title: A naturally occurring Vif mutant (I107T) attenuates anti-APOBEC3G activity and HIV-1 replication.
abstract: The human immunodeficiency virus type 1 (HIV-1) Vif protein counteracts the antiviral activity of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of proteins by targeting the proteins for degradation through the ubiquitin-proteasome pathway. Previous mutagenic studies have shown that multiple domains of Vif are required for interacting with APOBEC3G proteins and the proteasome pathway. However, very few mutagenesis and functional analyses of patient-derived Vif proteins have been conducted. In this study, we amplified and cloned the HIV-1 vif genes from the peripheral blood mononuclear cells (PBMCs) of five HIV-1-infected individuals in Nairobi and further tested the impact of the genes on anti-A3G activity and HIV-1 replication. The gene sequence analysis revealed high genetic variation of vif genes from different HIV-1-infected individuals. Interestingly, the Vif proteins derived from two of the three long-term survivors (LTSs) displayed a significantly impaired ability to mediate the degradation of A3G. In particular, a single amino acid change (I107T) in one of the non-functional LTS Vif variants, which has not been previously identified in the Los Alamos databases of vif sequences, was found to be responsible for the lack of anti-A3G activity. Further study demonstrated that HIV-1 carrying an I107T Vif mutation displayed significantly reduced fitness in A3G(+) T cells and PBMCs. Moreover, co-infecting A3G(+) T cells with both the wild-type and I107T Vif viruses resulted in decreased viral replication. Overall, the results of this study indicate that the HIV-1 Vif residue I107 is important for its anti-APOBEC3G activity and viral replication, which may have implications for viral fitness in vivo.
authors.affiliation: Laboratory of Molecular Human Retrovirology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Peng
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Ao
authors.forename: Chris
authors.initials: C
authors.lastname: Matthews
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.forename: Sue
authors.initials: S
authors.lastname: Ramdahin
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Junhua
authors.initials: J
authors.lastname: Li
authors.forename: Liyu
authors.initials: L
authors.lastname: Chen
authors.forename: Jianmei
authors.initials: J
authors.lastname: He
authors.forename: Blake
authors.initials: B
authors.lastname: Ball
authors.forename: Keith
authors.initials: K
authors.lastname: Fowke
authors.forename: Frank
authors.initials: F
authors.lastname: Plummer
authors.forename: Joanne
authors.initials: J
authors.lastname: Embree
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Yao
mesh_terms: D000071480:APOBEC-3G Deaminase; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors*; D014644:Genetic Variation; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007630:Kenya; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D059748:Proteolysis; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; 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
keywords: APOBEC3; APOBEC3G; HIV-1; HIV-1 replication; LTS; PBMC; PL; ProLabel; Vif; WB; Western blot; apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3; human immunodeficiency virus type 1; long-term survivor; long-term survivors; peripheral blood mononuclear cell