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

Citation
K. Yoshimura et al., In vitro induction of human immunodeficiency virus type 1 variants resistant to phosphoralaninate prodrugs of Z-methylenecyclopropane nucleoside analogues, ANTIM AG CH, 43(10), 1999, pp. 2479-2483
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Microbiology
Journal title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN journal
0066-4804 → ACNP
Volume
43
Issue
10
Year of publication
1999
Pages
2479 - 2483
Database
ISI
SICI code
0066-4804(199910)43:10<2479:IVIOHI>2.0.ZU;2-T
Abstract
Two methylenecyclopropane nucleoside analogues with a phenylphosphoralanina te moiety, QYL-685 and QYL-609, exert potent and specific activities agains t 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 exp osing 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 (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC) (>1,100-fold) than was HIV-1, and contained an M184I mutation. Two infectious clones, HIV -1(M184I) and HIV-1(M184V) were resistant to QYL-685, QYL-609, and 3TC, con firming that the M184I mutation was responsible for the observed resistance . Viral-fitness analyses (competitive HIV-1 replication assays) revealed th at in the absence of drugs, R M184I and M184V conferred a replication disad vantage on the virus compared to the replication efficiency of the wild-typ e infectious clone (HIV-1(wt)). However, in the presence of QYL-685 (4 mu M ), HIV-1(M184I) and HIV-1(M184V) showed greater fitness than HIV-1,. These data may provide structural and virological relevance with regard to the em ergence of M184I and M184V substitutions in HIV-1.