Molecular Mechanisms of the Cytomegalovirus Species Specificity

巨细胞病毒（CMV）具有高度的物种特异性，因为它们仅在其天然宿主物种的细胞中复制。然而，物种特异性的分子基础仍然知之甚少。在外来宿主的细胞中，对病毒基因表达和基因组复制的穿透后阻断限制了病毒复制和传播。此外，外来宿主的感染细胞经历程序性细胞死亡，这表明先天性抗病毒防御机制也参与其中。最近，我们已经分离出一个自发突变的小鼠CMV能够复制到高滴度在人类细胞。在编码病毒早期-1（E1）蛋白的区域中的特定突变被认为是扩展宿主范围表型的原因。本研究拟探讨巨细胞病毒E1蛋白在病毒基因表达和DNA复制中的作用。为此，我们将研究E1蛋白与其他病毒和细胞蛋白的相互作用。我们还将分析其他适应CMV突变体的DNA序列，以确定物种特异性的其他决定因素。将构建重组病毒以验证特定适应性突变的重要性。该项目的结果应导致更好地了解病毒复制机制和干扰宿主细胞的因素。

Cytomegaloviruses (CMVs) are highly species specific as they replicate only in cells of their natural host species. However, the molecular basis of the species specificity remains poorly understood. In cells of a foreign host, a post-penetration block to viral gene expression and genome replication restricts viral replication and spread. Moreover, infected cells of a foreign host undergo programmed cell death, suggesting that innate antiviral defense mechanisms are also involved. Recently we have isolated a spontaneous mutant of murine CMV capable of replicating to high titers in human cells. Specific mutations in the region encoding the viral Early-1 (E1) proteins were found to be responsible for the extended host range phenotype. In the proposed project we want to study the function of the cytomegalovirus E1 proteins in viral gene expression and DNA replication. To do this, we will investigate the interaction of the E1 proteins with other viral and cellular proteins. We will also analyze the DNA sequence of other adapted CMV mutants in order to identify additional determinants of the species specificity. Recombinant viruses will be constructed in order to verify the importance of specific adaptive mutations. The results of this project should lead to a better understanding of the viral replication machinery and interfering host cell factors.