In vitro induction of human immunodeficiency virus type 1 variants resistant to phosphoralaninate prodrugs of Z-methylenecyclopropane nucleoside analogues

Kazuhisa Yoshimura, Ron Feldman, Eiichi Kodama, Mark F. Kavlick, Yao Ling Qiu, Jiri Zemlicka, Hiroaki Mitsuya

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34 Citations (Scopus)

Abstract

Two methylenecyclopropane nucleoside analogues with a phenylphosphoralaninate moiety, QYL-685 and QYL-609, exert potent and specific activities against human immunodeficiency virus type 1 strain LAI (HIV-1(LAI)) and HIV-2 in vitro. In this study, we induced HIV-1 variants resistant to QYL-685 by exposing HIV-1(LAI) to increasing concentrations of QYL-685. After 16 passages, the virus (HIV-1(P16)) was less sensitive to QYL- 685 (104-fold), QYL-609 (>41-fold), and (-)-β-2',3'-dideoxy-3'-thiacytidine (3TC) (>1,100-fold) than was HIV-1(LAI) and contained an M184I mutation. Two infectious clones, HIV-1(M184I) and HIV-1(M184V), were resistant to QYL-685, QYL-609, and 3TC, confirming that the M184I mutation was responsible for the observed resistance. Viral-fitness analyses (competitive HIV-1 replication assays) revealed that in the absence of drugs, M184I and M184V conferred a replication disadvantage on the virus compared to the replication efficiency of the wild-type infectious clone (HIV-1(wt)). However, in the presence of QYL-685 (4 μM), HIV-1(M184I) and HIV-1(M184V) showed greater fitness than HIV-l(wt). These data may provide structural and virological relevance with regard to the emergence of M184I and M184V substitutions in HIV-1.

Original languageEnglish
Pages (from-to)2479-2483
Number of pages5
JournalAntimicrobial agents and chemotherapy
Volume43
Issue number10
DOIs
Publication statusPublished - 1999

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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