title: Positive selection pressure introduces secondary mutations at Gag cleavage sites in human immunodeficiency virus type 1 harboring major protease resistance mutations.
abstract: Human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) specifically target the HIV-1 protease enzyme. Mutations in the enzyme can result in PI resistance (termed PI mutations); however, mutations in the HIV-1 gag region, the substrate for the protease enzyme, might also lead to PI resistance. We analyzed gag and pol sequence data from the following 313 HIV-1-infected patients: 160 treatment-naïve patients, 93 patients failing antiretroviral treatment that included a PI (with no major PI mutations), and 60 patients failing antiretroviral treatment that included a PI (with major PI mutations). Additional sequences from 13 patients were included for longitudinal analysis. We assessed positive selection pressure on the gag/protease region using a test for the overall influence of positive selection and a total of five tests to identify positively selected single codons. We found that positive selection pressure was the driving evolutionary force for the gag region in all three patient groups. An increase in positive selection was observed in gag cleavage site regions p7/p1/p6 only after the acquisition of major PI mutations, suggesting that amino acids in gag cleavage sites under positive selection pressure could function as compensatory mutations for major PI mutations in the protease region. Isolated gag mutations did not appear to confer PI resistance, but mutations in the gag cleavage sites could substitute for minor PI resistance mutations in the protease region.
authors.affiliation: Virus BL-3 Laboratory, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark. SBK@ssi.dk
authors.forename: Søren
authors.initials: S
authors.lastname: Banke
authors.forename: Marie R
authors.initials: MR
authors.lastname: Lillemark
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.forename: Niels
authors.initials: N
authors.lastname: Obel
authors.forename: Louise B
authors.initials: LB
authors.lastname: Jørgensen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus