CORRELATES OF ELITE CONTROL OF SIV

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。 了解猕猴精英控制器(ECs)中的“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。 此前，我们发现猕猴群体中的精英控制与MHC-I类(MHC-I)等位基因MAMU-B*17的表达有关。MAMU-B*17蛋白向CD8+T细胞递送源自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在细胞免疫反应中发挥作用，因此我们推测，Mamu-B*17阳性动物产生的特异性CD8+T细胞反应使其有可能成为ECs。因此，该项目探索了CD8+T细胞反应，特别是那些被Mamu-B*17“限制”的反应，对SIV在猕猴内皮细胞中的免疫抑制作用。 通过瞬时耗尽一组内皮细胞中的CD8+T细胞，我们证明了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。我们设计了一种新的病毒抑制试验，表明CD8+T细胞和NK细胞都有助于ECs的这种免疫抑制。在这些研究过程中，我们发现另外一个MHC-I基因，MAMU-B*08，也与精英控制有关。我们确定了哪些SIV蛋白片段或表位是由MAMU-B*08分子呈递给CD8+T细胞的。我们测试了被这些等位基因“限制”的细胞免疫反应的能力，通过用突变病毒挑战动物来维持对病毒复制的控制，我们在突变病毒中引入了特殊的逃逸突变。令人惊讶的是，ECS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是如何维持对病毒突变体的控制的，这些病毒突变体应该会“敲除”它们最重要的免疫反应。重要的是，我们还发现了“免疫优势”的证据，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，这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地保护人们免受艾滋病毒感染，可能需要帮助调节免疫个人的这种免疫优势。 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。

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.