒适应性的影响可以忽略不计，这表明生长缺陷不能解释ECs控制表位突变病毒的能力。目前正在准备一份描述这些结果的手稿。 这项研究使用了WNPRC动物服务、遗传学服务和免疫学和病毒学服务。