Molecular Virology of Hepatitis B Virus for Clinicians

Block, Timothy M.; Guo, Haitao; Guo, Ju‐Tao

doi:10.1016/j.cld.2007.08.002

Cited by 153 publications

(134 citation statements)

References 93 publications

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“…Although most infected adults can resolve the infection, approximately 5 to 10% of adulthood infections and more than 90% of neonatal infections become lifelong persistent, which causes a significant public health burden currently affecting more than 350 million individuals worldwide (36,41). Patients with chronic hepatitis B carry a high risk of cirrhosis and primary hepatocellular carcinoma (5,36).…”

Section: Interestingly Ido-mediated Tryptophan Deprivation Preferentmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

Mao

Zhang

Jiang

et al. 2011

J Virol

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112

101

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Alpha interferon (IFN-␣) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-␥) is a key mediator of host innate and adaptive antiviral immunity against hepatitis B virus (HBV) infection in vivo.In an effort to elucidate the antiviral mechanism of these cytokines, 37 IFN-stimulated genes (ISGs), which are highly inducible in hepatocytes, were tested for their ability to inhibit HBV replication upon overexpression in human hepatoma cells. One ISG candidate, indoleamine 2,3-dioxygenase (IDO), an IFN-␥-induced enzyme catalyzing tryptophan degradation, efficiently reduced the level of intracellular HBV DNA without altering the steady-state level of viral RNA. Furthermore, expression of an enzymatically inactive IDO mutant did not inhibit HBV replication, and tryptophan supplementation in culture completely restored HBV replication in IDO-expressing cells, indicating that the antiviral effect elicited by IDO is mediated by tryptophan deprivation. Interestingly, IDO-mediated tryptophan deprivation preferentially inhibited viral protein translation and genome replication but did not significantly alter global cellular protein synthesis. Finally, tryptophan supplementation was able to completely restore HBV replication in IFN-␥-but not IFN-␣-treated cells, which strongly argues that IDO is the primary mediator of IFN-␥-elicited antiviral response against HBV in human hepatocyte-derived cells.Hepatitis B virus (HBV) is a hepatotropic virus in the family of Hepadnaviridae (18, 56) which has infected two billion people worldwide. Although most infected adults can resolve the infection, approximately 5 to 10% of adulthood infections and more than 90% of neonatal infections become lifelong persistent, which causes a significant public health burden currently affecting more than 350 million individuals worldwide (36,41). Patients with chronic hepatitis B carry a high risk of cirrhosis and primary hepatocellular carcinoma (5, 36).It is generally believed that the outcomes of HBV infection and disease pathogenesis are primarily determined by the host adaptive antiviral immune response (9). The resolution of HBV infection is associated with a robust, polyclonal viral antigen-specific cytotoxic T lymphocyte (CTL) response that kills and/or noncytopathically cures virally infected hepatocytes. The latter effect is primarily mediated by inflammatory cytokines, including gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) (17,18,20,21). Interestingly, although it has been shown that HBV can evade host innate immunity surveillance, as evidenced by its failure to induce the expression of interferon-stimulated genes (ISGs) in the liver of chimpanzees during the early phase of infection (66), the virus is sensitive to IFN-␣/␤-induced antiviral response in transgenic mice and in people (30,49). For example, treatment of chronic hepatitis B with pegylated IFN-␣ for 48 weeks can achieve sustained virological response in 30 to 40% of the treated patients (29).In efforts to elucidate the antiviral mechanism ...

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Section: Interestingly Ido-mediated Tryptophan Deprivation Preferentmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

Mao

Zhang

Jiang

et al. 2011

J Virol

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112

101

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“…In spite of the availability of an effective vaccine, near about 360 million people are chronically infected globally where about 1 million infected people die per year due to HBV-associated liver pathologies. 1 Despite the noncytopathic nature of HBV, the spectrum of liver infection often progresses to liver cirrhosis and development of hepatocellular carcinoma (HCC).…”

mentioning

confidence: 99%

Reduced Expression of DNA Damage Repair Genes High Mobility Group Box1 and Poly(ADP-ribose) Polymerase1 in Inactive Carriers of Hepatitis B Virus Infection-A Possible Stage of Viral Integration

Mukherjee

Shravanti

Jakkampudi

et al. 2013

Journal of Clinical and Experimental Hepatology

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Background: High mobility group box1 (HMGB1) and poly(ADP-ribose) polymerase1 (PARP1) proteins repair cellular DNA damage. Reduced expression of the corresponding genes can lead to an impaired DNA damage repair mechanism. Intracellular replication of hepatitis B virus (HBV) in such conditions can favor the integration of viral DNA into host genome leading to the development of hepatocellular carcinoma (HCC). Objective: This study was performed to assess the expression of HMGB1 and PARP1 mRNAs in conjunction with the estimation of HBV replication intermediate pregenomic RNA (PgRNA) in various phases of HBV infection. Materials: Eighty eight patients and 26 voluntary blood donors as controls were included in the study. Patients were grouped in to acute (AHB; n = 15), inactive carriers (IC; n = 36), cirrhosis (Cirr; n = 25) and hepatocellular carcinoma (HCC; n = 12). Serum HBV DNA was quantified by real time polymerase chain reaction (PCR) assay. Expression of HMGB1, PARP1 and PgRNA were evaluated using peripheral blood mononuclear cells (PBMCs) derived RNA by reverse transcription PCR (RT-PCR) and densitometry. Results: Significant reduction of HMGB1 and PARP1 gene expressions (P < 0.05) were observed in patients than controls with more explicit decline of PARP1 (P = 0.0002). Both genes were significantly downregulated (P < 0.001) in ICs than controls. In ICs, HMGB1 was significantly lowered than cirrhosis (P = 0.002) and HCC (P = 0.0006) while PARP1 declined significantly (P = 0.04) than HCC. Level of PgRNA was comparable in all the disease categories. Conclusion: In conclusion, our findings indicate impaired DNA damage repair mechanisms in HBV infected cells of ICs. This, along with low viral load but higher level of PgRNA in this group is suggestive of the diversion of HBV replication pathway that might facilitate viral DNA integration in to host genome. Intrusion of HBV PgRNA reverse transcription in early stage of infection might appear advantageous to thwart the development of HCC. ( J CLIN EXP HEPATOL 2013;3:89-95)

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“…These steps lead to the internalization of the covalently closed circular DNA (cccDNA) into the host's nucleus which is responsible for the persistent infection of hepatocytes. This is followed by viral assembly and release of the progeny virions [4][5][6].…”

Section: Hbv Life Cyclementioning

confidence: 99%

Management of chronic hepatitis B: New stopping rules

Noureddine

Issa

Moucari³

2015

Int Arch Med

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Chronic hepatitis B (CHB) treatment is limited by the availability of antiviral agents and the variable response to those agents. Currently, the only approved antiviral agents are Pegylated interferon and nucleos(t)-ide analogues. The response to these therapies varies widely between CHB patients. Thus, the patients with non-favorable response are ultimately exposed to unnecessary side effects and costs. All current guidelines provide information regarding the time to initiate therapy. However, a clear consensus regarding the predictors of non response and consequently terminating the treatment is still lacking. Many studies that determine the adequacy of the use of predictive markers early in the course of the disease will be reviewed here. During Pegylated interferon therapy, combination of decline in serum HBV DNA and HBsAg levels from baseline at week 12 could generate a solid stopping rule. Using nucleos(t)ide analogues in chronic HBeAg-positive patients, the on-treatment HBsAg quantitation at 6 months appears to have a useful role in determining the duration of therapy in patients who achieve HBeAg loss (or seroconversion) during treatment. In chronic HBeAg-negative patients, the Asian Pacific Association for the Study of Liver (APASL) stopping rules are adequate with proper off-therapy monitoring. Furthermore, the durability of off-therapy response for both classes based on long term follow-up studies will be discussed here. Through this review we will present a clear generation of stopping rules to guide the antiviral therapy early enough to predict non response and shift to other agents. Therefore, adopting a costeffective approach in the treatment of chronic hepatitis B.

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Molecular Virology of Hepatitis B Virus for Clinicians

Cited by 153 publications

References 93 publications

Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

Reduced Expression of DNA Damage Repair Genes High Mobility Group Box1 and Poly(ADP-ribose) Polymerase1 in Inactive Carriers of Hepatitis B Virus Infection-A Possible Stage of Viral Integration

Management of chronic hepatitis B: New stopping rules

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