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）是卡波西肉瘤的病原体。 肉瘤（KS）以及多中心Castleman病和体腔淋巴瘤。我们假设 HHV-8特异性CD 8 ~ T细胞免疫是控制HHV-8感染的关键， 机制导致HHV-8相关疾病的发展。我们已经证明HHV-8特异性T细胞 免疫力在原发性HHV-8感染后建立，在HIV-1感染者中较低。我们提出 为了扩展这些关于T细胞应答在HHV-8感染和疾病中的作用的研究， 诱导抗HHV-8 T细胞免疫的机制。在目标1中，我们将定义纵向CD 8 <$T细胞 在原发和持续HHV-8感染期间，对7种HHV-8裂解和潜伏周期蛋白的反应（病例- 交叉设计），以及它们在KS（巢式病例对照设计）发展中的作用，在HIV-1阴性和 多中心艾滋病队列研究（MACS）中的阳性受试者。这包括评估HHV-8表位- 特异性细胞溶解活性和γ干扰素产生。在目标2中，我们将分析 在细胞水平诱导抗HHV-8 T细胞免疫。我们假设HHV-8不复制 在抗原呈递树突状细胞（DC）中有效。因此，我们认为HHV-8感染的内皮细胞 B细胞和单核细胞作为抗原的主要来源，由DC加工和呈递， 用于激活抗HHV-8 CD 8 <$T细胞的替代HLA I类途径。因为这是我们 为了了解HHV-8感染如何诱导免疫，我们将评估HLA I类抗原的加工， HHV-8蛋白在负载HHV-8感染细胞的未成熟和成熟DC中的呈递途径， 与DC的直接HHV-8感染相比。在目的3中，我们假设由K3和K50 RF编码的蛋白质 通过调节HLA-I类和其它T细胞活化蛋白来改变抗HHV-8 T细胞应答的活化， DC.因此，我们将通过以下方法来表征K3和K5对初始和记忆性CD 8 <$T细胞活化的影响： HHV-8抗原负载DC。这些方法在评估细胞免疫和HHV-8中的应用 表达，结合进入纵向队列的HHV-8血清转换者和偶发KS病例， MACS提供了一个独特机会，以促进我们对免疫相关性的理解， HHV-8感染。这对于HHV-8感染的治疗和预防性疫苗的开发是重要的。

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.