title: Vif proteins from diverse primate lentiviral lineages use the same binding site in APOBEC3G.
abstract: APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeficiency virus type 1 (HIV-1) and other lentiviruses. Most of these viruses encode a Vif protein that directly binds A3G and leads to its proteasomal degradation. Both Vif proteins of HIV-1 and African green monkey simian immunodeficiency virus (SIVagm) bind residue 128 of A3G. However, this position does not control the A3G degradation by Vif variants derived from HIV-2 and SIVmac, which both originated from SIV of sooty mangabey monkeys (SIVsmm), suggesting that the A3G binding site for Vif proteins of the SIVsmm/HIV-2 lineage differs from that of HIV-1. To map the SIVsmm Vif binding site of A3G, we performed immunoprecipitations of individual A3G domains, Vif/A3G degradation assays and a detailed mutational analysis of human A3G. We show that A3G residue 129, but not the adjacent position 128, confers susceptibility to degradation by SIVsmm Vif. An artificial A3G mutant, the P129D mutant, was resistant to degradation by diverse Vifs from HIV-1, HIV-2, SIVagm, and chimpanzee SIV (SIVcpz), suggesting a conserved lentiviral Vif binding site. Gorilla A3G naturally contains a glutamine (Q) at position 129, which makes its A3G resistant to Vifs from diverse lineages. We speculate that gorilla A3G serves as a barrier against SIVcpz strains. In summary, we show that Vif proteins from distinct lineages bind to the same A3G loop, which includes positions 128 and 129. The multiple adaptations within this loop among diverse primates underscore the importance of counteracting A3G in lentiviral evolution.
authors.affiliation: The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Letko
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Frederick
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.forename: Omer
authors.initials: O
authors.lastname: Gokcumen
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.forename: Marcel
authors.initials: M
authors.lastname: Ooms
mesh_terms: D000071480:APOBEC-3G Deaminase; D000818:Animals; D001665:Binding Sites; D003564:Cytidine Deaminase / Q000378:metabolism*; D004252:DNA Mutational Analysis; D016346:Gene Products, vif / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D047468:Immunoprecipitation; D016086:Lentivirus / Q000302:isolation & purification / Q000502:physiology*; D008969:Molecular Sequence Data; D011323:Primates; D011485:Protein Binding; D059748:Proteolysis; D017422:Sequence Analysis, DNA
chemical_list: D016346:Gene Products, vif; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase