KIR and MHC Class I Immunogenetics in SIV Infection

项目摘要 自然杀伤（NK）细胞凭借其以下能力提供针对病毒病原体的关键早期防御： 识别并杀死病毒感染的细胞，而无需预先抗原刺激。这部分是通过 两种高度多态性分子之间的相互作用;免疫球蛋白样受体（KIR）， NK细胞及其MHC I类配体对靶细胞的作用。KIR和HLA I类多态性可以具有深刻的 对HIV-1感染过程的影响和基于NK细胞的治疗根除病毒感染的疗效 细胞;然而，动物研究，以解决潜在的免疫机制已受到限制，我们的 在非人灵长类动物模型中了解KIR-MHC I类相互作用。在上一个供资期间， 我们鉴定了五种恒河猴KIR的MHC I类配体，并揭示了病毒肽在 抑制NK细胞活化作为免疫逃避的潜在机制。我们还观察到高度动态的 NK细胞对SIV感染KIR和MHC I类定义的猕猴的反应的变化， 在支持高水平病毒的淋巴组织中富集由Bw 4配体调节的NK细胞 复制的在这里，我们建立在这些研究，以调查有关病毒的影响， 肽对NK细胞对病毒感染细胞的应答以及识别Bw 4的NK细胞的贡献 配体，以遏制免疫缺陷病毒感染。 在目标1中，我们将定义最常见的恒河猴的MHC I类配体并分离抗体 KIR。这一目标建立在最近的研究基础上，为研究NK提供更广泛的知识基础和关键试剂 恒河猴的细胞反应。在目标2中，我们将研究MHC结合的病毒肽的影响 I类配体对病毒感染细胞的NK细胞识别的影响。我们将在多大程度上确定 通过稳定MHC I类与抑制性KIR结合的病毒肽抑制NK细胞应答是一种免疫抑制剂， 某些KIR-MHC I类配对的常见现象或独特性质，以及是否衍生肽 来自内源性表达的病毒抗原的抗体也可以影响NK细胞对病毒感染细胞的活性。在Aim中 3中，我们将评估表达对Bw 4配体特异性的KIR的NK细胞群体对Bw 4配体的表达的贡献。 通过在SIV之前用KIR特异性抗体耗尽这些细胞来遏制动物中的病毒复制 感染这些前所未有的研究将提供一个更好的了解KIR的功能作用， 免疫缺陷病毒感染后NK细胞免疫应答中MHC I类分子的相互作用，包括病毒介导的作用 肽在NK细胞识别病毒感染的细胞和NK细胞的优势群体的影响 Bw 4配体对SIV发病机制的调节。

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.