title: Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir.
abstract: Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC(50)) change in susceptibility to nelfinavir only. Other mutations increased IC(50) correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% +/- 22% to 22% +/- 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.
authors.affiliation: National HIV Reference Center, Central Virology Laboratory, Sheba Medical Center, Tel Hashomer 52621, Israel. lcgross@inter.net.il
authors.forename: Zehava
authors.initials: Z
authors.lastname: Grossman
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Paxinos
authors.forename: Diana
authors.initials: D
authors.lastname: Averbuch
authors.forename: Shlomo
authors.initials: S
authors.lastname: Maayan
authors.forename: Neil T
authors.initials: NT
authors.lastname: Parkin
authors.forename: Dan
authors.initials: D
authors.lastname: Engelhard
authors.forename: Margalit
authors.initials: M
authors.lastname: Lorber
authors.forename: Valery
authors.initials: V
authors.lastname: Istomin
authors.forename: Yael
authors.initials: Y
authors.lastname: Shaked
authors.forename: Ella
authors.initials: E
authors.lastname: Mendelson
authors.forename: Daniela
authors.initials: D
authors.lastname: Ram
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Petropoulos
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schapiro
mesh_terms: D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D019888:Nelfinavir / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
chemical_list: D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019888:Nelfinavir