CYTOTOXIC T CELL RESPONSES TO HHV8

人类疱疹病毒8型（Human herpesvirus type 8，HHV-8）是1994年由Chang和摩尔发现的一种γ家族疱疹病毒。血清学抗体研究和PCR检测强烈暗示该病毒是卡波西肉瘤（KS）以及多中心Castleman病和体腔淋巴瘤的病原体。基于T细胞免疫应答在疱疹病毒感染中的作用，我们假设T细胞免疫是由HHV-8感染诱导的。我们进一步假设，细胞毒性T淋巴细胞（CTL）的活性特异性的病毒是中央控制的HHV-8感染，这种监督机制的失败导致HHV-8相关疾病的发展。关于CTL对HHV-8的应答的知识对于开发针对该药剂的适当治疗和预防方法可能是重要的。因此，我们提出了以下具体目标：（1）纵向T细胞免疫反应的表征（通过裂解活性、γ-干扰素产生细胞和四聚体染色）对正常成人受试者初次感染HHV-8过程中的调节蛋白、结构蛋白和潜伏蛋白的研究，包括T细胞表型、HLA限制性和肽表位作图;（2）确定抗HHV-8 CTL应答在HIV-1感染受试者KS发生中的作用;（3）确定原位CTL应答与HHV-8的裂解、潜伏和转化特性相关的病毒蛋白，并确定KS肿瘤细胞是否能够抑制CTL活性;以及（4）确定转化蛋白K1是否激发HHV-8进化枝特异性CTL应答。在我们的实验室中应用这些方法来评估细胞免疫和HHV-8表达，结合在多中心艾滋病队列研究中获得HHV-8血清转化者的纵向队列，为我们进一步了解抗HHV-8 CTL反应提供了一个独特的机会。原发性感染和KS的发展。这些信息对于理解HHV-8感染保护的免疫相关性也很重要，作为开发治疗方案和预防性疫苗的基础

Human herpesvirus type 8 (HHV-8) is a gamma family herpesvirus discovered in 1994 by Chang and Moore. The virus has been strongly implicated by serologic antibody studies and PCR detection as the etiologic agent of Kaposi's sarcoma (KS) as well as multicentric Castleman's disease and body cavity lymphomas. Based on the well-documented role of T cell immune responses in herpesvirus infections, we hypothesize that T cell immunity is induced by HHV-8 infection. We postulate further that cytotoxic T lymphocyte (CTL) activity specific for the virus is central to control of HHV-8 infection, and failure of this surveillance mechanism results in development of HHV-8 related disease. Knowledge regarding CTL responses to HHV-8 may be important in development of adequate treatment and prevention methods for this agent. Therefore, we propose the following specific aims for this project: (1) Characterize the longitudinal T cell immmunologic responses (by lytic activity, gamma interferon producing cells and tetramer staining) to regulatory, structural and latent proteins of HHV-8 during primary infection of normal adults subjects, including T cell phenotype, HLA restriction and peptide epitope mapping; (2) Define the role of the anti-HHV-8CTL response in the development of KS in HIV-1 infected subjects; (3) Determine the CTL response in situ to viral proteins related to lytic, latent and transforming properties of HHV-8, and determine if KS tumor cells are capable of suppressing CTL activity; and (4) Determine if the transforming protein K1 elicits HHV-8 clade- specific CTL responses. Application of these methodologies in our laboratories for assessing cellular immunity and HHV-8 expression, combined with access to a longitudinal cohort of HHV-8 seroconvertors in the Multicenter AIDS Cohort Study, offers a unique opportunity to advance our understanding of anti-HHV-8 CTL responses in primary infection and development of KS. Such information is also important for understanding the immune correlates of protection against HHV-8 infection as the basis for development of therapeutic regimens and prophylatic vaccines