f Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Nevertheless, the molecular mechanism of HBV replication remains elusive. SIRT1 is a class III histone deacetylase that is a structure component of the HBV cccDNA minichromosome. In this study, we found by using microarray-based gene expression profiling analysis that SIRT1 was upregulated in HBV-expressing cells. Gene silencing of SIRT1 significantly inhibited HBV DNA replicative intermediates, 3.5-kb mRNA, and core protein levels. In contrast, the overexpression of SIRT1 augmented HBV replication. Furthermore, SIRT1 enhanced the activity of HBV core promoter by targeting transcription factor AP-1. The c-Jun subunit of AP-1 was bound to the HBV core promoter region, as demonstrated by using a chromatin immunoprecipitation assay. Mutation of AP-1 binding site or knockdown of AP-1 abolished the effect of SIRT1 on HBV replication. Finally, SIRT1 inhibitor sirtinol also suppressed the HBV DNA replicative intermediate, as well as 3.5-kb mRNA. Our study identified a novel host factor, SIRT1, which may facilitate HBV replication in hepatocytes. These data suggest a rationale for the use of SIRT1 inhibitor in the treatment of HBV infection.
Hepatitis B virus (HBV) infection remains a major health problem worldwide despite the availability of an effective prevention vaccine. HBV is a hepatotropic, noncytopathic, 3.2-kb partially double-stranded DNA virus (1). Upon viral entry into a hepatocyte, the capsid dissociates, and the genomic relaxed circular DNA (rcDNA) is converted into a covalently closed circular DNA (cccDNA) molecule. The cccDNA is found as a viral minichromosome and acts as the major transcriptional template for the virus. Four major RNA species (3.5-, 2.4-, 2.1-, and 0.7-kb viral RNA transcripts) produced from this viral minichromosome are then transported to and translated in the cytoplasm to produce the viral proteins, namely, viral surface proteins, core protein, viral polymerase, and X protein (2).The control of HBV replication is one of the major strategies to reduce the morbidity and mortality associated with chronic HBV infection. Thus far, no treatment can completely eliminate the infection in all patients with chronic hepatitis B. The chemotherapeutic treatments (i.e., lamivudine, adefovir, entecavir, and telbivudine) inhibit the HBV replication by targeting the viral DNA polymerase. However, long-term treatment leads to the development of problematic drug-resistant virus. Alpha interferon is also useful for treating HBV infection but has substantial side effects. Therefore, identification and characterization of the viral and host factors responsible for HBV infection will provide valuable information for the development of anti-HBV therapeutics.The sirtuin family (SIRT1 to SIRT7) are mammalian homologues of the yeast silent information regulator 2 (Sir2), which are class III histone deacetylases (HDACs) that utilize NAD ϩ as a cofactor for their functions (3). SIRT1, the most wid...