Cytomegalovirus virulence in immunodeficient hosts

描述（由申请人提供）：人巨细胞病毒（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。CMV系统性感染的研究应提供深入了解播散性CMV疾病的发病机制和毒力。在原发性急性感染期间，脾中产生的病毒传播到其他器官，并且是许多器官（包括唾液腺、肾和骨髓）的后续感染的主要来源之一，CMV最终在这些器官中建立持续和潜伏感染。此外，脾脏也是病毒持续和潜伏感染的部位。CMV在脾脏中的复制是病毒毒力和发病机制的主要决定因素。了解脾脏中CMV感染的机制对于制定阻断器官中病毒复制的策略非常重要，并将为CMV相关疾病的治疗和预防提供见解。使用小鼠巨细胞病毒（MCMV）感染免疫缺陷动物作为模型系统，拟议的研究是确定CMV复制所需的病毒基因在脾脏中，并研究这些病毒决定簇在支持CMV感染的器官中的功能。我们最近已经产生了一个池的MCMV突变体，其中包含一个转座子序列，并已分离出一种病毒突变体，这是不是致命的，在所有在杀死免疫缺陷动物，并在脾脏中复制缺陷。在拟议的研究中，动物将通过直接将病毒接种到脾脏而感染病毒突变体，并将分离出那些在脾脏中复制缺陷的突变体。将研究这些突变体的毒力，并鉴定突变的基因。此外，将研究所鉴定的病毒决定簇如何在支持脾脏MCMV感染中起作用的机制。这些研究将导致CMV复制在脾脏中的病毒决定簇的鉴定和这些基因在系统性CMV感染中的功能的调查。鉴定病毒毒力因子，了解CMV毒力和致病机制，将有助于开发新的策略，用于治疗和预防播散性CMV感染。

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.