CYTOTOXIC T CELL RESPONSES TO HHV-8

人类疱疹病毒8型(HHV-8；卡波西肉瘤相关疱疹病毒)是卡波西氏病的病原体。 肉瘤(KS)以及多中心性Castleman病和体腔淋巴瘤。我们假设 ：CD8？针对HHV-8的T细胞免疫是控制HHV-8感染的核心，但这种监测失败 机制导致HHV-8相关疾病的发展。我们已经证明了HHV-8特异性T细胞 免疫力是在感染HHV-8后建立的，在感染了HIV-1的人中免疫力较低。我们建议 扩展这些关于T细胞反应在HHV-8感染和疾病中的作用以及潜在的 抗HHV-8T细胞免疫诱导机制的研究在目标1中，我们将定义纵向CD8？T细胞 在HHV-8初次和持续感染期间对7种HHV-8裂解和潜伏周期蛋白的反应(病例- 交叉设计)，以及它们在发展嵌套病例对照设计(KS)中的作用 多中心艾滋病队列研究(MACS)的阳性受试者。这包括评估HHV-8表位- 特定的细胞溶解活性和γ干扰素的产生。在目标2中，我们将分析 在细胞水平诱导抗HHV-8T细胞免疫。我们假设HHV-8病毒不会复制 高效的抗原提呈树突状细胞(DC)。因此，我们认为HHV-8感染内皮细胞 B细胞和单核细胞是抗原的主要来源，由DC通过 激活抗HHV-8 CD8？T细胞的可选的HLAI类途径。因为这是我们的核心 了解HHV-8感染是如何诱导免疫的，我们将评估人类白细胞抗原I类抗原的处理和 携带HHV-8感染细胞的未成熟和成熟DC中HHV-8蛋白的提呈途径 与DC直接感染HHV-8的比较。在目标3中，我们假设K3和K50RF编码的蛋白质 通过调节人类白细胞抗原I类和其他T细胞活化蛋白改变抗HHV-8 T细胞应答的激活 华盛顿特区。因此，我们将通过以下方式表征K3和K5对初始和记忆性CD8？T细胞激活的影响 HHV-8抗原负载DC。这些方法在细胞免疫和HHV-8检测中的应用 表达，结合获得HHV-8血清转换者和发生的KS病例的纵向队列 Mac提供了一个独特的机会来促进我们对免疫相关保护的理解。 HHV-8感染。这对HHV-8感染的治疗和预防性疫苗的开发具有重要意义。

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.