CYTOTOXIC T CELL RESPONSES TO HHV-8

HHV-8 的细胞毒性 T 细胞反应

• 批准号: 7117055
• 负责人: CHARLES R RINALDO
• 金额: $ 3.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117055
• 关键词: CYTOTOXIC; CELL; RESPONSES; HHV

EXCEED THE SPACE PROVIDED. Human herpesvirus type 8 (HHV-8; Kaposi's sarcoma associated herpesvirus) is the etiologic agent of Kaposi's sarcoma (KS) as well as multicentric Castleman's disease and body cavity lymphomas. We hypothesize that :CD8 ¿ T cell immunity specific for HHV-8 is central to control of HHV-8 infection, and failure of this surveillance mechanism results in development of HHV-8 related disease. We have shown that HHV-8 specific T cell immunity is established after primary HHV-8 infection, and is lower in persons with HIV-1 infection. We propose to extend these studies of the role of T cell responses in HHV-8 infection and disease, and on the underlying mechanisms of induction of anti-HHV-8 T cell immunity. In Aim 1, we will define longitudinal CD8 ¿ T cell responses to 7 HHV-8 lytic and latency cycle proteins during primary and persistent HHV-8 infection (case- crossover design), and their role in development of KS (nested case-control design), in HIV-1 negative and positive subjects in the Multicenter AIDS Cohort Study (MACS). This includes assessment of HHV-8 epitope- specific cytolytic activity and gamma interferon production. In Aim 2, we will analyze the mechanisms of induction of anti-HHV-8 T cell immunity at the cellular level. We hypothesize that HHV-8 does not replicate efficiently in antigen-presenting dendritic cells (DC). Therefore, we believe that HHV-8 infected endothelial cells B cells and monocytes serve as major sources of antigen and are processed and presented by DC through alternative HLA class I pathways for activation of anti-HHV-8 CD8 ¿ T cells. Because this is central to our understanding of how HHV-8 infection induces immunity, we will assess HLA class I antigen processing and presentation pathways for HHV-8 proteins in immature and mature DC loaded with HHV-8 infected cells, in comparison to direct HHV-8 infection of DC. In Aim 3, we hypothesize that proteins encoded by K3 and K50RF alter activation of anti-HHV-8 T cell responses by modulating HLA class I and other T cell activation proteins on DC. We will therefore characterize the effects of K3 and K5 on activation of naive and memory CD8 ¿ T cells by HHV-8 antigen loaded DC. Application of these methodologies for assessing cellular immunity and HHV-8 expression, combined with access to a longitudinal cohort of HHV-8 seroconverters and incident KS cases in the MACS, offer a unique opportunity to advance our understanding of immune correlates of protection against HHV-8 infection. This is important for development of therapies and prophylactic vaccines for HHV-8 infection. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。人类疱疹病毒8型（HHV-8； Kaposi的肉瘤相关疱疹病毒）是Kaposi的肉瘤（KS）的病因学药物，以及多中心骑士疾病和体腔淋巴瘤。我们假设：HHV-8的CD8€T细胞免疫特异性对于控制HHV-8感染至关重要，并且该监测机制的失败导致HHV-8相关疾病的发展。我们已经表明，HHV-8特异性T细胞免疫特异性是在原发性HHV-8感染后建立的，并且HIV-1感染的人较低。我们建议将T细胞反应在HHV-8感染和疾病以及抗HHV-8 T细胞免疫诱导的基本机制中的作用扩展这些研究。在AIM 1中，我们将定义对原发和持续性HHV-8感染期间对7 HHV-8裂解和潜伏期循环蛋白的T细胞反应（案例 - 杂交设计）及其在KS（嵌套病例对照设计）的发展中的作用，在HIV-1负面和阳性受试者中，在HIV-1负和阳性受试者中，在多中心辅助研究中（MACS）。这包括评估HHV-8表位特异性细胞溶作用和伽马干扰素的产生。在AIM 2中，我们将分析抗HHV-8 T细胞免疫学在细胞水平上的诱导机制。我们假设HHV-8在抗原呈递的树突状细胞（DC）中不会有效复制。因此，我们认为HHV-8感染的内皮细胞B细胞和单核细胞是抗原的主要来源，并由DC通过替代HLA I类途径进行处理和表示，用于激活抗HHV-8 CD8 CD8»T细胞。因为这对于我们对HHV-8感染如何影响免疫学的理解至关重要，因此我们将评估HHV-8蛋白质中HHV-8蛋白质中的HLA I类抗原加工和呈现途径，而与直接HHV-8 DC感染直接感染了HHV-8感染细胞的成熟DC。在AIM 3中，我们假设由K3和K50RF编码的蛋白质通过调节DC上的HLA I类和其他T细胞激活蛋白来改变抗HHV-8 T细胞反应的激活。因此，我们将表征K3和K5对HHV-8抗原DC激活Naive和Memore CD8细胞的影响。这些方法在评估细胞免疫学和HHV-8表达中的应用，再加上MAC中的HHV-8血清控制器和入射KS病例的纵向队列，提供了一个独特的机会，可以促进我们对针对HHV-8感染的保护型的理解。性能站点====段end =====