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: 7715956
• 负责人: VICTOR Robert DEFILIPPIS
• 金额: $ 2.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715956
• 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 巨细胞病毒（CMV）蛋白pp 65调节宿主免疫应答。同时，它也是细胞免疫应答的主要抗病毒靶点。pp 65是恒河猴CMV（RhCMV）和人CMV（HCMV）被膜的最丰富的组分，所述被膜是衣壳和被膜之间释放到细胞质中的富含蛋白质的层。有趣的是，两种病毒的体外生长都不需要pp 65。这使我们能够产生pp 65缺陷型RhCMV，以检查1）蛋白质的免疫调节功能是否对病毒在体内的存活至关重要;或2）pp 65的已证明的免疫原性在功能性免疫的存在下限制病毒复制。用突变型RhCMV感染恒河猴（RM）将允许检查pp 65对于体内CMV感染的重要性。因此，我们将用缺失pp 65的重组病毒感染CMV初治RM，并评估该病毒是否能够建立原发性和慢性感染，如果是，则病毒学和免疫学参数如何与野生型RhCMV感染期间的先前观察结果进行比较。根据本实验的结果，我们将评估pp 65缺失的病毒是否能够重新感染这些动物。如果pp 65编码的功能是生产性体内感染所必需的，我们预计缺失病毒的复制要么检测不到，要么比野生型RhCMV的检测结果更不稳定。相反，如果pp 65免疫原性对宿主免疫应答控制病毒感染的能力至关重要，我们预测pp 65缺失病毒的复制将大于野生型RhCMV。这些实验的结果对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。