Hepatitis B virus (HBV) is the most prevalent human tumor virus. It is estimated that chronic HBV infectioncauses 1,000,000 cases of liver cancer annually. HBV actively replicates within liver cells to maintain itschronic infection. We work to understand the mechanisms by which HBV replicates in order to identifytargets for new therapies. During this last funding period our most significant findings and progress included:(1) learning that HBV genome replication requires complex contributions from the replication template. Thegenomic RNA and DMA replication intermediates are not passive templates, but proceed through dynamictopologies that guide their own replication; (2) elucidating the involvement of the host cellular multivesicularbody pathway in HBV virion production; and (3) conducting the first high throughput genetic screen tosystematically identify host genes involved in HBV replication. This present proposal will build uponprogress engendered during the last funding period. This project has three aims: (1) to study the synthesisof plus-strand DNA to elucidate (a) the mechanisms of template switching and inhibition of in situ priming, (b)the role of the C-terminus of capsid protein, and (c) the relationship between genome maturation and capsidenvelopment; (2) to study the synthesis, accumulation and maintenance of cccDNA; and (3) to study the roleof the Rho GTPase pathway in HBV virion production. These studies will uncover new mechanisms of virusreplication and identify targets for new and better HBV therapies.
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