title: APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis.
abstract: The mammalian APOBEC3 proteins are an important component of the cellular innate immune response to retroviral infection. APOBEC3G can extinguish HIV-1 infectivity by its incorporation into virus particles and subsequent cytosine deaminase activity that attacks the nascent viral cDNA during reverse transcription, causing lethal mutagenesis. It has been suggested, but not formally shown, that APOBEC3G can also induce sublethal mutagenesis, which would maintain virus infectivity and contribute to HIV-1 variation. To test this, we developed a novel model system utilizing an HIV-1 vector and a panel of APOBEC3G-expressing cells. We observed proviruses with single APOBEC3G-mediated mutations (in the presence or absence of Vif), occurring at distinct hot spots and which could be rescued and shown to have infectivity. These data indicate that APOBEC3G-dependent restriction of HIV-1 can result in viable viral progeny that harbor sublethal levels of G-to-A mutations. Such mutations have the potential to contribute significantly to HIV-1 evolution, pathogenesis, immune escape, and drug resistance.
authors.affiliation: Institute for Molecular Virology, 18-242 Moos Tower, 515 Delaware St. SE, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Sadler
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stenglein
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: Louis M
authors.initials: LM
authors.lastname: Mansky
mesh_terms: D000071480:APOBEC-3G Deaminase; D001483:Base Sequence; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D016341:Genes, vif; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011533:Proviruses / Q000235:genetics / Q000378:metabolism; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase
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