A NON-HUMAN PRIMATE MODEL FOR CYTOMEGALOVIRUS VACCINES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本项目的目的是（a）表征RhCMV白细胞介素-10和US 28蛋白在RhCMV复制周期中的作用，以及（B）通过构建病毒白细胞介素-10和US 28基因缺失的RhCMV变体来开发针对人巨细胞病毒的新型疫苗设计。 巨细胞病毒（CMV）感染的免疫功能正常的个体很少引起感染的临床症状。 相反，在具有完全功能的免疫系统的人中，绝大多数原发性感染是无症状的。 相比之下，在那些没有功能性免疫系统的人中，CMV感染是发病率和死亡率的重要原因。 这包括合并感染艾滋病毒的人中的CMV感染。 因此，通过这两项赠款开发的CMV疫苗策略将对保护那些最有可能感染CMV疾病的人（包括HIV AIDS患者）具有直接的临床意义。 目前尚无针对人巨细胞病毒（HCMV）的许可疫苗。 已对减毒活疫苗和重组亚单位疫苗进行了有限的临床试验。 尽管在肾移植受者中预防疾病取得了部分成功，但开发增强保护性免疫的HCMV疫苗的目标尚未实现。HCMV疫苗的开发存在障碍。 设计有效的HCMV疫苗需要表征保护性免疫的相关性和更好地理解HCMV自然史。HCMV的这两个方面都没有完全解决，难以在人类中进行研究。研究表明，体液免疫的两个指标，中和抗体和抗体亲合力，以及细胞免疫的一个指标，CTL，可用于评估保护性抗HCMV免疫。与保护性免疫应答相关的两种HCMV蛋白gB和pp 65代表了任何合理疫苗的起点。 HCMV和密切相关的恒河猴CMV（RhCMV）的最新数据强烈暗示病毒调节宿主免疫反应作为CMV自然史的重要组成部分。 CMV似乎已经进化出改变淋巴细胞信号传导和运输的策略。基于序列同源性，可以合理地推断HCMV在感染期间具有靶向促炎免疫应答以破坏。HCMVs调节宿主免疫应答能力的减弱应限制病毒复制和疾病后遗症。因此，HCMV疫苗必须针对结构和免疫调节ORF两者以降低感染和/或疾病的病毒学参数。换句话说，当疫苗接种针对鉴定的免疫原，如gB和pp 65，以及由免疫调节ORF代表的新疫苗靶标时，保护性免疫将增强。这种方法的成功结果将证明，通过免疫接种使CMV免疫调节ORF减毒代表了合理的疫苗策略。这将从根本上改变HCMV疫苗方法的范式。

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.