Regulation of microRNA by hepatitis B virus infection and their possible association with control of innate immunity

Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex interactions between HBV and the immune system including adaptive and innate immunity.Tolllike receptors(TLRs)and TLR-signaling pathways are important parts of the innate immune response in HBV infections.It is well known that TLR-ligands could suppress HBV replication and that TLRs play important roles in anti-viral defense.Previous immunological studies demonstrated that HBV e antigen(HBeAg)is more efficient at eliciting T-cell tolerance,including production of specific cytokines IL-2 and interferon gamma,than HBV core antigen.HBeAg downregulates cytokine production in hepatocytes by the inhibition of MAPK or NF-κB activation through the interaction with receptor-interacting serine/threonine protein kinase.MicroRNAs(miRNAs)are also able to regulate various biological processes such as the innate immune response.When the expressions of approximately 1000 miRNAs were compared between human hepatoma cells HepG2 and HepG2.2.15,which could produce HBV virion that infects chimpanzees,using real-time RT-PCR,we observed several different expression levels in miRNAs related to TLRs.Although we and others have shown that HBV modulates the host immune response,several of the miRNAs seem to be involved in the TLR signaling pathways.The possibility that alteration of these miRNAs during HBV infection might play a critical role in innate immunity against HBV infection should be considered.This article is intended to comprehensively review the association between HBV and innate immunity,and to discuss the role of miRNAs in the innate immune response to HBV infection.

IL-28B polymorphisms and treatment response in hepatitis C virus patients with persistently normal alanine aminotransferase

AIM:To examine the association between the interleukin 28B(IL-28B)genotype and treatment response in hepatitis C virus(HCV)-infected patients with persistently normal alanine aminotransferase(PNALT).METHODS:We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT.Between February 2010 and April2013,278 patients infected with HCV were enrolled in this study.All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin.In addition,180μg of peginterferon alpha-2a or 1.5μg/kg peginterferon alpha-2b per week plus weight-based ribavirin(600-1000 mg/d)were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients.In all of the patients,the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay.HCV RNA was measured using the COBAS TaqMan HCV test.RESULTS:Female patients were dominant in the PNALT group(P【0.0001).Among 72 HCV genotype 1-infected patients with PNALT,the early virologic response(EVR)rates(P【0.01)and the sustained virologic response(SVR)rates(P【0.01)were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype.In HCV genotype 1-infected patients with PNALT,multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type(P【0.05)and having an EVR(P【0.01).The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT.CONCLUSION:The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.

Platelet count and sustained virological response in hepatitis C treatment

AIM:To examine the epidemiological data,hematological safety and treatment responses of peginterferonalpha 2a plus ribavirin therapy for hepatitis C.METHODS:Between March 2008 and February 2011,196 hepatitis C virus(HCV)genotype 1 infected Japanese(127 treatment-naive and 69 treatment-experienced patients)patients treated with peginterferonalpha 2a plus ribavirin were enrolled.We examined the epidemiological data and treatment responses were retrospectively analyzed in terms of hematological safety.HCV RNA was measured by the COBAS TaqMan HCV test.RESULTS:Overall sustained virological response(SVR)rates of treatment-naive and treatment-experienced patients were 56% and 39%,respectively.Multivariate logistic regression analysis showed that SVR was attained independently of early virological response in both treatment-naive and treatment-experienced patients.SVR rates did not differ between the pretreatment hemoglobin < 13 g/dL and ≥ 13 g/dL groups.However,in treatment-naive patients,the SVR rate of the pretreatment platelet count < 130000/μL group was significantly lower than that of the pretreatment platelet count ≥ 130000/μL group.CONCLUSION:Attention should be paid to potential thrombocytopenia in the treatment of chronic hepatitis C patients.

Direct-acting Antiviral Agents for the Treatment of Chronic Hepatitis C Virus Infection

Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan.Therefore,eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals.In 2011,the use of firstgeneration HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV.Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients.However,this treatment regimen also led to severe adverse events.Second-generation direct-acting antiviral agents (DAAs) for HCV,such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates,with similar adverse events to other peg-interferon and ribavirin treatments.Higher SVR rates in HCV genotype 1-and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin,respectively,For "difficult-to-treat"HCV-infected patients,more therapeutic options are needed.Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments.