Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Rosmorduc, Olivier; Sirma, Hüseyin; Soussan, Patrick Ben; Gordien, Emmanuel; Lebon, Pierre; Horisberger, Michel A.; Br√©chot, C; Kremsdorf, Dina

doi:10.1099/0022-1317-80-5-1253

Cited by 47 publications

(49 citation statements)

References 44 publications

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“…The majority of ISGs, however, are expressed and inducible in both HepG2 and HepG2.2.15 cells, indicating that the HBV gene expression and replication had no effect on these ISGs. Consistently, Rosmorduc et al [17] demonstrated that 2´5OAS expression is not affected by HBV. Our results support the view that the HBV-mediated inhibition of the IFN-response, if any, represents a specific rather than global effect.…”

Section: Discussionmentioning

confidence: 52%

“…There may be multiple reasons for the different ISG expression profiles in these cell lines, though HepG2.2.15 was derived from HepG2 [16] . Previous data indicated that the expression of the IFN-inducible gene MxA was specifically inhibited by HBV proteins in HBV-transfected HepG2 or HuH7 cells [13] , and this was accompanied by diminished antiviral activity of IFN [17] . In our study, we confirmed this finding with MxA expression being completely diminished in HBV-transfected HepG2.2.15 cells.…”

Section: Discussionmentioning

confidence: 97%

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Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

Guan

Lu²,

Grunewald³

et al. 2007

WJG

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AIM:To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBVtransfected HepG2.2.15 cells. METHODS:H e p G 2 . 2 . 1 5 a n d H e p G 2 c e l l s w e r e stimulated with various concentrations of IFN-a2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes (ISGs). In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. RESULTS:Two genes (MxA, Cig5) with completely abolished and 4 genes (IFITM1, -2, -3, and 6-16) with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes (IFITM1, 6-16), the response to IFN-a could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Stat1 activation and ISGF3 formation after stimulation with IFN-a in HepG2.2.15 compared to HepG2 cells. CONCLUSION:These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expression by reducing HBV gene expression and replication.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 97%

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

Guan

Lu²,

Grunewald³

et al. 2007

WJG

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“…We showed that, in vivo, at least one of these defective particles was detected in the sera of patients with chronic hepatitis or acute hepatitis developing towards chronicity, but not in patients who had recovered from their acute hepatitis (Rosmorduc et al, 1995) (Figure 5). We also showed that the expression of this defective HBV DNA (unlike wild-type HBV DNA) inhibited the expression of the IFN-a-inducible MxA protein and that accumulation of viral capsid protein, observed during expression of defective HBV DNA, was responsible for this inhibition (Rosmorduc et al, 1999). The antiviral activity of this protein versus a certain number of RNA viruses has clearly been demonstrated (Haller et al, 1998).…”

Section: Hbv-related Hcc D Kremsdorf Et Almentioning

confidence: 68%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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As discussed in detail in other chapters of this review, chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated with the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarize the current knowledge on the mechanisms involved in HBVrelated liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus, as well as between viral infections and other environmental factors, such as alcohol.

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“…pSpLuc, SpLuc, CpLuc and XpLuc were obtained from Alan McLachlan (The Scripps Research Institute, USA) (Raney et al, 1990). The pMxA 550 Luc has been described elsewhere (Rosmorduc et al, 1999). The commercial pCH110 plasmid expressing b-galactosidase (Pharmacia biotech) was used to monitor transfection efficiency.…”

Section: Methodsmentioning

confidence: 99%

“…The p.f.u. ml 21 was counted for each point after fixation with 10 % formaldehyde in PBS for 15 min and subsequent staining with crystal violet (Rosmorduc et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene

Williams

Brichler

Radjef

et al. 2009

Journal of General Virology

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Co-infection and superinfection of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV replication both in patients and in animal and cellular models. The mechanisms behind this inhibition have not previously been explored fully. HBV replication is governed by four promoters and two enhancers, Enh1 and Enh2. Repression of these enhancers has been reported to be one of the main mechanisms of HBV inhibition. Moreover, in a previous study, it has been demonstrated that alpha interferon (IFN-a)-inducible MxA protein inhibits HBV replication. HDV encodes two proteins, p24 and p27. p27 was shown to activate several heterologous promoters, including HBV promoters. In an attempt to analyse the mechanisms of HBV inhibition by HDV, the question was raised whether HDV proteins could act directly by repressing HBV enhancers, and/or indirectly by activating the MxA gene. This issue was addressed in a co-transfection model in Huh-7 cells, using p24-or p27-expressing plasmids along with Enh1, Enh2, HBV and MxA promoter-luciferase constructs. Enh1 and Enh2 were strongly repressed, by 60 and 80 % and 40 and 60 %, by p24 and p27, respectively. In addition, p27 was responsible for threefold activation of the MxA promoter and potentiation of IFN-a on this promoter. MxA mRNA quantification and a virus yield reduction assay confirmed these results. In conclusion, this study shows that HDV proteins inhibit HBV replication by trans-repressing its enhancers and by trans-activating the IFN-a-inducible MxA gene. INTRODUCTIONChronic hepatitis B virus (HBV) infection is an important worldwide cause of acute and end-stage liver diseases, including cirrhosis and hepatocellular carcinoma. Two billion individuals have been infected with HBV and more than 400 million are chronic carriers. Hepatitis delta virus (HDV) is a naturally defective RNA virus, a satellite of HBV, which requires HBV surface antigen (HBsAg) for packaging and transmission. Between ten and twenty million HBV-infected individuals are thought to be coinfected with HDV, leading to disease chronicity and worsening histological lesions.Concomitant HBV/HDV infection often results in inhibition of HBV replication both in human patients (Arribas et al., 2005;Colombo et al., 1991;Govindarajan, 1990;Jardi et al., 2001;Lee et al., 1987;Pastore et al., 1990) and in animals (Negro et al., 1989). One in vitro transient cotransfection model of HBV DNA and HDV-expressing plasmids in Huh-7 cells has been described (Wu et al., 1991). In that study, the authors showed remarkably reduced levels of 3.5 and 2.1 kb HBV RNAs involving the delta proteins. However, the mechanisms of such inhibition remain unknown and, to our knowledge, have not been explored further. The HBV genome consists of a 3.2 kb circular, partially double-stranded DNA genome. HBV replication is governed by four promoters (pre-S, S, core and X) and two enhancer elements, Enh1 and Enh2 (Lo & Ting, 1994;Moolla et al., 2002;Park et al., 1997;Yuh & Ting, 1990). It has been hypothesized that the two...

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Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

Cited by 47 publications

References 44 publications

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene

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