title: Remarkable lethal G-to-A mutations in vif-proficient HIV-1 provirus by individual APOBEC3 proteins in humanized mice.
abstract: Genomic hypermutation of RNA viruses, including human immunodeficiency virus type 1 (HIV-1), can be provoked by intrinsic and extrinsic pressures, which lead to the inhibition of viral replication and/or the progression of viral diversity. Human APOBEC3G was identified as an HIV-1 restriction factor, which edits nascent HIV-1 DNA by inducing G-to-A hypermutations and debilitates the infectivity of vif-deficient HIV-1. On the other hand, HIV-1 Vif protein has the robust potential to degrade APOBEC3G protein. Although subsequent investigations have revealed that lines of APOBEC3 family proteins have the capacity to mutate HIV-1 DNA, it remains unclear whether these endogenous APOBEC3s, including APOBEC3G, contribute to mutations of vif-proficient HIV-1 provirus in vivo and, if so, what is the significance of these mutations. In this study, we use a human hematopoietic stem cell-transplanted humanized mouse (NOG-hCD34 mouse) model and demonstrate the predominant accumulation of G-to-A mutations in vif-proficient HIV-1 provirus displaying characteristics of APOBEC3-mediated mutagenesis. Notably, the APOBEC3-associated G-to-A mutation of HIV-1 DNA that leads to the termination of translation was significantly observed. We further provide a novel insight suggesting that HIV-1 G-to-A hypermutation is independently induced by individual APOBEC3 proteins. In contrast to the prominent mutation in intracellular proviral DNA, viral RNA in plasma possessed fewer G-to-A mutations. Taken together, these results provide the evidence indicating that endogenous APOBEC3s are associated with G-to-A mutation of HIV-1 provirus in vivo, which can result in the abrogation of HIV-1 infection.
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, 53 Shogoinkawara-cho, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Sato
authors.forename: Taisuke
authors.initials: T
authors.lastname: Izumi
authors.forename: Naoko
authors.initials: N
authors.lastname: Misawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Masahide
authors.initials: M
authors.lastname: Ohmichi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Koyanagi
mesh_terms: D000071480:APOBEC-3G Deaminase; D000818:Animals; D003564:Cytidine Deaminase / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D017354:Point Mutation; D011533:Proviruses / Q000235:genetics* / Q000276:immunology*; D054320:vif Gene Products, Human Immunodeficiency Virus / 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