Naturally Occurring Hepatitis B Virus Genomes Bearing the Hallmarks of Retroviral G → A Hypermutation

Günther, Stephan; Sommer, Gunhild; Plikat, Uwe; Iwanska, Alicja; Wain‐Hobson, Simon; Will, Hans; Meyerhans, Andreas

doi:10.1006/viro.1997.8676

Cited by 73 publications

(47 citation statements)

References 25 publications

(12 reference statements)

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“…13 In keeping with this notion, serum-derived HBV variants bearing the hallmarks of G3 A hypermutation have been described in two studies. 43,44 The factors influencing efficiency of APOBEC-mediated HBV editing remain to be determined. Clearly, less single-stranded HBV DNA-the substrate of A3G-and A3F-mediated deamination-is produced in cotransfected cells because of the effects on proper pgRNA encapsidation, as detailed above.…”

Section: Discussionmentioning

confidence: 99%

APOBEC-mediated interference with hepadnavirus production

et al. 2005

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APOBEC3G is a cellular cytidine deaminase displaying broad antiretroviral activity. Recently, it was shown that APOBEC3G can also suppress hepatitis B virus (HBV) production in human hepatoma cells. In the present study, we characterized the mechanisms of APO-BEC-mediated antiviral activity against HBV and related hepadnaviruses. We show that human APOBEC3G blocks HBV production in mammalian and nonmammalian cells and is active against duck HBV as well. Early steps of viral morphogenesis, including RNA and protein synthesis, binding of pregenomic RNA to core protein, and self-assembly of viral core protein, were unaffected. However, APOBEC3G rendered HBV core protein-associated full-length pregenomic RNA nuclease-sensitive. Ongoing reverse-transcription in capsids that had escaped the block in morphogenesis was not significantly inhibited. The antiviral effect was not modulated by abrogating or enhancing expression of the accessory HBV X protein, suggesting that HBV X protein does not represent a functional homologue to the HIV vif protein. Furthermore, human APOBEC3F but not rat APOBEC1 inhibited HBV DNA production. Viral RNA and low-level DNA produced in the presence of APOBEC3F or rat APOBEC1 occasionally displayed mutations, but the majority of clones were wild-type. In conclusion, APOBEC3G and APOBEC3F but not rat APOBEC1 can downregulate the production of replication-competent hepadnaviral nucleocapsids. In contrast to HIV and other retroviruses, however, APOBEC3G/3F-mediated editing of nucleic acids does not seem to represent an effective innate defense mechanism for hepadnaviruses. H epadnaviruses are a group of small enveloped DNA viruses with a narrow host range and a relative tropism for the liver. Hepatitis B virus (HBV), the prototypic member of the hepadnavirus family, is a major cause of liver disease worldwide, ranging from acute and chronic hepatitis to cirrhosis and hepatocellular carcinoma. 1,2 Other members of the family include the duck hepatitis B virus (DHBV) and the woodchuck hepatitis virus. 3,4 Hepadnaviral replication involves reverse-transcription of a pregenomic RNA (pgRNA) intermediate inside nucleocapsids, which are formed by 180 or 240 core protein subunits. Inside the capsid, the viral polymerase converts pgRNA into minus-strand DNA, which in turn is completed to a double-stranded, relaxed circular DNA molecule. 5,6 This life cycle places HBV into the large family of retroelements, which all require reverse-transcription of an RNA intermediate.Recently, a cellular defense mechanism targeting a wide range of retroviruses was identified. It was shown that the propagation of HIV-1 strains lacking the accessory protein Vif is suppressed in a number of nonpermissive cells and that this block was due to expression of the cytidine deaminase APOBEC3G (A3G). 7,8 Further studies revealed that A3G induces massive C3 U deamination of single stranded retroviral DNA, resulting in DNA degradation or lethal G3 A hypermutation. [9][10][11] Interestingly, A3G can also interfere with the HBV life c...

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Section: Discussionmentioning

confidence: 99%

APOBEC-mediated interference with hepadnavirus production

et al. 2005

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“…In addition, fluctuations in the intracellular [dTTP]/[dCTP] pools might give rise to a G to A hypermutation, which in some cases results in several Gs that are replaced by As throughout the entire genome. 55,56 …”

Section: The Hbv Polymerase Gene: Genome Organization and Comparison mentioning

confidence: 99%

Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region

et al. 2001

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“…[24][25][26] G-to-A hypermutated HBV genomes have been detected in the plasma of HBV-infected patients, suggesting that APOBEC3 editing enzymes have edited the minus strand cDNA during HBV replication. [27][28][29] In hepatoma cells, transfection of A3B, A3C, A3F, or A3G induced extensive hypermutations in a minor fraction (approximately 10 Ϫ3 ) of HBV genomes that was detected by a novel polymerase chain reaction technique (3D-PCR) designed to selectively amplify AT-hypermutated sequences. 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.…”

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confidence: 99%

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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Naturally Occurring Hepatitis B Virus Genomes Bearing the Hallmarks of Retroviral G → A Hypermutation

Cited by 73 publications

References 25 publications

APOBEC-mediated interference with hepadnavirus production

APOBEC-mediated interference with hepadnavirus production

Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region

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

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