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===========================================

超出提供的空间。人类疱疹病毒8型(HHV-8；Kaposi肉瘤相关疱疹病毒)是Kaposi肉瘤(KS)以及多中心Castleman病和体腔淋巴瘤的病原体。我们推测：针对HHV-8的CD8T细胞免疫是控制HHV-8感染的核心，这种监测机制的失败会导致HHV-8相关疾病的发生。我们已经证明，HHV-8特异性T细胞免疫是在HHV-8原发感染后建立的，并且在HIV-1感染者中较低。我们建议扩大T细胞反应在HHV-8感染和疾病中的作用，以及诱导抗HHV-8 T细胞免疫的潜在机制的研究。在目标1中，我们将在多中心艾滋病队列研究(MACS)中，确定在初次和持续感染HHV-8期间，CD8细胞对7个HHV-8裂解和潜伏周期蛋白的纵向反应(病例交叉设计)，以及它们在KS(嵌套病例对照设计)发展中的作用。这包括评估HHV-8表位特异性的细胞溶解活性和伽马干扰素的产生。在目的2中，我们将从细胞水平分析抗HHV-8T细胞免疫诱导机制。我们假设HHV-8不能在抗原提呈树突状细胞(DC)中有效复制。因此，我们认为HHV-8感染的内皮细胞、B细胞和单核细胞是主要的抗原来源，DC通过替代的HLAI类途径处理和提呈抗HHV-8 CD8？T细胞。由于这是我们理解HHV-8感染诱导免疫的核心，我们将评估在负载HHV-8感染细胞的未成熟和成熟DC中HHV-8蛋白的HHV-I类抗原处理和递送途径，并与直接感染HHV-8的DC进行比较。在目标3中，我们假设K3和K50RF编码的蛋白通过调节DC上的HLAI类和其他T细胞激活蛋白来改变抗HHV-8T细胞反应的激活。因此，我们将研究K3和K5对HHV-8抗原负载的DC激活初始和记忆性CD8？T细胞的影响。这些用于评估细胞免疫和HHV-8表达的方法的应用，再加上对MAC中HHV-8血清转换者和KS事件病例的纵向队列的访问，为我们提供了一个独特的机会来促进我们对预防HHV-8感染的免疫相关性的理解。这对HHV-8感染的治疗和预防性疫苗的开发具有重要意义。表演网站========================================Section End===========================================