Cytomegalovirus virulence in immunodeficient hosts

描述（由申请人提供）：人类巨细胞病毒（HCMV）的播散性感染，如肺炎和视网膜炎，是最常见的艾滋病相关机会性并发症之一。巨细胞病毒全身性感染的研究将有助于深入了解播散性巨细胞病毒疾病的发病机制和毒力。在原发性急性感染期间，在脾脏产生的病毒传播到其他器官，是随后许多器官感染的主要来源之一，包括唾液腺、肾脏和骨髓，巨细胞病毒最终在这些器官建立持久和潜伏感染。此外，脾脏也是病毒持续性和潜伏性感染的一个部位。巨细胞病毒在脾脏中的复制是病毒毒力和发病机制的主要决定因素。了解脾脏巨细胞病毒感染的机制对于制定阻断病毒在该器官复制的策略非常重要，并将为巨细胞病毒相关疾病的治疗和预防提供见解。利用免疫缺陷动物的小鼠巨细胞病毒（MCMV）感染作为模型系统，本研究旨在确定巨细胞病毒在脾脏复制所需的病毒基因，并研究这些病毒决定因素在支持巨细胞病毒感染器官中的功能。我们最近产生了一个包含转座子序列的MCMV突变体库，并分离出一种病毒突变体，该突变体在杀死免疫缺陷动物时完全没有毒性，并且在脾脏中复制有缺陷。在该研究中，将病毒直接注入动物的脾脏，使其感染病毒突变体，并将在脾脏中复制有缺陷的突变体分离出来。这些突变体的毒力将被研究，被突变的基因将被识别。此外，还将研究已确定的病毒决定因子如何支持脾脏MCMV感染的机制。这些研究将导致鉴定脾脏巨细胞病毒复制的病毒决定因素，并研究这些基因在系统性巨细胞病毒感染中的功能。鉴定病毒毒力因子，了解巨细胞病毒毒力和发病机制，将有助于开发治疗和预防播散性巨细胞病毒感染的新策略。

DESCRIPTION (provided by applicant): Disseminated infections by human cytomegalovirus (HCMV), such as pneumonia and retinitis, account for one of the most common AIDS-associated opportunistic complications. Studies of CMV systemic infection should provide insight into the pathogenesis and virulence of disseminated CMV diseases. During primary acute infection, the viruses produced in the spleen disseminate to other organs and represent one of the major sources for subsequent infection of many organs, including the salivary gland, kidney, and bone marrow, where CMV ultimately establishes persistent and latent infections. Moreover, the spleen is also a site for viral persistent and latent infections. CMV replication in the spleen is a major determinant of viral virulence and pathogenesis. Understanding the mechanism of CMV infections in the spleen is important for developing strategies to block viral replication in the organ and will provide insight into the treatment and prevention of CMV-associated diseases. Using murine cytomegalovirus (MCMV) infection in immunodeficient animals as a model system, the proposed study is to identify the viral genes required for CMV replication in the spleen and to study the functions of these viral determinants in supporting CMV infections in the organ. We have recently generated a pool of MCMV mutants that contained a transposon sequence and have isolated a viral mutant that was not virulent at all in killing immunodeficient animals and was defective in replication in the spleen. In the proposed research, animals will be infected with viral mutants though direct administering the virus to the spleens and those mutants that are defective in replicating in the spleens will be isolated. The virulence of these mutants will be studied and the genes that are mutated will be identified. Moreover, the mechanism of how the identified viral determinants function in supporting MCMV infections in the spleen will be investigated. These studies will lead to the identification of viral determinants for CMV replication in the spleen and the investigation of the functions of these genes in systemic CMV infections. Identification of viral virulence factors and understanding the mechanism of CMV virulence and pathogenesis will facilitate the development of novel strategies for treatment and prevention of disseminated CMV infections.