title: The resistance of human APOBEC3H to HIV-1 NL4-3 molecular clone is determined by a single amino acid in Vif.
abstract: Some human APOBEC3 cytidine deaminases have antiviral activity against HIV-1 and other retroviruses. The single deaminase domain APOBEC3H (A3H) enzyme is highly polymorphic and multiple A3H haplotypes have been identified. A3H haplotype II (A3H-hapII) possesses the strongest activity against HIV-1. There remains, however, uncertainty regarding the extent to which A3H-hapII is sensitive to HIV-1 Vif mediated degradation. We tested, therefore, the two different reference Vif proteins widely used in previous studies. We show that A3H-hapII is resistant to NL4-3 Vif while it is efficiently degraded by LAI Vif. Co-immunoprecipitation assays demonstrate that LAI Vif, but not NL4-3 Vif associates with A3H-hapII. Chimeras between NL4-3 and LAI Vif identify the amino acid responsible for the differential degradation activity: A histidine at position 48 in Vif confers activity against A3H-hapII, while an asparagine abolishes its anti-A3H activity. Furthermore, the amino acid identity at position 48 only affects the degradation of A3H-hapII, whereas recognition of and activity against human A3D, A3F and A3G are only minimally affected. NL4-3 encoding 48H replicates better than NL4-3 WT (48N) in T cell-lines stably expressing A3H hapII, whereas there is no fitness difference in the absence of APOBEC3. These studies provide an explanation for the conflicting reports regarding A3H resistance to Vif mediated degradation.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Marcel
authors.initials: M
authors.lastname: Ooms
authors.forename: Michael
authors.initials: M
authors.lastname: Letko
authors.forename: Mawuena
authors.initials: M
authors.lastname: Binka
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
mesh_terms: D000595:Amino Acid Sequence; D000619:Aminohydrolases / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D059748:Proteolysis; D013379:Substrate Specificity; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; C529313:APOBEC3H protein, human; D000619:Aminohydrolases