Persistent but benign infection with cytomegalovirus (CMV) is a nearly ubiquitous occurrence in most human populations. However, primary infection of a mother, especially in the first trimester of pregnancy, can lead to serious CNS disease in a developing fetus or newborn infant, and reactivated acute infection causes retinitis and life-threatening pneumonitis and hepatitis in immunosuppressed AIDS and bone marrow or solid organ transplant patients. Some unresolved chronic disease is also thought to be associated with the virus especially in donor tissue in transplant recipients. Despite the fact that CMV has a very large and complex DNA genome (229-kb, 180 ORFs), current evidence suggests that it can persist in many cell types in one of two principal types of quiescent states that the applicant refers to as Class I latency (no detectable viral protein synthesis) and Class II latency (only the major immediate-early proteins being expressed). In vivo monocytes provide one type of Class I latency that can be converted to Class II and productive infection after differentiation into macrophages. In this research program, the applicants have been involved in identifying and studying the detailed molecular genetics and mechanism of action of the key CMV encoded regulatory proteins (IE1 and IE2) and two associated inducible cis-acting enhancer motifs (MIE and IES) that control the state of infection. These genes and elements sense appropriate intracellular conditions for non-permissive or permissive infection and are believed to trigger the switch between Class I and Class II latency and full productive lytic cycle infection. Further detailed knowledge of the very earliest nuclear events in CMV: host cell interactions is necessary for an understanding of the factors that govern permissive, latent and reactivated infections and could provide a basis for eventual more successful therapeutic interventions. In the current funding period they propose to extend studies of the interplay between these genes and enhancers and cellular cell cycle and growth regulatory mechanisms using: (I) A cell culture U937 based monocyte to macrophage induction system model; (II) Semi-permissive U373 astrocytoma cell lines in which IE1 and IE2 are constitutively inducibly-expressed; (III) Recombinant CMV vectors in which various IE function have been deleted or can be conditionally disrupted.
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