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。 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。 以前，我们表明，猕猴队列中的精英控制与MHC I类（MHC-I）等位基因Mamu-B*17的表达有关。 MAMU-B*17蛋白呈现从SIV蛋白到CD8+ T细胞的肽“表位”，并将“标记”感染的细胞进行破坏。 由于Mamu-B*17在细胞免疫反应中起作用，因此我们假设Mamu-B*17阳性动物制造的特定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“限制”对猕猴EC中SIV的免疫遏制的贡献。 通过在EC中瞬时耗尽CD8+ T细胞，我们表明细胞免疫反应确实对于对这些动物中的SIV复制的持续控制确实至关重要。 我们设计了一种新型的病毒抑制测定法，以表明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，我们发现另外的MHC-I基因Mamu-B*08也与精英控制有关。 我们确定了哪些SIV蛋白或表位的片段通过MAMU-B*08分子呈现给CD8+ T细胞。我们测试了这些等位基因“限制”细胞免疫反应通过用突变病毒挑战动物来维持病毒复制的能力，我们引入了特定的逃生突变。 令人惊讶的是，EC控制了这些突变病毒的复制。 我们现在正在尝试了解这些动物如何保持对病毒突变体的控制，这些病毒突变体应该“消除”其最重要的免疫反应。 重要的是，我们还发现了证据表明，“免疫优势”，即对一个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，可能在确定动物控制SIV复制能力方面起主要作用。 我们的数据表明，如果要成功保护患者免受艾滋病毒的侵害，艾滋病疫苗可能需要帮助调节这种免疫力。 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。