title: Anti-APOBEC3G activity of HIV-1 Vif protein is attenuated in elite controllers.
abstract: HIV-1-infected individuals who control viremia to below the limit of detection without antiviral therapy have been termed elite controllers (EC). Functional attenuation of some HIV-1 proteins has been reported in EC. The HIV-1 accessory protein Vif (virion infectivity factor) enhances viral infectivity through anti-retroviral factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G) degradation; however, little is known regarding Vif function in EC. Here, the anti-APOBEC3G activities of clonal, plasma HIV RNA-derived Vif sequences from 46 EC, 46 noncontrollers (NC), and 44 individuals with acute infection (AI) were compared. Vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped viruses were generated by cotransfecting 293T cells with expression plasmids encoding patient-derived Vif, human APOBEC3G, VSV-G, and a vif/env-deficient luciferase-reporter HIV-1 proviral DNA clone. Viral stocks were used to infect 293T cells, and Vif anti-APOBEC3G activity was quantified in terms of luciferase signal. On average, the anti-APOBEC3G activities of EC-derived Vif sequences (median log10 relative light units [RLU], 4.54 [interquartile range {IQR}, 4.30 to 4.66]) were significantly lower than those of sequences derived from NC (4.75 [4.60 to 4.92], P < 0.0001) and AI (4.74 [4.62 to 4.94], P < 0.0001). Reduced Vif activities were not associated with particular HLA class I alleles expressed by the host. Vif functional motifs were highly conserved in all patient groups. No single viral polymorphism could explain the reduced anti-APOBEC3G activity of EC-derived Vif, suggesting that various combinations of minor polymorphisms may underlie these effects. These results further support the idea of relative attenuation of viral protein function in EC-derived HIV sequences.
  
  
  OBJECTIVE
  HIV-1 elite controllers (EC) are rare individuals who are able to control plasma viremia to undetectable levels without antiretroviral therapy. Understanding the pathogenesis and mechanisms underpinning this rare phenotype may provide important insights for HIV vaccine design. The EC phenotype is associated with beneficial host immunogenetic factors (such as HLA-B*57) as well as with functions of attenuated viral proteins (e.g., Gag, Pol, and Nef). In this study, we demonstrated that HIV-1 Vif sequences isolated from EC display relative impairments in their ability to counteract the APOBEC3G host restriction factor compared to Vif sequences from normal progressors and acutely infected individuals. This result extends the growing body of evidence demonstrating attenuated HIV-1 protein function in EC and, in particular, supports the idea of the relevance of viral factors in contributing to this rare HIV-1 phenotype.
authors.affiliation: The Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Iwabu
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tada
authors.affiliation: The Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Kawana-Tachikawa
authors.affiliation: The Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Koga
authors.affiliation: The Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Hosoya
authors.affiliation: The Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nomura
authors.affiliation: Simon Fraser University, Burnaby, BC, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.affiliation: Praxis Jessen2+Kollegen, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: The Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
authors.affiliation: National Institute of Infectious Diseases, Tokyo, Japan tokunaga@nih.go.jp toshiyuki.miura@gmail.com.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: The Institute of Medical Science, the University of Tokyo, Tokyo, Japan tokunaga@nih.go.jp toshiyuki.miura@gmail.com.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
mesh_terms: D000071480:APOBEC-3G Deaminase; D002460:Cell Line; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000276:immunology*; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D005822:Genetic Vectors; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D018116:Vesiculovirus / Q000235:genetics; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D012367:RNA, Viral; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D008156:Luciferases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase