Epstein-Barr Virus: A persistent vaccine vector

描述（由申请人提供）：本申请是对“重大机遇”（GO） RFA-OD-09-004“艾滋病相关恶性肿瘤疫苗开发探索性研究”的回应。我们将重点探索使用爱泼斯坦-巴尔病毒作为持久性疫苗载体，诱导对HIV感染的终身免疫反应。诱导针对艾滋病毒感染的终身保护性免疫的战略仍然难以捉摸。疱疹病毒在人类中建立持久性、终身感染，并根据其遗传和生物学分为三类。目前正在研究α (HSV)、β (CMV)和γ -2 （RRV）疱疹病毒作为诱导终身免疫的潜在持续性疫苗载体。爱泼斯坦-巴尔病毒是一种γ -1疱疹病毒，在抗原呈递细胞（即B细胞）中终生存在，并刺激有效的终身细胞和体液免疫反应。EBV感染上调了许多与抗原呈递相关的细胞基因，与其他疱疹病毒相比，EBV携带的免疫逃避基因很少。EBV永生化淋巴母细胞系因其免疫刺激能力而被广泛用于体外实验。EBV的生物学特性不同于其他人类疱疹病毒，作为诱导终身免疫的疫苗载体，EBV可能具有独特的优势。所有新大陆和旧大陆的非人灵长类动物都自然感染与EBV密切相关的疱疹病毒，并且属于同一种γ -1或淋巴隐病毒（LCV）属。自然感染恒河猴的LCV （rhLCV）已被完全测序，具有与EBV相同的病毒基因库。恒河猴的实验性rhLCV感染准确地复制了人类的EBV感染，我们最近开发了一种细菌人工染色体系统来创建重组rhLCV。我们将使用这种EBV动物模型来评估表达SIV或HIV抗原的重组rhLCV诱导对γ -疱疹病毒疫苗的体液和细胞免疫反应的能力。这些试点研究将探索一种诱导终身持续疫苗反应的新方法，也将为EBV生物学提供重要的新见解。这些研究的数据将为在恒河猴EBV和HIV动物模型中设计和测试γ -1疱疹病毒疫苗对SIV/SHIV攻击的保护作用提供基础。

DESCRIPTION (provided by applicant): This application is in response to Grand Opportunity (GO) RFA-OD-09-004 for Exploratory Research in the Development of Vaccines for AIDS-associated Malignancies. We will focus explore using the Epstein-Barr virus as a persistent vaccine vector for inducing life- long immune responses against HIV infection. Strategies for inducing life long, protective immunity against HIV infection remain elusive. Herpesviruses establish persistent, life-long infection in humans and are divided into three different classes based on their genetics and biology. Alpha (HSV), beta (CMV), and gamma-2 (RRV) herpesviruses are being studied as potential persistent vaccine vectors for inducing life-long immunity. Epstein-Barr virus is a gamma-1 herpesvirus that persists for life in an antigen presenting cell, i.e. B cell, and stimulates potent life long cellular and humoral immune responses. EBV infection upregulates many cell genes associated with antigen presentation and EBV carries very few immune evasion genes relative to other herpesviruses. EBV immortalized lymphoblastoid cell lines are commonly used in vitro for their immunostimulatory ability. EBV biology is different from other human herpesviruses, and EBV may provide unique advantages as a vaccine vector for inducing life-long immunity. All New and Old World non-human primates are naturally infected with herpesviruses closely related to EBV and in the same gamma-1, or lymphocryptovirus (LCV), genus. The LCV naturally infecting rhesus macaques (rhLCV) has been fully sequenced and has an identical repertoire of viral genes as EBV. Experimental rhLCV infection of rhesus macaques accurately reproduces EBV infection in humans, and we have recently developed a Bacterial Artificial Chromosome system for creating recombinant rhLCV. We will use this EBV animal model to evaluate the ability of recombinant rhLCV expressing SIV or HIV antigens to induce humoral and cellular immune responses to the gamma-herpesvirus vaccines. These pilot studies will explore a novel approach for inducing life-long persistent vaccine responses and will also provide important new insights for EBV biology. The data from these studies will provide the foundations for designing and testing the protective effect of a gamma-1 herpesvirus vaccine against SIV/SHIV challenge in the rhesus macaque animal model for EBV and HIV. PUBLIC HEALTH RELEVANCE: Strategies for inducing life long, protective immunity against HIV infection remains a major challenge. Herpesviruses establish persistent infection in humans and induce vigorous life-long cellular and humoral immune responses. These studies will determine whether the unique biology of persistent gamma-1 herpesvirsues, like Epstein-Barr virus and the EBV-related lymphocryptovirus that naturally infects rhesus macaques (rhLCV), will provide unique advantages as a persistent viral vaccine vector for inducing durable humoral and cellular immune responses to HIV and SIV.