In vitro induction of human immunodeficiency virus type 1 variants resistant to phosphoralaninate prodrugs of Z-methylenecyclopropane nucleoside analogues.
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 (-)-beta-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 microM), HIV-1(M184I) and HIV-1(M184V) showed greater fitness than HIV-1(wt). These data may provide structural and virological relevance with regard to the emergence of M184I and M184V substitutions in HIV-1.
Yoshimura
K
K
Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Feldman
R
R
Kodama
E
E
Kavlick
M F
MF
Qiu
Y L
YL
Zemlicka
J
J
Mitsuya
H
H
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial / Q000235:genetics; D015684:Gene Products, pol / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D054302:pol Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015684:Gene Products, pol; C060467:HIV pol protein p65; D011355:Prodrugs; C400943:QYL 609; D054302:pol Gene Products, Human Immunodeficiency Virus; D015075:2-Aminopurine; C400942:QYL 685; D000409:Alanine