title: Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors.
abstract: HIV-1 integrase is the third enzymatic target of antiretroviral (ARV) therapy. However, few data have been published on the distribution of naturally occurring amino acid variation in this enzyme. We therefore characterized the distribution of integrase variants among more than 1,800 published group M HIV-1 isolates from more than 1,500 integrase inhibitor (INI)-naïve individuals. Polymorphism rates equal or above 0.5% were found for 34% of the central core domain positions, 42% of the C-terminal domain positions, and 50% of the N-terminal domain positions. Among 727 ARV-naïve individuals in whom the complete pol gene was sequenced, integrase displayed significantly decreased inter- and intra-subtype diversity and a lower Shannon's entropy than protease or RT. All primary INI-resistance mutations with the exception of E157Q--which was present in 1.1% of sequences--were nonpolymorphic. Several accessory INI-resistance mutations including L74M, T97A, V151I, G163R, and S230N were also polymorphic with polymorphism rates ranging between 0.5% to 2.0%.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA, USA. syrhee@stanford.edu
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.forename: Tommy F
authors.initials: TF
authors.lastname: Liu
authors.forename: Mark
authors.initials: M
authors.lastname: Kiuchi
authors.forename: Rafael
authors.initials: R
authors.lastname: Zioni
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gifford
authors.forename: Susan P
authors.initials: SP
authors.lastname: Holmes
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D024882:Drug Resistance, Viral; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy* / Q000662:veterinary / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; D054303:HIV Reverse Transcriptase; D016333:HIV Protease