Cytomegalovirus virulence in immunodeficient hosts

描述(申请人提供)：人类巨细胞病毒(HCMV)播散性感染，如肺炎和视网膜炎，是与艾滋病相关的最常见的机会性并发症之一。对CMV全身性感染的研究将有助于深入了解播散性CMV疾病的发病机制和毒力。在初次急性感染期间，脾中产生的病毒传播到其他器官，并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，在这些器官中，CMV最终建立持续和潜伏的感染。此外，脾也是病毒持续和潜伏感染的场所。巨细胞病毒在脾中的复制是病毒毒力和致病的主要决定因素。了解脾中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洞察力。本研究以免疫缺陷动物中的小鼠巨细胞病毒(MCMV)感染为模型系统，旨在确定CMV在脾内复制所需的病毒基因，并研究这些病毒决定簇在支持器官内CMV感染中的作用。我们最近产生了一个含有转座子序列的MCMV突变体，并分离出了一个病毒突变体，它对杀死免疫缺陷的动物完全没有毒力，而且在脾中的复制存在缺陷。在这项拟议的研究中，动物将通过直接给脾注射病毒来感染病毒突变株，并分离出在脾中复制有缺陷的突变株。这些突变株的毒力将被研究，突变的基因将被识别。此外，还将研究已确定的病毒决定因素如何在支持脾内MCMV感染方面发挥作用的机制。这些研究将有助于确定CMV在脾中复制的病毒决定因素，并调查这些基因在系统性CMV感染中的功能。识别病毒毒力因子，了解CMV毒力和致病机制，将有助于开发新的治疗和预防播散性CMV感染的策略。

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.