title: Characterization of human immunodeficiency virus type 1 strains resistant to the non-nucleoside reverse transcriptase inhibitor RD4-2217.
abstract: The non-nucleoside reverse transcriptase (RT) inhibitor RD4-2217 is a thiadiazole derivative that has proved to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. In this study we examined genotypic and phenotypic characteristics of RD4-2217-resistant mutants that have been obtained by serial passage of HIV-1 in MT-4 cells in the presence of increasing concentrations (0.05, 0.25, 1 and 10 microM) of the compound. The strains obtained, III(B/2217RE/0.05) and III(B/2217RE/0.25,) were two- and 15-fold resistant to RD4-2217, respectively, whereas III(B/2217RE/1) and III(B/2217RE/10) displayed 161- and >238-fold resistance, respectively. Both III(B/2217RE/1) and III(B/2217RE/10) had two amino acid substitutions, V1891 and T2401, in the RT. Furthermore, RD4-2217 did not inhibit the replication of an HIV-1 molecular clone, which had the same mutation, at concentrations up to 10 microM, indicating that the V1891 plus T2401 mutation confers high-level resistance to RD4-2217. Interestingly, the replicability of III(B2217RE/1) and III(B/2217RE/10) appeared to be lower than that of wildtype III(B) in MT-4 cells, suggesting that the V1891 plus T2401 mutation may impair the enzymatic activity of HIV-1 RT.
authors.affiliation: Rational Drug Design Laboratories, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fujiwara
authors.forename: E N
authors.initials: EN
authors.lastname: Kodama
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: K
authors.initials: K
authors.lastname: Tokuhisa
authors.forename: T
authors.initials: T
authors.lastname: Ide
authors.forename: Y
authors.initials: Y
authors.lastname: Hanasaki
authors.forename: K
authors.initials: K
authors.lastname: Katsuura
authors.forename: H
authors.initials: H
authors.lastname: Takayama
authors.forename: N
authors.initials: N
authors.lastname: Aimi
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
authors.forename: S
authors.initials: S
authors.lastname: Shigeta
authors.forename: K
authors.initials: K
authors.lastname: Konno
authors.forename: T
authors.initials: T
authors.lastname: Yokota
authors.forename: M
authors.initials: M
authors.lastname: Baba
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D004352:Drug Resistance, Microbial; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; C106815:RD 4-2217; D018894:Reverse Transcriptase Inhibitors; D013830:Thiadiazoles