Strategies for Therapeutic Vaccination Against KSHV

描述（由申请人提供）：我们项目的目标是开发针对最常见艾滋病恶性肿瘤的病毒病原体的疫苗策略，即使在CD4+ T细胞计数低的不利免疫环境中也是如此。CD4+ T细胞计数低是hiv感染患者的典型特征。在本提案中，我们选择卡波西肉瘤（KS）相关疱疹病毒（KSHV或HHV8）作为我们的模型靶点，它是KS、原发性积液性淋巴瘤和多中心Castleman病的病因。具体来说，我们将从KSHV的基因产物中鉴定出相关的CD8+ T细胞表位，并制定疫苗接种方案，以诱导对这些表位特异性的效应和记忆CD8+ T细胞。该项目有可能为脆弱患者群体的疫苗接种或患病个体的过继性转移治疗提供相关靶点，并为免疫功能低下患者的新型疫苗接种方法的有效性提供证据。该申请与RFA的目标高度相关，因此更适合“大机遇”招标，而不是“挑战”资助。它将提供机会扩大Kedes和Bullock实验室之间新生但已经取得成果的跨学科合作，从而确定疫苗靶点，一个新的模型系统来测试所选靶点的相关性和正在研究的疫苗接种方法的有效性（可能验证它们用于与免疫功能低下个体相关的多种恶性肿瘤和疾病状态）。随着项目的发展，还会有新的就业机会。

DESCRIPTION (provided by applicant): The goal of our project is to develop vaccine strategies that will target viral pathogens underlying the most common AIDS malignancies even in the unfavorable immunologic setting of low CD4+ T cell counts that typically characterizes HIV-infected patients. In this proposal, we have chosen as our model target Kaposi's sarcoma (KS)-associated herpesvirus (KSHV or HHV8), the etiologic agent of KS, primary effusion lymphoma and multicentric Castleman's disease. Specifically, we will identify relevant CD8+ T cell epitopes from gene products of KSHV and develop vaccination schemes that will elicit effector and memory CD8+ T cells specific for these epitopes. This project has the potential to provide relevant targets for the vaccination of vulnerable patient populations or the adoptive transfer therapy of afflicted individuals, and evidence for the efficacy of novel vaccination approaches in immunocompromised patients. This application is highly relevant to the goals of the RFA and, thus, more suitable for the Grand Opportunities solicitation rather than the Challenges Grant: It will provide the opportunity to expand a nascent but already fruitful cross- disciplinary collaboration between the Kedes and Bullock laboratories, leading to the identification of vaccine targets, a novel model system to test the relevance of the selected targets and the efficacy of the vaccination approaches being studied (potentially validating their use for multiple malignancies and disease states associated with immunocompromised individuals), and immediate new employment opportunities with additional ones as the program grows. PUBLIC HEALTH RELEVANCE: People with HIV/AIDS are unable to fight off many infectious diseases, including specific viruses that can cause cancers. Despite good HIV therapy available in relatively wealthy countries such as the U.S. and other developed nations, nearly one third of all deaths in AIDS patients are due to cancer and one half of these are caused by one of two viruses, EBV and lesser known one, KSHV. In the research that we are proposing, we are focusing on KSHV, which causes Kaposi's sarcoma, the single most common AIDS-related cancer. It is our hope to develop a better understanding of how immune cells in the body normally recognize and suppress KSHV and the cancers it can cause and then to develop new ways of using vaccines made from parts of this virus to boost the ability of AIDS patients to fight off KSHV and prevent and treat the diseases it causes.