Characterization of human immunodeficiency virus type 1 strains resistant to the non-nucleoside reverse transcriptase inhibitor RD4-2217

Masatoshi Fujiwara, Eiichi N. Kodama, Masayuki Okamoto, Kenji Tokuhisa, Teruhiko Ide, Yasuaki Hanasaki, Kimio Katsuura, Hiromitsu Takayama, Norio Aimi, Hiroaki Mitsuya, Shiro Shigeta, Kenji Konno, Tomoyuki Yokota, Masanori Baba

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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 μM) 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(B2217RE/10) displayed 161- and > 238-fold resistance, respectively. Both III(B/2217RE/1) and III(B/2217RE/10) had two amino acid substitutions, V189I and T240I, 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 μM, indicating that the V189I plus T240I mutation confers high-level resistance to RD4-2217. Interestingly, the replicability of III(B/2217RE/1) and III(B/2217RE/10) appeared to be lower than that of wild-type III(B) in MT-4 cells, suggesting that the V189I plus T240I mutation may impair the enzymatic activity of HIV-1 RT.

Original languageEnglish
Pages (from-to)315-320
Number of pages6
JournalAntiviral Chemistry and Chemotherapy
Volume10
Issue number6
DOIs
Publication statusPublished - 1999

Keywords

  • NNRTI
  • Resistance
  • Thiadiazole

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Virology

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