A NON-HUMAN PRIMATE MODEL FOR CYTOMEGALOVIRUS VACCINES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本项目的目的是(A)鉴定RhCMV IL-10和US28蛋白在RhCMV复制周期中的作用，以及(B)通过构建含有病毒IL-10和US28基因缺失的RhCMV变异体来开发针对人类巨细胞病毒的新型疫苗设计。 巨细胞病毒(CMV)感染在免疫功能正常的个体中很少引起感染的临床症状。相反，在那些拥有完全功能的免疫系统的人中，绝大多数原发感染都是无症状的。相比之下，在那些没有功能免疫系统的人中，CMV感染是发病率和死亡率的重要原因。这包括那些与艾滋病毒共同感染的人感染CMV。因此，通过这两项赠款开发的CMV疫苗战略将对保护CMV疾病的最高风险人群，包括艾滋病毒艾滋病患者具有直接的临床意义。 目前还没有获得许可的人类巨细胞病毒(HCMV)疫苗。已经对减毒活疫苗和重组亚单位疫苗进行了有限的临床试验。尽管部分成功地保护了肾移植受者免受疾病的侵袭，但开发引起保护性免疫的巨细胞病毒疫苗的目标尚未实现。人类巨细胞病毒疫苗的发展存在障碍。设计有效的巨细胞病毒疫苗需要对保护性免疫的相关因素进行表征，并更好地了解巨细胞病毒的自然病史。人巨细胞病毒的这两个方面都没有完全解决，很难在人类身上进行研究。研究表明，两种体液免疫指标，中和抗体和抗体亲和力，以及一种细胞免疫指标，CTL，可用于评估保护性抗HCMV免疫。与保护性免疫反应相关的两种巨细胞病毒蛋白Gb和pp65代表了任何合理疫苗的起点。最近关于巨细胞病毒和与之密切相关的恒河猴巨细胞病毒(RhCMV)的数据强烈表明，病毒对宿主免疫反应的调节是CMV自然历史的关键组成部分。 巨细胞病毒似乎已经进化出改变淋巴细胞信号和运输的策略。根据序列同源性，可以合理地推断，在感染过程中，HCMV具有针对促炎免疫反应的干扰作用。巨细胞病毒调节宿主免疫反应的能力减弱应该会限制病毒复制和疾病后遗症。因此，巨细胞病毒疫苗必须针对结构和免疫调节ORF，以减少感染和/或疾病的病毒学参数。换句话说，当针对已识别的免疫原，如Gb和pp65，以及以免疫调节ORF为代表的新疫苗靶点进行免疫接种时，保护性免疫将得到增强。这一方法的成功结果将证明，通过免疫来减弱CMV的免疫调节ORF是一种合理的疫苗策略。这将从根本上改变疫苗应对巨细胞病毒的模式。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this project is to (a) characterize the roles of the RhCMV interleukin-10 and US28 proteins in the RhCMV replication cycle, and (b) develop novel vaccine designs against human cytomegalovirus by constructing RhCMV variants containing deletions in the viral interleukin-10 and US28 genes. Cytomegalovirus (CMV) infection in an immunocompetent individual infrequently causes clinical signs of infection. Rather, the vast majority of primary infections in those with a fully functional immune system are asymptomatic. In contrast, CMV infection in those without a functional immune system is a significant cause of morbidity and mortality. This includes CMV infections in those co-infected with HIV. Therefore, CMV vaccine strategies developed through these two grants will have direct clinical relevance to protecting those most at risk for CMV disease, including HIV AIDS patients. There are no licensed vaccines for human cytomegalovirus (HCMV). Limited clinical trials have been conducted with live attenuated and recombinant subunit vaccines. Despite partial success protecting from disease in renal transplant recipients, the goal of developing an HCMV vaccine that elicits protective immunity has not been achieved. There are impediments to the development of an HCMV vaccine. Design of an effective HCMV vaccine requires characterization of the correlates of protective immunity and a better understanding of HCMV natural history. Both aspects of HCMV are incompletely resolved and difficult to investigate in humans. Studies have suggested that two measures of humoral immunity, neutralizing antibodies and antibody avidity, and one measure of cellular immunity, CTL, are useful for assessing protective anti-HCMV immunity. The two HCMV proteins associated with protective immune responses, gB and pp65, represent starting points for any rational vaccine. Recent data on HCMV and the closely related rhesus CMV (RhCMV) strongly implicate viral modulation of host immune responses as a critical component of CMV natural history. CMV appears to have evolved strategies that alter lymphoid cell signaling and trafficking. Based on sequence homologies, it is reasonable to infer that HCMV has targeted pro-inflammatory immune responses for disruption during infection. Attenuation of HCMVs ability to modulate host immune responses should limit viral replication and disease sequelae. Accordingly, HCMV vaccines must be directed against both structural and immune modulating ORF to reduce virologic parameters of infection and/or disease. In other words, protective immunity will be enhanced when vaccination is directed against identified immunogens, such as gB and pp65, together with novel vaccine targets represented by immune modulating ORF. A successful outcome of this approach will demonstrate that attenuation of the CMV immunomodulatory ORF by immunization represents a rational vaccine strategy. This would fundamentally alter the paradigm for vaccine approaches to HCMV.