CORRELATES OF ELITE CONTROL OF SIV

精英控制 SIV 的相关性

• 批准号: 7716467
• 负责人: Thomas C. Friedrich
• 金额: $ 16.38万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-23 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716467
• 关键词: AIDS Vaccines; Alleles; Animals; Biological Assay; CD8B1 gene; Cells; Computer Retrieval of Information on Scientific Projects Database; Containment; Data; Epitopes; Funding; Genetic Services; Grant; HIV; HIV Infections; Human; Immune; Immune response; Immunology; Individual; Institution; Knock-out; MHC Class I Genes; Macaca; Mutation; Natural Killer Cells; Peptides; Play; Process; Proteins; Research; Research Personnel; Resources; Role; SIV; Services; Source; T-Lymphocyte; Testing; United States National Institutes of Health; Vaccinated; Viral; Virus; Virus Replication; cohort; interest; mutant; novel virus; response; 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. 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. Previously we showed that elite control in our macaque cohort was associated with expression of the MHC class I (MHC-I) allele Mamu-B*17. The Mamu-B*17 protein presents peptide "epitopes" derived from SIV proteins to CD8+ T cells, "flagging" infected cells for destruction. Since Mamu-B*17 plays a role in the cellular immune response, we therefore hypothesized that the specific CD8+ T cell responses made by Mamu-B*17-positive animals 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, to immune containment of SIV in macaque ECs. By transiently depleting CD8+ T cells in a cohort of ECs, we showed that cellular immune responses are indeed crucial for the ongoing control of SIV replication seen in these animals. We devised a novel virus suppression assay to show that CD8+ T cells and NK cells both contribute to this immune containment in ECs. In the course of these studies, we discovered that an additional MHC-I gene, Mamu-B*08, is also associated with elite control. We determined which fragments of SIV proteins, or epitopes, are presented to CD8+ T cells by Mamu-B*08 molecules. We tested the ability of the cellular immune responses "restricted" by these alleles to maintain control of virus replication by challenging animals with mutant viruses, into which we had introduced particular escape mutations. Surprisingly, the ECs controlled replication of these mutant viruses. We are now trying to understand how these animals maintain control of virus mutants that should "knock out" their most important immune responses. Importantly, we have also found evidence that "immunodominance," the process by which immune responses to one viral epitope can inhibit responses that recognize different epitopes, may play a major role in determining animals' ability to control SIV replication. Our data suggest that AIDS vaccines may need to help modulate this immunodominance in immunized individuals if they are to successfully protect people from HIV. This research used Immunology & Virology Services, Genetics Services and Animal Services.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 了解猕猴精英控制者 (EC) 中的“控制相关性”。 “保护的相关性”，即保护接种疫苗的个体免受艾滋病毒感染的免疫反应，尚不清楚。 正因为如此，人们对研究“精英控制者”（EC）产生了浓厚的兴趣，这些人是自发控制艾滋病毒复制的罕见个体。 在过去的几年里，我们聚集了一群精英控制猕猴，它们在几个重要方面与人类 EC 相似。 之前我们表明，我们的猕猴队列中的精英控制与 MHC I 类 (MHC-I) 等位基因 Mamu-B*17 的表达相关。 Mamu-B*17 蛋白将源自 SIV 蛋白的肽“表位”呈现给 CD8+ T 细胞，“标记”受感染的细胞以进行破坏。 由于Mamu-B * 17在细胞免疫反应中发挥作用，因此我们假设Mamu-B * 17阳性动物产生的特异性CD8 + T细胞反应使它们有可能成为EC。 因此，该项目探讨了 CD8+ T 细胞反应（特别是受 Mamu-B*17“限制”的反应）对猕猴 EC 中 SIV 免疫遏制的贡献。 通过瞬时耗尽一组 EC 中的 CD8+ T 细胞，我们发现细胞免疫反应对于这些动物中 SIV 复制的持续控制确实至关重要。 我们设计了一种新型病毒抑制测定，以证明 CD8+ T 细胞和 NK 细胞都有助于 EC 中的这种免疫遏制。 在这些研究过程中，我们发现另一个 MHC-I 基因 Mamu-B*08 也与精英控制有关。 我们确定了哪些 SIV 蛋白片段或表位通过 Mamu-B*08 分子呈递给 CD8+ T 细胞。我们通过用突变病毒攻击动物来测试受这些等位基因“限制”的细胞免疫反应维持病毒复制控制的能力，我们在其中引入了特定的逃逸突变。 令人惊讶的是，EC 控制了这些突变病毒的复制。 我们现在正试图了解这些动物如何保持对病毒突变体的控制，这些突变体应该“消除”它们最重要的免疫反应。 重要的是，我们还发现了证据表明“免疫优势”，即对一种病毒表位的免疫反应可以抑制识别不同表位的反应的过程，可能在决定动物控制 SIV 复制的能力方面发挥重要作用。 我们的数据表明，艾滋病疫苗如果要成功保护人们免受艾滋病毒感染，可能需要帮助调节免疫个体的这种免疫优势。 这项研究使用了免疫学和病毒学服务、遗传学服务和动物服务。