title: Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication.
abstract: 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.
authors.affiliation: Department of Clinical Research,University Hospital Berne, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Bonvin
authors.forename: François
authors.initials: F
authors.lastname: Achermann
authors.forename: Isabell
authors.initials: I
authors.lastname: Greeve
authors.forename: Deborah
authors.initials: D
authors.lastname: Stroka
authors.forename: Adrian
authors.initials: A
authors.lastname: Keogh
authors.forename: Daniel
authors.initials: D
authors.lastname: Inderbitzin
authors.forename: Daniel
authors.initials: D
authors.lastname: Candinas
authors.forename: Peter
authors.initials: P
authors.lastname: Sommer
authors.forename: Simon
authors.initials: S
authors.lastname: Wain-Hobson
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vartanian
authors.forename: Jobst
authors.initials: J
authors.lastname: Greeve
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000235:genetics*; D022781:Hepatocytes; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
chemical_list: D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D007372:Interferons; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase