title: The antiretroviral activity of APOBEC3 is inhibited by the foamy virus accessory Bet protein.
abstract: Genome hypermutation of different orthoretroviruses by cellular cytidine deaminases of the APOBEC3 family during reverse transcription has recently been observed. Lentiviruses like HIV-1 have acquired proteins preventing genome editing in the newly infected cell. Here we show that feline foamy virus (FFV), a typical member of the foamy retrovirus subfamily Spumaretrovirinae, is also refractory to genome deamination. APOBEC3-like FFV genome editing in APOBEC3-positive feline CRFK cells only occurs when the accessory FFV Bet protein is functionally inactivated. Editing of bet-deficient FFV genomes is paralleled by a strong decrease in FFV titer. In contrast to lentiviruses, cytidine deamination already takes place in APOBEC3-positive FFV-producing cells, because edited proviral DNA genomes are consistently present in released particles. By cloning the feline APOBEC3 orthologue, we found that its homology to the second domain of human APOBEC3F is 48%. Expression of feline APOBEC3 in APOBEC3-negative human 293T cells reproduced the effects seen in homologous CRFK cells: Bet-deficient FFV displayed severely reduced titers, high-level genome editing, reduced particle release, and suppressed Gag processing. Although WT Bet efficiently preserved FFV infectivity and genome integrity, it sustained particle release and Gag processing only when fe3 was moderately expressed. Similar to lentiviral Vif proteins, FFV Bet specifically bound feline APOBEC3. In particles from Bet-deficient FFV, feline APOBEC3 was clearly present, whereas its foamy viral antagonist Bet was undetectable in purified WT particles. This is the first report that, in addition to lentiviruses, the foamy viruses also developed APOBEC3-counter-acting proteins.
authors.affiliation: Department Genome Modifications and Carcinogenesis, Focus Infection and Cancer, German Cancer Research Center, 69009 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Löchelt
authors.forename: Fabian
authors.initials: F
authors.lastname: Romen
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bastone
authors.forename: Heide
authors.initials: H
authors.lastname: Muckenfuss
authors.forename: Nadine
authors.initials: N
authors.lastname: Kirchner
authors.forename: Yong-Boum
authors.initials: YB
authors.lastname: Kim
authors.forename: Uwe
authors.initials: U
authors.lastname: Truyen
authors.forename: Uwe
authors.initials: U
authors.lastname: Rösler
authors.forename: Marion
authors.initials: M
authors.lastname: Battenberg
authors.forename: Ali
authors.initials: A
authors.lastname: Saib
authors.forename: Egbert
authors.initials: E
authors.lastname: Flory
authors.forename: Klaus
authors.initials: K
authors.lastname: Cichutek
authors.forename: Carsten
authors.initials: C
authors.lastname: Münk
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002415:Cats; D002460:Cell Line; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D016678:Genome; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D011533:Proviruses / Q000235:genetics*; D012191:Retroviridae Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D016092:Spumavirus / Q000235:genetics* / Q000378:metabolism; D014771:Virion / Q000378:metabolism
chemical_list: D003062:Codon; D017931:DNA Primers; D018076:DNA, Complementary; D012191:Retroviridae Proteins; D003564:Cytidine Deaminase