Viral and Cellular Gene Expression During Cytomegalovirus Infection. Infection with CMV and expression of 208 nonredundant viral genes alters host cells in many ways that may be important for virus survival in the immunocompetent host as well as for the generation of acute and chronic diseases in the immunocompromised host. The recent generation of microarrays with thousands of human cDNAs makes it possible to comprehensively and simultaneously sample expression of viral and cellular gene expression during infection. Preliminary screening of a 10,000 human gene microarray has shown that, by 24 hpi, CMV significantly activates levels of transcripts encoding particular classes of genes (cellular DNA replication, proteasome components, RNA splicing, and others), but markedly suppresses levels of transcripts from gene classes involved in cell motility, inflammation, vascular regulation and immune response in a manner that mimics the impact of corticosteroids on these same cells. We propose to include all CMV genes along with 10,000 cellular genes to: (i) identify the viral genes controlling the suppression of immune-related host cell gene expression, and (ii) investigate the role of the viral genes expressing the major regulatory proteins IE1, IE2 and UL37 in activation and suppression of viral and cellular gene expression. Microarray evaluation of viral strains that differ in their complement of genes and of defined mutants will be used to systematically map those viral functions that control suppression of cellular gene expression and to understand how the expression of other viral genes may play a role in this process. These analyses will lead to an understanding of viral and cellular genetic pathways that accompany regulator functions will focus on understanding the role that these functions play in activating or repressing cellular gene expression and blocking apoptosis. These studies will reveal the role viral regulatory genes have in controlling gene expression in different cell types. It is this ability to interact on many levels with the host and maintain favorable conditions that we believe leads CMV to alter the host cell and replicate successfully, evade natural and adaptive immune surveillance, and cause disease in immunocompromised individuals.
