HBV cccDNA and integrated DNA in HIV coinfection and HBV monoinfection

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Project summary/ Abstract: Chronic hepatitis B (CHB) remains a substantial public health burden despite the availability of effective vaccines and approved therapies. Functional cure with HBsAg clearance is the current HBV treatment endpoint. Although prolonged therapy with nucleos(t)ide analogs can suppress HBV DNA replication, the rate of functional cure remains low. With functional cure, it is expected that the intrahepatic cccDNA would be in a transcriptional inactive state regardless the status of the integrated HBV DNA (iDNA). We and others provided evidence that the iDNA produces a major source of HBsAg especially in HBeAg-negative CHB. The current serum assay cannot distinguish HBsAg generated from intrahepatic cccDNA versus iDNA. In this proposal, we focus to 1) evaluate both the concentrations and the transcriptional activities of cccDNA and iDNA in CHB with and without HIV; 2) assess the roles of epigenetic mechanisms in cccDNA and iDNA transcription in treatment response; 3) compare the intrahepatic and plasma iDNA levels, and to correlate iDNA levels with HBsAg titers and treatment outcomes; 4) evaluate second generation serum HBV pgRNA and novel HBV core Ag (HBcAg) biomarkers as surrogate markers for cccDNA; 5) apply the clinical, serological and virological parameters to generate predictors of treatment-induced transcriptionally inactive cccDNA and HBsAg loss. This is a unique translational research study that utilize well-characterized liver and blood samples as well as advanced molecular technologies and methods to understand the virological mechanisms of HBV persistence, inactivity, and clearance. The success of our study will have significant impacts in the development of novel therapies leading to a complete HBV cure.