title: Population level analysis of human immunodeficiency virus type 1 hypermutation and its relationship with APOBEC3G and vif genetic variation.
abstract: APOBEC3G and APOBEC3F restrict human immunodeficiency virus type 1 (HIV-1) replication in vitro through the induction of G-->A hypermutation; however, the relevance of this host antiviral strategy to clinical HIV-1 is currently not known. Here, we describe a population level analysis of HIV-1 hypermutation in [corrected] clade B proviral DNA sequences (n = 127). G-->A hypermutation conforming to expected APOBEC3G polynucleotide sequence preferences was inferred in 9.4% (n = 12) of the HIV-1 sequences, with a further 2.4% (n = 3) conforming to APOBEC3F, and was independently associated with reduced pretreatment viremia (reduction of 0.7 log(10) copies/ml; P = 0.001). Defective vif was strongly associated with HIV-1 hypermutation, with additional evidence for a contribution of vif amino acid polymorphism at residues important for APOBEC3G-vif interactions. A concurrent analysis of APOBEC3G polymorphism revealed this gene to be highly conserved at the amino acid level, although an intronic allele (6,892 C) was marginally associated with HIV-1 hypermutation. These data indicate that APOBEC3G-induced HIV-1 hypermutation represents a potent host antiviral factor in vivo and that the APOBEC3G-vif interaction may represent a valuable therapeutic target.
authors.affiliation: Centre for Clinical Immunology and Biomedical Statistics, 2nd Floor, North Block, Royal Perth Hospital, Wellington Street, Perth 6000, Western Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Pace
authors.forename: Jean
authors.initials: J
authors.lastname: Keller
authors.forename: David
authors.initials: D
authors.lastname: Nolan
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Corey
authors.initials: C
authors.lastname: Moore
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
mesh_terms: D000071480:APOBEC-3G Deaminase; D015331:Cohort Studies; D003564:Cytidine Deaminase; D005260:Female; D016346:Gene Products, vif / Q000235:genetics*; D014644:Genetic Variation; D005828:Genetics, Population; D015658:HIV Infections / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009700:Nucleoside Deaminases / Q000235:genetics*; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000737:chemistry; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D054320:vif Gene Products, Human Immunodeficiency Virus
chemical_list: D016346:Gene Products, vif; D019713:Receptors, CCR5; D012097:Repressor Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase