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The study was designed to investigate whether serum hepatitis B virus (HBV) RNA is a strong surrogate marker for intrahepatic HBV covalently closed circular DNA (cccDNA) compared with serum HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) in HBeAg-positive chronic hepatitis B (CHB) patients. Serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA were quantitatively detected at baseline (n ϭ 82) and 96 weeks (n ϭ 62) after treatment with nucleos(t)ide analogue (NUC) in HBeAg-positive CHB patients. The correlations among serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA levels were then statistically analyzed. The results showed that pretreatment intrahepatic cccDNA levels correlated better with serum HBV DNA levels (r ϭ 0.36, P Ͻ 0.01) than with serum HBV RNA levels (r ϭ 0.25, P ϭ 0.02), whereas no correlations were found between pretreatment intrahepatic cccDNA levels and HBsAg (r ϭ 0.15, P ϭ 0.17) or HBeAg (r ϭ 0.07, P ϭ 0.56) levels. At 96 weeks after NUC treatment, intrahepatic cccDNA levels correlated well with HBsAg levels (r ϭ 0.39, P Ͻ 0.01) but not with serum HBV RNA, HBV DNA, and HBeAg levels (all P Ͼ 0.05). Besides, the decline in the intrahepatic cccDNA level from baseline to week 96 correlated better with the reduction in the serum HBsAg levels than with the decreases in the levels of the other markers (for the HBsAg decline, r ϭ 0.38, P Ͻ 0.01; for the HBV DNA decline, r ϭ 0.35, P ϭ 0.01; for the HBV RNA decline, r ϭ 0.28, P Ͻ 0.05; for the HBeAg decline, r ϭ 0.18, P ϭ 0.19). In conclusion, the baseline serum HBV RNA level or its decline after 96 weeks of NUC therapy correlated with the corresponding intrahepatic cccDNA level, while it was less than that seen with serum HBV DNA at baseline and HBsAg (or its decline) at 96 weeks after treatment, respectively. KEYWORDS chronic hepatitis B, covalently closed circular DNA, HBV DNA, HBV RNA, hepatitis B surface antigen, nucleos(t)ide analogue H epatitis B virus (HBV) infection is a global health problem; an estimated 240 million persons are chronically infected, and about 650,000 people die annually due to chronic hepatitis B (CHB) worldwide (1). Though the currently available antiviral drugs can effectively reduce HBV DNA levels in serum of CHB patients, HBV may not be eliminated due to the persistence of HBV covalently closed circular DNA (cccDNA) in the infected hepatocytes, which represents the key HBV replicative intermediate (2). The fundamental role of intrahepatic cccDNA is as a template for transcription of all viral RNAs, including pregenomic RNA (pgRNA), which further produces the offspring virion

Treatment with exogenous interferon (IFN)-a is not effective in the majority of patients with chronic hepatitis B virus (HBV) infection. Recent evidence suggests that HBV has evolved strategies to block the nuclear translocation of signal transducer and activator of transcription (STAT) 1 to limit IFN-a-induced cellular antiviral responses. However, it remains unclear whether STAT1 translocation is impaired in chronic hepatitis B patients and what mechanisms are involved. Here we report that the expression of HBV polymerase (Pol) in human hepatic cell lines inhibited induction of IFN-stimulated genes and resulted in a weakened antiviral activity of IFN-a. Ectopic expression of Pol suppressed IFN-a-induced STAT1 serine 727 phosphorylation and STAT1/2 nuclear accumulation, whereas STAT1 tyrosine 701 phosphorylation, and STAT1-STAT2 heterodimer formation were not affected. Further studies demonstrated that Pol interacted with the catalytic domain of protein kinase C-d (PKC-d) and perturbed PKC-d phosphorylation and its association with STAT1, which resulted in the suppression of STAT1 Ser727 phosphorylation. Moreover, Pol was found to interfere with nuclear transportation of STAT1/2 by competitively binding to the region of importin-a5 required for STAT1/2 recruitment. Truncation analysis suggested that the terminal protein and RNase H domains of Pol were able to bind to PKC-d and importin-a5, respectively, and were responsible for the inhibition of IFN-a signaling. More importantly, the inhibition of STAT1 and PKC-d phosphorylation were confirmed in a hydrodynamicbased HBV mouse model, and the blockage of IFN-a-induced STAT1/2 nuclear translocation was observed in HBV-infected cells from liver biopsies of chronic HBV patients.Conclusions: These results demonstrate a role for Pol in HBV-mediated antagonization of IFN-a signaling and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains its persistence. (HEPATOLOGY 2013;57:470-482) C hronic hepatitis B (CHB) caused by hepatitis B virus (HBV) is a serious health problem worldwide. The mechanism by which chronic infection is established and maintained is unknown but is thought to be due, in part, to a suppressed host immune response. One key component of the host antiviral responses is the interferon (IFN) system. Viral infection of the host initiates the synthesis of type I IFNs, which consist predominantly of IFN-a and IFN-b (IFN-a/b). By binding to type I IFN receptors,