IDENTIFICATION AND CHARACTERIZATION OF HUMAN CYTOMEGALOVIRUS/CELLULAR PROTEINS

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Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen capable of establishing either a persistent or latent infection. In most cases, HCMV infection is benign or asymptomatic in healthy ndividuals. However, serious illness occurs upon infection in infants and immunocompromised adults. The genome is expressed in et temporally ordered manner and occurs in three separate phases: immediate early IE), early, and late. The early phase, which begins just prior to DNA replication, is further divided into three subclasses based on the expression level of early transcripts through the course of infection. / Studies on several HCMV early promoters have been undertaken to determine how HCMV early gene expression is regulated. Several specific DNA sequences as well as proteins have been identified. Some HCMV early promoter sequences are bound by HCMV specific proteins (IE86) as well as such as cellular proteins such as the cyclic AMP response element binding protein (CREB) or activated transcription factor [ATF). Activation of the early promoters requires the presence of IE86 and IE72 proteins or IE86 alone. * The UL98 early gene encodes a 58-65 kDa protein and is part of a family of nested 3' coterminal ORFs that share a polyadenylation site. The alkaline exonuclease plays a critical role in processing newly synthesized replicated copies of genome during maturation. We have determined that the HCMV UL98 promoter utilizes CRE and gamma (g) IRE to optimally regulate the expression of this early gene. In deletion analysis, a Tcell factor-like element (TCP) has also been implicated. Studies have also shown that the protein CREB interacts with the CRE sequences in gel mobility shift assays. However, the specific proteins associated with regulation through the TCF-1 and gIRE sites have yet to be characterized. Our objective in the following studies will be to identify the viral/cellular protein(s) that bind the TCF-1 element and gIRE. The analysis of regulatory mechanisms for this key viral early gene will provide insight into the overall regulation of early gene expression and the future development of novel antiviral therapies.