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Hepatitis B Overview

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hepb overview

Chronic infection with hepatitis B virus (HBV) represents an enormous unmet medical need. Worldwide, there is an estimated 350 million people chronically infected with HBV. HBV can establish infection in the liver that lasts for decades and leads to persistent liver injury. Serious liver complications can occur over time including fibrosis, cirrhosis and hepatocellular carcinoma. To date, the HBV polymerase represents the prime candidate for antiviral intervention. During the 10-year period 1998–2008, five nucleoside or nucleotide analogs have been approved for HBV treatment. Nucleoside/tide analogs decrease serum HBV DNA to below detectable limits. This occurs by the incorporation of nucleoside analog triphosphates into actively replicating viral genomes by the polymerase resulting in chain termination of viral genomes as well as in the blocking of both new DNA synthesis and viral particle release. Importantly, during viral infection the genome is repaired to form a covalently closed circular DNA (cccDNA), which serves as a transcriptional reservoir template that will continually transcribe viral mRNA for export to the cytoplasm (see Table below). These viral messenger RNAs are sufficient to produce new virus and thus as soon as nucleoside/tide analog therapy is halted, viral production resumes and serum HBV DNA levels rebound. In addition, cccDNA continuously gives rise to other viral antigens, including high titers of serum HBsAg, despite potent nucleoside analog inhibition of new genome replication. Blocking active HBV replication through nucleoside/tide analog treatment conceptually prevents the cycling of new genomes back to the nucleus to amplify or replenish cccDNA levels. However, existing pools of cccDNA have a sufficiently long half-life to maintain chronic infection despite years of potent antiviral suppression. (Adapted from Delaney W.E. IV, Antiviral Research 99, 2013, 34-48). Therefore, anti-HBV therapeutic strategies are urgently needed. Very recent findings from several laboratories suggest that cyclophilins may represent additional drug targets for hepatitis B treatment. Indeed, cyclophilin inhibitors (CypI), as in those for HCV, interfere with HBV replication. Interestingly, they interfere at multiple steps in HBV replication. First, CypI, by binding to the newly discovered HBV receptor (NTCP), inhibit HBV entry (see Model). Second, CypI when added to HBV-infected or –transfected cells, significantly reduce HBV DNA replication and HBs/eAg expression. However, the mechanisms underlining the second CypI-mediated block remain obscure. A main goal of our laboratory is to understand the role(s) of cyclophilins in HBV replication and to elucidate the antiviral mechanisms of action of CypI.