title: Effect of human immunodeficiency virus type 1 protease inhibitor therapy and subtype on development of resistance in subtypes B and G.
abstract: Europe is currently observing a significant rise in non-B subtypes. Consequently, the effect of genetic variability on therapy response or genotypic resistance interpretation algorithms is an emerging concern. The purpose of this study is to investigate the amino acid substitutions selected under drug pressure in the protease of human immunodeficiency virus type 1 (HIV-1) subtypes B and G, and determine if there are any significant differences. We investigated therapy-related and subtype-related substitutions in the protease, considering subtype, overall protease inhibitor treatment and individual drug exposure. Many mutations were significantly related to protease inhibitor (PI) therapy, with mutations exclusive to subtype B or subtype G. Some mutations are at positions related to resistance in both subtypes, but the amino acid substitution is different. Other mutations were significantly associated with subtype and PI selective pressure (p<0.05), pointing towards a differential selective pressure in both subtypes. We confirmed previous reports on the subtype-dependent selection of D30N and 89I, and identified a new mutation with such differential selective pressure: 37D was preferentially selected by lopinavir in subtype B. Other novel mutations found under therapy pressure were 13A, 35N, K55R, I66F, I72L/T, T74S, 82M and 89I/V. Our study indicates that even though in general, drug selective pressure and resistance pathways are relatively similar between subtypes B and G, some differences do occur, leading to subtype-dependent substitutions.
authors: Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Portugal. carolina.palma@uz.kuleuven.be
authors: Ana Carolina
authors: AC
authors: Palma
authors: Ana Barroso
authors: AB
authors: Abecasis
authors: Jurgen
authors: J
authors: Vercauteren
authors: Ana Patricia
authors: AP
authors: Carvalho
authors: Joaquim
authors: J
authors: Cabanas
authors: Anne-Mieke
authors: AM
authors: Vandamme
authors: Ricardo Jorge
authors: RJ
authors: Camacho
mesh_terms: D019943:Amino Acid Substitution / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000235:genetics*; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D061466:Lopinavir; D010802:Phylogeny; D011744:Pyrimidinones / Q000627:therapeutic use; D012641:Selection, Genetic; D020539:Sequence Analysis, Protein
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019469:Indinavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1