THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO

巨细胞病毒磷酸蛋白65在体内病毒复制中的作用

• 批准号: 7561989
• 负责人: VICTOR Robert DEFILIPPIS
• 金额: $ 7.59万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561989
• 关键词: Animals; Antiviral Agents; Capsid; Chronic; Computer Retrieval of Information on Scientific Projects Database; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Cytoplasm; Development; Funding; Grant; Growth; Immune response; Immunity; In Vitro; Infection; Institution; Macaca mulatta; Measures; Outcome; Proteins; Research; Research Personnel; Resources; Role; Source; Time; United States National Institutes of Health; Virus; Virus Diseases; Virus Replication; cellular targeting; cytomegalovirus matrix protein 65kDa; design; immunogenicity; in vivo; mutant; recombinant virus; research study; vector vaccine

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cytomegalovirus (CMV) protein pp65 modulates the host immune response. At the same time it is also the primary antiviral target of cellular immune responses. pp65 is the most abundant component of the Rhesus CMV (RhCMV) and human CMV (HCMV) tegument, a protein-rich layer between the capsid and the envelope that is released into the cytoplasm. Interestingly, pp65 is not required for in vitro growth of either virus. This allowed us to generate a pp65-deficient RhCMV to examine whether 1) The protein's immunomodulatory functions are critical for virus survival in vivo; or 2) The demonstrated immunogenicity of pp65 limits virus replication in the presence of functional immunity. Infection of rhesus macaques (RMs) with mutant RhCMV will allow examination of the importance of pp65 for CMV infection in vivo. Therefore we will infect CMV-na¿ve RM with a pp65-deleted recombinant virus and evaluate whether this virus is able to establish primary and chronic infection and, if so, how virological and immunological parameters compare to previous observations made during infection with wild type RhCMV. Depending on the outcome of this experiment, we will then evaluate whether pp65-deleted virus is able to re-infect these animals. If pp65-encoded functions are required for productive in vivo infection, we expect replication of the deletion virus to be either undetectable or less robust than that measured for wild type RhCMV. Conversely, if the pp65 immunogenicity is crucial to the ability of the host immune response to control virus infection we predict that replication of the pp65-deleted virus will be greater than that for wild type RhCMV. The outcome of these experiments has implications both for the design of CMV vaccines and antiviral treatments as well as the development of CMV as a vaccine vector.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 巨细胞病毒 (CMV) 蛋白 pp65 调节宿主免疫反应。同时它也是细胞免疫反应的主要抗病毒靶点。 pp65 是恒河猴 CMV (RhCMV) 和人 CMV (HCMV) 外皮中最丰富的成分，外皮是衣壳和释放到细胞质中的包膜之间富含蛋白质的层。有趣的是，这两种病毒的体外生长都不需要 pp65。这使我们能够生成 pp65 缺陷的 RhCMV，以检查：1) 该蛋白的免疫调节功能对于病毒在体内的存活至关重要；或 2) pp65 已证明的免疫原性在存在功能性免疫的情况下限制病毒复制。用突变体 RhCMV 感染恒河猴 (RM) 将可以检查 pp65 对于体内 CMV 感染的重要性。因此，我们将用 pp65 缺失的重组病毒感染 CMV-na¿ve RM，并评估该病毒是否能够建立原发性和慢性感染，如果是的话，与之前在野生型 RhCMV 感染过程中观察到的情况相比，病毒学和免疫学参数如何。根据该实验的结果，我们将评估 pp65 缺失的病毒是否能够重新感染这些动物。如果 pp65 编码的功能是有效的体内感染所必需的，我们预计缺失病毒的复制要么无法检测到，要么不如野生型 RhCMV 的复制稳健。相反，如果 pp65 免疫原性对于宿主免疫反应控制病毒感染的能力至关重要，我们预测删除 pp65 的病毒的复制将比野生型 RhCMV 的复制更大。这些实验的结果对于 CMV 疫苗和抗病毒治疗的设计以及 CMV 作为疫苗载体的开发都有影响。