CYTOTOXIC T CELL RESPONSES TO HHV8

人疱疹病毒8型(HHV-8)是由Chang和Moore于1994年发现的一种伽玛家族疱疹病毒。血清学抗体研究和聚合酶链式反应检测表明，该病毒是卡波西氏肉瘤(KS)以及多中心Castleman病和体腔淋巴瘤的病原体。根据T细胞免疫反应在疱疹病毒感染中的作用已有文献记载，我们假设T细胞免疫是由HHV-8感染诱导的。我们进一步推测，针对病毒的细胞毒性T淋巴细胞(CTL)活性是控制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。关于对HHV-8的CTL反应的知识对于开发针对这种病毒的适当的治疗和预防方法可能很重要。因此，我们提出了该项目的以下具体目标：(1)研究正常成人初次感染过程中对HHV-8调节蛋白、结构蛋白和潜伏蛋白的纵向T细胞免疫应答(通过裂解活性、产生干扰素的细胞和四聚体染色)，包括T细胞表型、HLA限制性和多肽表位定位；(2)明确抗HHV-8CTL应答在HIV-1感染者KS发生中的作用；(3)原位检测与HHV-8裂解、潜伏和转化相关的病毒蛋白的CTL反应，并确定KS肿瘤细胞是否具有抑制CTL活性的能力；(4)确定转化蛋白K1是否能诱导HHV-8分支特异性CTL反应。在我们的实验室中应用这些方法来评估细胞免疫和HHV-8的表达，再加上在多中心艾滋病队列研究中获得HHV-8血清转换子的纵向队列，为我们提供了一个独特的机会来促进我们对抗HHV-8 CTL反应在原发感染和KS发展中的理解。这些信息对于理解预防HHV-8感染的免疫相关性也是重要的，因为这是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