Molecular Mechanisms of the Cytomegalovirus Species Specificity

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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.