CYTOTOXIC T CELL RESPONSES TO HHV-8

超出所提供的空间。人类疱疹病毒8型（HHV-8；卡波西肉瘤相关疱疹病毒）是卡波西肉瘤（KS）以及多中心Castleman病和体腔淋巴瘤的病因。我们假设：针对HHV-8特异性的CD8 - T细胞免疫是控制HHV-8感染的核心，而这种监测机制的失败导致HHV-8相关疾病的发展。我们已经证明HHV-8特异性T细胞免疫在原发性HHV-8感染后建立，并且在HIV-1感染者中较低。我们建议将这些研究扩展到T细胞应答在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。在Aim 1中，我们将在多中心艾滋病队列研究（MACS）中定义原发性和持续性HHV-8感染（病例交叉设计）期间CD8¿T细胞对7种HHV-8裂解蛋白和潜伏期周期蛋白的纵向反应，以及它们在HIV-1阴性和阳性受试者中KS（巢式病例对照设计）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γ干扰素的产生。在Aim 2中，我们将在细胞水平上分析诱导抗hhv -8 T细胞免疫的机制。我们假设HHV-8在抗原呈递树突状细胞（DC）中不能有效复制。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HLA I类途径加工和呈递抗HHV-8 CD8¿T细胞。因为这是我们理解HHV-8感染如何诱导免疫的核心，我们将评估HLA I类抗原加工和HHV-8蛋白在装载HHV-8感染细胞的未成熟和成熟DC中的递呈途径，并与直接感染HHV-8的DC进行比较。在Aim 3中，我们假设由K3和K50RF编码的蛋白通过调节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对装载HHV-8抗原的DC活化幼稚和记忆CD8¿T细胞的影响。应用这些方法来评估细胞免疫和HHV-8表达，结合对MACS中HHV-8服务器转换者和事件KS病例的纵向队列的访问，提供了一个独特的机会来推进我们对HHV-8感染保护的免疫相关因素的理解。这对于开发针对HHV-8感染的治疗方法和预防性疫苗非常重要。网站性能 ======================================== 节结束 ===========================================

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