KIR and MHC Class I Immunogenetics in SIV Infection

项目总结 自然杀伤(NK)细胞通过其能力提供对病毒病原体的关键早期防御 识别和杀死感染病毒的细胞，而不需要事先的抗原刺激。这在一定程度上是通过 两个高度多态的分子之间的相互作用；杀伤细胞免疫球蛋白样受体(KIRS) NK细胞及其靶细胞表面的MHC-I类配体。KIR和HLAI类基因的多态可能具有深刻的 对HIV-1感染病程的影响及以NK细胞为基础的根除病毒的疗效 然而，解决潜在免疫学机制的动物研究一直受到我们的 非人灵长类动物模型中KIR-MHC I类相互作用的理解。在上一次筹资期间， 我们确定了5只恒河猴的MHC-I类配体，并揭示了病毒多肽在 抑制NK细胞活化是免疫逃避的一种潜在机制。我们还观察到了高度动态的 KIR和MHC-I类定义的猕猴对SIV感染的NK细胞反应的变化，包括 受Bw4配体调控的NK细胞在支持高水平病毒的淋巴组织中的浓缩 复制。在这里，我们以这些研究为基础，调查有关病毒影响的具体假设 NK细胞对病毒感染细胞的应答及识别Bw4的NK细胞的作用 用来抑制免疫缺陷病毒感染的配体。 在目标1中，我们将定义MHC I类配体并分离最常见的恒河猴抗体 基尔斯。这一目标建立在最近的研究基础上，为研究NK提供更广泛的知识库和关键试剂 猕猴体内的细胞反应。在目标2中，我们将研究MHC结合的病毒多肽的作用。 I类配体对NK细胞识别病毒感染细胞的影响。我们将确定在多大程度上 稳定MHC-I类分子与抑制性KIR结合的病毒多肽对NK细胞反应的抑制作用 某些KIR-MHC I类物质对的普遍现象或独特性质，以及多肽是否源于 来自内源性表达的病毒抗原也可以影响NK细胞对病毒感染细胞的活性。在AIM 3，我们将评估一群表达Bw4配体特异性KIR的NK细胞对 在SIV前用KIR特异性抗体清除这些细胞以遏制动物体内的病毒复制 感染。这些史无前例的研究将提供对KIR功能影响的更好理解- 免疫缺陷病毒感染对NK细胞应答中MHC-I类相互作用的影响 多肽在NK细胞识别病毒感染细胞中的作用及其对优势群NK细胞的影响 Bw4配体对SIV发病机制的调控

PROJECT SUMMARY Natural killer (NK) cells provide a critical early defense against viral pathogens by virtue of their ability to recognize and kill virus-infected cells without prior antigenic stimulation. This is accomplished in part through interactions between two highly polymorphic molecules; the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their MHC class I ligands on target cells. KIR and HLA class I polymorphisms can have profound effect on the course of HIV-1 infection and the efficacy of NK cell-based therapies for eradicating virus-infected cells; however, animal studies to address underlying immunological mechanisms have been limited by our understanding of KIR-MHC class I interactions in nonhuman primate models. Over the previous funding period, we identified MHC class I ligands for five rhesus macaque KIRs and revealed a role for viral peptides in suppressing NK cell activation as a potential mechanism of immune evasion. We also observed highly dynamic changes in NK cell responses to SIV infection of KIR- and MHC class I-defined macaques, including an enrichment of NK cells regulated by Bw4 ligands in lymphoid tissues that support high levels of virus replication. Here we build on these studies to investigate specific hypotheses concerning the influence of viral peptides on NK cell responses to virus-infected cells and the contribution of NK cells that recognize Bw4 ligands to the containment of immunodeficiency virus infection. In Aim 1, we will define MHC class I ligands and isolate antibodies for the most common rhesus macaque KIRs. This aim builds on recent studies to provide a broader knowledge base and key reagents for studying NK cell responses in the rhesus macaque. In Aim 2, we will investigate the effects of viral peptides bound by MHC class I ligands on NK cell recognition of virus-infected cells. We will determine the extent to which the suppression of NK cell responses by viral peptides that stabilize MHC class I binding to inhibitory KIRs is a common phenomenon or a unique property of certain KIR-MHC class I pairs, and whether peptides derived from endogenously expressed viral antigens can also affect NK cell activity against virus-infected cells. In Aim 3, we will assess the contribution of a population of NK cells expressing a KIR specific for Bw4 ligands to the containment of virus replication in animals by depleting these cells with a KIR-specific antibody prior to SIV infection. These unprecedented studies will provide a better understanding of the functional effects of KIR- MHC class I interactions on NK cell responses to immunodeficiency virus infection, including the role of viral peptides in NK cell recognition of virus-infected cells and the impact of a dominant population of NK cells regulated by Bw4 ligands on SIV pathogenesis.