Inhibition of Hepatitis B Virus Replication by APOBEC3G

Turelli, Priscilla; Mangeat, Bastien; Jost, Stéphanie; Vianin, Sandrine; Trono, Didier

doi:10.1126/science.1092066

Cited by 409 publications

(377 citation statements)

References 7 publications

Supporting

Mentioning

352

Contrasting

Unclassified

Order By: Relevance

“…[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%

“…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. PCR amplification with non-degenerate primers therefore is likely to select for wild-type sequences.…”

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.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2006

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2006

View full text Add to dashboard Cite

show abstract

TGF‐β triggers HBV cccDNA degradation through AID‐dependent deamination

et al. 2016

View full text Add to dashboard Cite

The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a viral center molecule for HBV infection and persistence. However, the cellular restriction factors of HBV cccDNA are not well understood. Here, we show that TGF-b can induce nuclear viral cccDNA degradation and hypermutation via activation-induced cytidine deaminase (AID) deamination activity in hepatocytes. This suppression by TGF-b is abrogated when AID or the activity of uracil-DNA glycosylase (UNG) is absent, which indicates that AID deamination and the UNG-mediated excision of uracil act in concert to degrade viral cccDNA. Moreover, the HBV core protein promotes the interaction between AID and viral cccDNA. Overall, our results indicate a novel molecular mechanism that allows cytokine TGF-b to restrict viral nuclear cccDNA in innate immunity, thereby suggesting a novel method for potentially eliminating cccDNA.Keywords: AID; cccDNA; HBV; Hypermutation; UNG Highlights • AID triggers HBV cccDNA degradation via its deamination activity.• AID induces viral cccDNA hypermutation.• TGF-b reduces viral cccDNA through AID in hepatocytes.Almost 350 million people who are chronically infected with hepatitis B virus (HBV) worldwide are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Thus, HBV infection is a major global health concern [1-3]. The covalently closed circular DNA (cccDNA) of HBV plays an essential role in virus replication and persistence. After entry into the hepatocytes, HBV first forms cccDNA in the host cell's nucleus before transcribing viral RNAs, including a replicative RNA intermediate called pregenomic (pg) RNA that encodes two viral proteins, HBV core (HBc), and HBV polymerase (Pol), which encapsidate pgRNA to form a nucleocapsid. HBV Pol reverse transcribes pgRNA to produce relaxed circular DNA

show abstract

AID recruits the RNA exosome to degrade HIV‐1 nascent transcripts through interaction with the Tat‐P‐TEFb‐TAR RNP complex

et al. 2018

View full text Add to dashboard Cite

Activation-induced cytidine deaminase (AID), a member of the APOBEC family that induces antibody diversification, has been shown to inhibit the replication of hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and retro-transposons. However, whether AID can inhibit human immunodeficiency virus 1 (HIV-1) replication remains unclear. Here, we report that AID impairs the synthesis of HIV-1 components by interacting with the complex of Tat. This interaction recruits the RNA exosome to degrade the nascent HIV-1 transcript. AID also targets the HIV-1-integrated genome via the Tat-P-TEFb-TAR complex. Thus, we propose a novel function for AID as an adaptor protein that represses viral transcription. Our findings provide insights into developing anti-HIV therapeutics and understanding how host cells restrict integrated virus replication.

show abstract

Inhibition of Hepatitis B Virus Replication by APOBEC3G

Cited by 409 publications

References 7 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

TGF‐β triggers HBV cccDNA degradation through AID‐dependent deamination

AID recruits the RNA exosome to degrade HIV‐1 nascent transcripts through interaction with the Tat‐P‐TEFb‐TAR RNP complex

Contact Info

Product

Resources

About