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的艾滋病恶性肿瘤的病毒病原体的疫苗策略，即使在HIV感染患者典型的低CD4+T细胞计数的不利免疫环境中也是如此。在这个方案中，我们选择了Kaposi肉瘤(KS)相关疱疹病毒(KSHV或HHV8)作为我们的模型目标，KS、原发渗出性淋巴瘤和多中心Castleman病的病原体。具体地说，我们将从KSHV的基因产物中识别相关的CD8+T细胞表位，并开发疫苗接种计划，以诱导针对这些表位的效应性和记忆性CD8+T细胞。该项目有可能为脆弱患者群体的疫苗接种或受影响个人的过继转移治疗提供相关目标，并提供证据证明新的疫苗接种方法对免疫功能低下的患者有效。这项申请与RFA的目标高度相关，因此更适合于Grand Opportunities征集而不是Challenges Grant：它将提供机会，扩大Kedes和Bullock实验室之间新生但已富有成效的跨学科合作，从而确定疫苗靶标、测试所选靶标的相关性和正在研究的疫苗接种方法的有效性的新型模型系统(潜在地验证它们对多种恶性肿瘤和与免疫受损个人相关的疾病状态的使用)，以及随着计划的发展立即提供更多新的就业机会。 与公共卫生相关：艾滋病毒/艾滋病患者无法抵抗许多传染病，包括可能导致癌症的特定病毒。尽管美国和其他发达国家等相对富裕的国家可以获得良好的艾滋病毒治疗，但艾滋病患者近三分之一的死亡是由于癌症，其中一半是由两种病毒中的一种引起的，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，KSHV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免疫细胞如何正常识别和抑制KSHV及其可能导致的癌症，然后开发新的方法，使用这种病毒的部分制成的疫苗来提高艾滋病患者抵御KSHV并预防和治疗其引起的疾病的能力。

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.