Develop a therapeutic vaccine approach by removing viral immune evasion

描述(申请人提供)：人类伽马疱疹病毒、爱泼斯坦-巴尔病毒(EBV或HHV-4)和卡波西肉瘤相关疱疹病毒(KSHV或HHV-8)的持续感染与几种恶性肿瘤有关，这些恶性肿瘤经常在免疫缺陷病毒(HIV)感染的艾滋病患者中发展，并经常在他们的口腔中发现。通过与宿主的共同进化，疱疹病毒已经获得了许多策略来对抗干扰素反应的各个方面，这有力地表明了I型干扰素对病毒的强大选择压力，以对抗病毒成功感染。I型干扰素不仅是先天免疫的主要抗病毒效应器，而且对长期记忆适应性反应的发展也很重要。总体假设是，逃避I型干扰素反应的能力对病毒在宿主中的有效生长至关重要，而从病毒中去除抗干扰素的能力会导致高度减毒的免疫原性病毒适合于 接种疫苗。为了验证这一假说，将致力于以下具体目标：1)阐明病毒基因抑制I型干扰素信号的机制；2)确定体内和体外抗干扰素基因的生物学意义；3)通过选择性灭活病毒免疫逃避基因来测试合理的治疗疫苗策略。长期目标是制定预防和治疗与持续感染KSHV和EBV相关的癌症的战略。上述目标的实现是实现长期目标的重要一步，将证明治疗性疫苗方法的可行性，并为未来KSHV灵长类动物模型的临床前研究奠定基础。此外，阐明一组保守的病毒蛋白的抗干扰素功能可能揭示治疗措施的潜在靶点。

DESCRIPTION (provided by applicant): Persistent infections of human gamma-herpesviruses, Epstein-Barr virus (EBV or HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8), are associated with several malignancies, which frequently develop in immunodeficiency virus (HIV)-infected AIDS patients and often found in their oral cavities. Through co-evolution with hosts, herpesviruses have acquired many strategies to counteract various aspects of the type interferon (IFN) responses, strongly indicating a powerful selective pressure from type I IFNs on the virus to antagonize it for successful infection. Type I IFNs are not only the major anti-viral effector of innate immunity but also important for the development of long-term memory adaptive responses. The overall hypothesis is that the ability to evade the type I IFN response is critical for effective viral growth in a host and that removal f the anti-IFN ability from the virus leads to a highly attenuated but immunogenic virus suitable for vaccination. To test the hypothesis, the following specific aims will be pursued: 1) to elucidate the mechanisms by which the viral genes inhibit type I IFN signaling, 2) to determine the biological significance of anti-IFN genes in vitro and in vivo, and 3) to test a rational therapeutc vaccine strategy by selective inactivation of viral immune evasion genes. The long-term goal is to develop strategies for preventing and treating cancers associated with persistent infections of KSHV and EBV. Accomplishment of the above aims, which is an important step towards achievement of the long-term goal, will demonstrate the feasibility of the therapeutic vaccine approach and establish a foundation for future pre-clinical studies in the KSHV primate model. Moreover, elucidating the anti-IFN function of a group of conserved viral proteins may reveal potential targets for therapeutic measures.