Comment on "Inhibition of Hepatitis B Virus Replication by APOBEC3G"

Rösler, Christine; Köck, Josef; Malim, Michael H.; Blum, Hubert E.; Weizsäcker, Fritz von

doi:10.1126/science.1100464

Cited by 79 publications

(68 citation statements)

References 10 publications

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“…[30][31][32][33] Inhibition of pregenomic HBV RNA packaging by A3G was originally proposed by Turelli et al 30 as the mode of action. This is in line with a recent investigation by Rösler et al, 33 who reported an increased nuclease sensitivity of core-protein associated full-length pregenomic HBV RNA on expression of A3G.…”

Section: Discussionmentioning

confidence: 99%

“…The extent of hypermutations in replicating HBV DNA induced by APOBEC3 editing enzymes is another matter of debate. 29,30,32 The most important issue in this research field-the expression of APOBEC3 editing enzymes in the human liver and their potential upregulation in response to IFN-␣-had not been addressed in detail so far. The initial report of the APO-BEC3 gene cluster failed to detect expression of A3G or A3B in human liver by Northern blotting; however, two subsequent studies demonstrated co-expression of A3G and A3F in many organs, including the human liver, by Northern blotting or RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

“…Our results strongly argue against the notion that A3G requires cellular cofactors for HBV DNA editing that might be missing in HuH-7 cells as previously proposed. 32 Deducing the frequency of hypermutated sequences within a background of wild-type sequences from PCR analyses with non-degenerate primers is difficult. [30][31][32][33] G-to-A hypermutations are extensively present in edited HBV genomes and certainly interfere with primer annealing.…”

Section: Discussionmentioning

confidence: 99%

“…29 In addition, two groups showed that A3G and also A3F, but not rat APOBEC-1, can inhibit the replication of HBV and of duck hepatitis B virus in transfected hepatoma cells in vitro. [30][31][32][33] Whether this inhibition of HBV replication in vitro is linked to catalytic cytidine deamination is unknown, and a non-editing mechanism has been proposed as the mode of inhibition. [30][31][32][33] The low or even absent expression of APOBEC3 genes in human liver, however, has raised the important question as to their impact on HBV replication in vivo.…”

mentioning

confidence: 99%

“…[30][31][32][33] Whether this inhibition of HBV replication in vitro is linked to catalytic cytidine deamination is unknown, and a non-editing mechanism has been proposed as the mode of inhibition. [30][31][32][33] The low or even absent expression of APOBEC3 genes in human liver, however, has raised the important question as to their impact on HBV replication in vivo. Because IFN-␣ induces cellular pathways in hepatocytes that lead to a noncytolytic clearance of HBV, we investigated whether any of the APOBEC3 genes might be up-regulated in human primary hepatocytes in response to IFN-␣ and studied their effect on HBV replication, core-particle association, and HBV DNA editing in vitro.…”

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Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

et al. 2006

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Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-␣) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3B L inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B S and A3C had no effect. A3B L and A3B S were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. T he hepatitis B virus (HBV) infects more than 350 million people worldwide and is a leading cause of end-stage liver disease and of hepatocellular carcinoma. 1 HBV is non-cytopathic for hepatocytes; however, most newly HBV infected adult patients develop acute hepatitis because of a strong immune response that clears HBV from the liver, whereas approximately 5% of newly HBV-infected adult patients generate insufficient immunity and become chronically infected. 1,2 Administration of interferon alpha (IFN-␣) is a mainstay of therapy for chronically HBV-infected patients. 2 Interferons restrict the replication of HBV by inducing the expression of antiviral proteins that inhibit the formation of replication-competent HBV nucleocapsids, and ultimately can result in the resolution of the chronic HBV infection. 2-7 HBV and other hepadnaviruses replicate their partially double-stranded DNA genome within cytoplasmic core particles by reverse transcription of encapsidated pregenomic RNA and thus are related to retroviruses. 8,9 The cytidine deaminase APOBEC3G (A3G), which is encoded within a cluster of seven related editing enzymes (APOBEC3A-G) on chromosome 22, provides broad innate immunity against exogenous and endogenous retroelements. 10-16 Encapsidated into the retroviral particle A3G deaminates dCs of the retroviral minus strand

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

et al. 2006

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Editing Hbv Into Oblivion

Wain‐Hobson

Vartanian

2004

Hepatology

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Regulatory T (T(R)) cells consist of phenotypically and functionally distinct CD4 ؉ and CD8 ؉ T-cell subsets engaged both in maintaining self-tolerance and in preventing anti-non-self effector responses (microbial, tumor, transplant, and so on) that may be harmful to the host. Here we propose that the proinflammatory function of virus-specific memory effector CCR7 ؊ CD8 ؉ T cells, which are massively recruited in the liver, are inefficient (in terms of IFN-gamma production) in patients with chronic hepatitis C virus (HCV) infection because of the concomitant presence of virus-specific CCR7 ؊ CD8 ؉ T(R) cells producing considerable amounts of IL-10. These CD8 ؉ T(R) cells are antigen specific, as they can be stimulated by HCV epitopes and suppress T-cell responses that are in turn restored by the addition of neutralizing anti-IL-10. This study provides direct evidence of the existence of virus-specific CD8 ؉ T(R) cells that infiltrate the livers of patients with chronic HCV infection, identifies IL-10 as a soluble inhibitory factor mediating suppression, and suggests that these cells play a pivotal role in controlling hepatic effector CD8 ؉ T-cell responses.

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G to A hypermutation of hepatitis B virus†

et al. 2005

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G to A hypermutation of the human immunodeficiency virus type 1 (HIV-1) is induced by a deaminase APOBEC3G and is related to host antiviral defense. APOBEC3G has also been found to reduce the replication of HIV-1 by an unknown mechanism. This enzyme also reduces the production of hepatitis B virus, although the mechanism for this action has not been clearly elucidated. The hypermutated hepatitis B virus (HBV) is rarely found in usual sequencing analyses. Using peptide nucleic acid mediated by polymerase chain reaction clamping, we detected the hypermutated HBV DNA in 1 of 8 patients with acute HBV infection and 4 of 10 with chronic HBV infection. In the latter group, hypermutated genomes were found only in eAb-positive patients. As much as 72.5% of G residues were mutated in the hypermutated clones. G to A substitutions were predominant in almost all clones sequenced compared with other substitutions. G to A mutated viral genomes also were found in HepG2-derived cell lines that continuously produced HBV into the supernatant. Both alpha and gamma interferon reduced virus production in these cell lines, but they did not alter the frequency of the hypermutation. Transcripts of APOBEC3G, as well as some other deaminases, were found in these cell lines. In conclusion, our results show that part of the minus strand DNA of HBV is hypermutated both in vitro (HepG2 cell lines) and in vivo. The role and mechanism of hypermutation in reducing HBV replication should be further investigated to understand the anti-HBV defense system. (HEPATOLOGY 2005;41:626-633.)

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Comment on "Inhibition of Hepatitis B Virus Replication by APOBEC3G"

Cited by 79 publications

References 10 publications

Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

Editing Hbv Into Oblivion

G to A hypermutation of hepatitis B virus†

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