Human adenoviruses are under intense scrutiny as vehicles for gene therapy and as anticancer agents in humans. Nevertheless, many basic aspects of the mechanisms by which these viruses replicate efficiently in permissive cells remain poorly understood. These processes include the co-ordination of synthesis of progeny viral DNA genome with production of the structural proteins of virus particles. In adenovirus-infected cells, transcription of the genes encoding the latter proteins requires viral DNA synthesis. The long term objective of these studies is elucidation of the mechanisms by which viral and cellular components co-operate in such temporal regulation of viral transcription. To this end, a cellular transcriptional repressor responsible for the viral DNA synthesis-dependent transcription of the late IVa2 gene will be identified and characterized, so that its normal function and mechanism of action can be investigated. The protein encoded by the IVa2 gene is a sequence-specific DNA binding protein that has been implicated in stimulation of transcription from the promoter of the major late transcription, which contains the coding sequences for all but one structural protein, and in virion assembly. Complementary biochemical, molecular and genetic methods will be used to establish the roles of this important viral protein in infected cells and investigate the mechanisms by which it acts. The possibility that a novel mechanism regulates the rate at which the viral replication proteins are produced will also be assessed by genetic methods.
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