A novel immune evasion strategy of KSHV K3 and K5

KSHV K3 和 K5 的新型免疫逃避策略

• 批准号: 6515143
• 负责人: Jae U Jung
• 金额: $ 28.57万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-08 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515143
• 关键词: Callithricidae; Herpesvirus saimiri; Kaposi's sarcoma; MHC class I antigen; Saimiri; cell adhesion molecules; clinical research; cytotoxic T lymphocyte; host organism interaction; human herpesvirus 8; human subject; lymphoma; membrane proteins; microorganism immunology; natural killer cells; polymerase chain reaction; protein structure function; recombinant virus; site directed mutagenesis; viral carcinogenesis; virus genetics; virus protein; virus virus interaction

DESCRIPTION (Provided by the applicant): Host immune responses including cytoxic T lymphocytes (CTLs) and Natural killer (NK) cells play a role in the elimination of virus-infected cells. To avoid these immune responses, herpesviruses have evolved elaborate mechanisms that target and modulate different aspects of the host's immune system. The proposed research is directed toward investigating a novel immune evasion strategy employed by KSHV K3 and K5 proteins. We have shown that both K3 and K5 membrane proteins downregulate MHC class I molecules and that K5 additionally downregulates B7-2 and ICAM-1. We hypothesis that KSHV uses two genes similar but distinct activities to ensure comprehensive protection from host immune effectors. Specifically, K3 plays a major role in the inhibition of CTL lysis whereas K5 is primarily involved in suppression of NK cell-mediated cytotoxicity and T helper (Th) cell-mediated immune response. In this proposal, we will draw upon our experience in the biochemical analysis of viral gene function and in the development and utilization of nonhuman primate models to define the detailed mechanisms of immune evasion of K3 and K5. Our biochemical and immunological studies will define in greater detail the mechanisms used by K3 and K5 to inhibit CTL lysis, NK cell-mediated cytotoxicity, and Th cell-mediated immune response. To define the role of K3 and K5 in viral immune evasion in vivo, we will test whether K3 and K5 are capable of contributing to the establishment of persistent infection of herpesvirus saimiri (HVS) in the natural host, squirrel monkeys, and to the induction of lymphoma by HVS in the non-natural hosts, common marmosets. Because of the lack of cell culture systems and animal models for KSHV, this approach provides a unique opportunity to investigate the contribution of the K3 and K5 genes to the escape of KSHV from hostile host immune responses. The proposed studies will provide an understanding of a novel immune evasion strategy of KSHV to survive destruction by host immune effector cells and to achieve persistent infection.

描述（申请人提供）：主机免疫反应，包括 细胞毒性T淋巴细胞（CTL）和天然杀伤（NK）细胞在 消除病毒感染的细胞。为了避免这些免疫反应， 疱疹病毒已经进化出了靶向和调节的精美机制 宿主免疫系统的不同方面。拟议的研究是 致力于研究KSHV采用的新型免疫逃避策略 K3和K5蛋白。我们已经表明K3和K5膜蛋白均 下调MHC I类分子，K5还下调了B7-2 和ICAM-1。我们假设KSHV使用两个基因相似但不同 确保宿主免疫效应子的全面保护的活动。 具体而言，K3在抑制CTL裂解中起主要作用，而K5 主要参与NK细胞介导的细胞毒性和T的抑制 助手（Th）细胞介导的免疫反应。在此提案中，我们将借鉴 我们在病毒基因功能的生化分析和 非人类灵长类动物模型的开发和利用来定义详细的 K3和K5免疫逃避的机制。我们的生化和免疫学 研究将更详细地定义K3和K5使用的机制 抑制CTL裂解，NK细胞介导的细胞毒性和TH细胞介导的免疫 回复。为了定义K3和K5在体内病毒免疫逃避中的作用，我们 将测试K3和K5是否有助于建立 天然宿主中的疱疹病毒Saimiri（HVS）的持续感染，松鼠 猴子，以及非天然宿主中HVS诱导淋巴瘤， 常见的果饼。由于缺乏细胞培养系统和动物模型 对于KSHV，这种方法提供了一个独特的机会来调查 K3和K5基因对KSHV从敌对主机逃脱的贡献 免疫反应。拟议的研究将提供对小说的理解 KSHV免疫逃避策略，以生存宿主免疫效应器的破坏 细胞并实现持续感染。