title: APOBEC3G-induced hypermutation of human immunodeficiency virus type-1 is typically a discrete "all or nothing" phenomenon.
abstract: The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host-pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete "all or nothing" phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Armitage
authors.forename: Koen
authors.initials: K
authors.lastname: Deforche
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chang
authors.forename: Edmund
authors.initials: E
authors.lastname: Wee
authors.forename: Beatrice
authors.initials: B
authors.lastname: Kramer
authors.forename: John J
authors.initials: JJ
authors.lastname: Welch
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.forename: Andrew
authors.initials: A
authors.lastname: McMichael
authors.forename: Andrew
authors.initials: A
authors.lastname: Rambaut
authors.forename: Astrid K N
authors.initials: AK
authors.lastname: Iversen
mesh_terms: D000071480:APOBEC-3G Deaminase; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D009154:Mutation; D011533:Proviruses / Q000235:genetics / Q000254:growth & development; D014779:Virus Replication; 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