Characterization of human immunodeficiency virus type 1 strains resistant to the non-nucleoside reverse transcriptase inhibitor RD4-2217.
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.
Fujiwara
M
M
Rational Drug Design Laboratories, Tokyo, Japan.
Kodama
E N
EN
Okamoto
M
M
Tokuhisa
K
K
Ide
T
T
Hanasaki
Y
Y
Katsuura
K
K
Takayama
H
H
Aimi
N
N
Mitsuya
H
H
Shigeta
S
S
Konno
K
K
Yokota
T
T
Baba
M
M
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
D019380:Anti-HIV Agents; C106815:RD 4-2217; D018894:Reverse Transcriptase Inhibitors; D013830:Thiadiazoles