Strategies for Therapeutic Vaccination Against KSHV

描述（由申请人提供）：我们项目的目标是开发疫苗策略，即使在通常表征HIV感染患者的低CD 4 + T细胞计数的不利免疫学环境中，也能靶向最常见的AIDS恶性肿瘤的病毒病原体。在这个提议中，我们选择卡波西肉瘤（KS）相关疱疹病毒（KSHV或HHV 8）作为我们的模型靶点，KS，原发性渗出性淋巴瘤和多中心Castleman病的病原体。具体来说，我们将确定相关的CD 8 + T细胞表位从基因产物的KSHV和开发疫苗接种计划，将引发效应和记忆CD 8 + T细胞特异性的这些表位。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。此应用程序与RFA的目标高度相关，因此更适合大机会征集而不是挑战补助金：它将提供机会，扩大科德斯实验室和布洛克实验室之间新生但已经富有成效的跨学科合作，从而确定疫苗靶点，一个新的模型系统，用于测试所选目标的相关性和正在研究的疫苗接种方法的有效性（潜在地验证它们用于与免疫受损个体相关的多种恶性肿瘤和疾病状态），随着项目的发展，新的就业机会会立即增加。 公共卫生相关性：艾滋病毒/艾滋病患者无法抵抗许多传染病，包括可导致癌症的特定病毒。尽管在相对富裕的国家，如美国和其他发达国家，艾滋病患者的所有死亡中有近三分之一是由于癌症，其中一半是由两种病毒之一引起的，EBV和鲜为人知的KSHV。在我们提出的研究中，我们将重点放在KSHV上，它会导致卡波西肉瘤，这是一种最常见的艾滋病相关癌症。我们希望更好地了解体内的免疫细胞如何识别和抑制KSHV及其可能导致的癌症，然后开发使用这种病毒部分制成的疫苗的新方法，以提高艾滋病患者抵抗KSHV的能力，并预防和治疗它引起的疾病。

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.