HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and
IntroductionHepatitis B Virus (HBV) infection remains a major health problem worldwide despite the availability of a highly effective preventive vaccine. HBV is a noncytopathic hepatotropic DNA virus that belongs to the family Hepadnaviridae, whose members share a distinctive strategy for replication. HBV replication occurs in the cytoplasm within viral capsids (core particles), where a genomesized RNA replicative intermediate, termed the pregenome (pgRNA), is converted by the virally encoded RNA-dependent and DNA-dependent reverse transcriptase/polymerase into a specific open circular (OC) duplex DNA (1). Transcription in the nucleus of the pgRNA from the covalently closed circular DNA (cccDNA) is the critical step for genome amplification and ultimately determines the rate of HBV replication (2). The cccDNA, which also serves as the template for the transcription of all viral messenger RNAs, is organized into a minichromosome in the nuclei of infected hepatocytes by histone and nonhistone proteins, and its function is regulated, similarly to cellular chromatin, by the activity of nuclear transcription factors, transcriptional coactivators and corepressors, and chromatin-modifying enzymes (2-4).Current antiviral therapies involve the use of nucleoside analogs and pegylated IFN-α (5). IFN-α, a type I IFN, engages the IFN-α/β receptor complex to activate the intracellular Jak/Stat signaling pathway, which modulates the transcription of a diverse set of target genes, referred to as IFN-stimulated genes (ISGs) (6). ISG
I nfection with hepatitis B virus (HBV) causes acute and chronic hepatitis and is strongly associated with the development of cirrhosis and hepatocellular carcinoma. Immediately after infection of hepatocytes, the viral DNA is transferred to the nucleus, where the viral polymerase is removed, and the double-stranded, open circular DNA is converted to a covalently closed circular DNA molecule (cccDNA). During chronic HBV infection (CH-B), cccDNA accumulates in hepatocyte nuclei, apparently at a level of about 5-50 copies per cell, where it persists as a minichromosome and functions as the template for the transcription of viral genes. 1 The RNA pregenome, in addition to producing capsid and polymerase proteins, becomes encapsidated and is reverse-transcribed. A particularity of the hepadnavirus life cycle is that DNA-containing nucleocapsids can either recycle back to the nucleus to amplify and maintain the pool of cccDNA or become enveloped and secreted into the blood, where new viral particles can spread to other hepatocytes. 2,3 Because cccDNA is the transcriptional template of the virus, it is required for maintenance of HBV infection.Evidence from the woodchuck hepatitis virus system indicated that the pool of cccDNA persisted even when viral production was strongly reduced by the presence of nucleoside analogues. 4,5 Woodchuck studies 6,7 and recent
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