Vif Proteins from Diverse Primate Lentiviral Lineages Use the Same Binding Site in APOBEC3G

• Authors: Michael Letko, Icahn School of Medicine at Mount Sinai; Guido Silvestri, Emory University; Beatrice H. Hahn, University of Pennsylvania; Frederick Bibollet-Ruche, University of Pennsylvania; Omer Gokcumen, Harvard University; Viviana Simon, Icahn School of Medicine at Mount Sinai; Marcel Ooms, Icahn School of Medicine at Mount Sinai
• Journal Title: Journal of Virology
• Volume: Volume 87, Number 21
• Publisher: American Society for Microbiology | 2013-11, Pages 11861-11871
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1128/JVI.01944-13
• Subjects: Biology, Virology; Biology, Microbiology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Virology; VIROLOGY; SIMIAN IMMUNODEFICIENCY VIRUS; SINGLE AMINO-ACID; INFECTIOUS MOLECULAR CLONES; EDITING ENZYME APOBEC3G; HIV-1 VIF; TYPE-1 VIF; SEQUENCE-ANALYSIS; SOOTY MANGABEY; RHESUS-MONKEYS; IDENTIFICATION

Abstract

APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeciency 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 greenmonkey simian immunodeciency virus (SIVagm) bind residue 128 of A3G. However, this position does not control the A3G degradation by Vif variants derived fromHIV-2 and SIVmac, which both originated fromSIV of sooty mangabeymonkeys (SIVsmm), suggesting that the A3G binding site for Vif proteins of the SIVsmm/HIV-2 lineage differs from that of HIV-1. Tomap the SIVsmmVif binding site of A3G, we performed immunoprecipitations of individual A3G domains, Vif/A3G degradation assays and a detailedmutational analysis of human A3G. We show that A3G residue 129, but not the adja-cent position 128, confers susceptibility to degradation by SIVsmmVif. An articial A3Gmutant, the P129Dmutant, was resis-tant to degradation by diverse Vifs fromHIV-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, whichmakes its A3G resistant to Vifs fromdi-verse lineages. We speculate that gorilla A3G serves as a barrier against SIVcpz strains. In summary, we show that Vif proteins fromdistinct lineages bind to the same A3G loop, which includes positions 128 and 129. Themultiple adaptations within this loop among diverse primates underscore the importance of counteracting A3G in lentiviral evolution.