TY - JOUR
T1 - In vitro induction of human immunodeficiency virus type 1 variants resistant to phosphoralaninate prodrugs of Z-methylenecyclopropane nucleoside analogues
AU - Yoshimura, Kazuhisa
AU - Feldman, Ron
AU - Kodama, Eiichi
AU - Kavlick, Mark F.
AU - Qiu, Yao Ling
AU - Zemlicka, Jiri
AU - Mitsuya, Hiroaki
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
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U2 - 10.1128/aac.43.10.2479
DO - 10.1128/aac.43.10.2479
M3 - Article
C2 - 10508028
AN - SCOPUS:0032820094
VL - 43
SP - 2479
EP - 2483
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 10
ER -