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

Bonvin, Marianne; Achermann, François; Greeve, Isabell; Stroka, Deborah; Keogh, Adrian; Inderbitzin, Daniel; Candinas, Daniel; Sommer, Peter; Wain-Hobson, Simon; Vartanian, Jean-Pierre; Greeve, Jobst (2006). Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication. Hepatology, 43(6), pp. 1364-74. Hoboken, N.J.: Wiley Interscience 10.1002/hep.21187

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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-alpha) 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. Moreover, A3G, A3F, and A3B(L), but not A3B(S), induced extensive G-to-A hypermutations in a fraction of the replicated HBV genomes. In conclusion, the editing enzymes A3B(L), A3F, and most markedly A3G, which are expressed in liver and up-regulated by IFN-alpha in hepatocytes, are candidates to contribute to the noncytolytic clearance of HBV.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Massenspektrometrie- und Proteomics-Labor
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Tiefenau Hospital (discontinued) > Forschungsgruppe Biologie und Karzinogenese der Brustdrüse (discontinued)
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine

UniBE Contributor:

Achermann, François; Greeve, Isabell; Inderbitzin, Daniel; Candinas, Daniel and Greeve, Jobst

ISSN:

0270-9139

ISBN:

16729314

Publisher:

Wiley Interscience

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:46

Last Modified:

18 Jul 2014 16:36

Publisher DOI:

10.1002/hep.21187

PubMed ID:

16729314

Web of Science ID:

000237984500023

URI:

https://boris.unibe.ch/id/eprint/19085 (FactScience: 1454)

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