Human cytomegalovirus (CMV), a member of the human herpes virus family, has a propensity for the establishment of latent and persistent infections. Most individuals acquire CMV early in life, but disease in normal healthy individuals is rare. CMV infection is problematic in pregnant women since virus has the ability to cross the placenta and infect the fetus in utero. As a result, CMV can cause congenital abnormalities including cytomegalic inclusion disease and even death in newborns is a leading cause of birth defects. CMV infection and reactivation is a major cause of concern in transplant patients, and in individuals that suffer from immunodeficiencies such as the acquired immune deficiency syndrome (AIDS). The immediate early proteins of CMV are involved in the coordinate regulation of gene expression in the infected cell. Clearly, these proteins regulate viral genes and probably cellular genes, or at least some aspect of cell gene expression. The goal of this study is to identify the regulatory mechanisms employed by CMV, and in particular, those related to the IE proteins, during interaction with the host cell. The following studies will be performed: 1. Mutational analysis of functional IE protein domains. The goal of this study is to generate point mutants within these putative regulatory domains and to assess their function in biological and molecular analyses. 2. Structural and functional analysis of IE genes. Our studies demonstrate that IE 1 codes for additional proteins of 85kd, 38kd and 31kd. Also, we have identified new gene products from IE 2. We will accurately map the coding regions of these proteins and assess their role during CMV replication. 3. Analysis of the IE gene region at early and late times. We have identified new transcripts and proteins from the IE gene region which are expressed at early and late times. We will map these proteins to their specific genes and assess their potential regulatory function. 4. Mutational analysis of CMV early promotors. Early promotor regulatory mutants will be employed in biological and molecular analyses to assess their role during CMV replication.
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