The Role of HBeAg in HBV Persistence

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

ABSTRACT Chronic hepatitis B virus (HBV) infection remains a substantial public health burden affecting approximately 296 million individuals worldwide and at least 1.2 million in the United States. Chronic hepatitis B (CHB) is one of the leading risk factors of cirrhosis and the deadly liver cancer. Therefore, it is important to elucidate the mechanism of HBV persistence and find a cure for chronic hepatitis B. The development of HBV persistence is due to the failure of host immune system to clear the virus infection, and the longevity of the persistent form of HBV DNA genome, namely the covalently closed circular (ccc) DNA in a nuclear episomal minichromosome structure. The overall goal of this research project aims to elucidate the role of the understudied hepatitis B e antigen (HBeAg) in HBV persistence. HBeAg positivity and its high titer reflect the high level of HBV replication and immune tolerance in CHB patients. HBeAg seroconversion is usually considered to be a beneficial milestone and evidence of reduced viral replication. In the prior funding period, we have revealed that the circulating HBeAg inhibits host anti-HBV T cell responses via inducing the expansion of monocytic myeloid-derived suppressor cells (mMDSCs), and the intracellular HBeAg intermediate p22 blunts IFNα-elicited JAK-STAT signal cascade through blocking STAT proteins nuclear import. In the current project, we will focus on the intracellular events of HBeAg to study the mechanisms of p22 biogenesis, interactome, epigenetic regulations of viral cccDNA transcription and host ISG expression. The accomplishment of this project will shed new lights on the mechanism of HBeAg-mediated HBV persistence, and ultimately lead to the development of novel therapeutics to cure HBV infection.