In Vitro Induction of Human Immunodeficiency Virus Type 1 Variants Resistant to Phosphoralaninate Prodrugs of Z-Methylenecyclopropane Nucleoside Analogues
AUTOR(ES)
Yoshimura, Kazuhisa
FONTE
American Society for Microbiology
RESUMO
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-1LAI) and HIV-2 in vitro. In this study, we induced HIV-1 variants resistant to QYL-685 by exposing HIV-1LAI to increasing concentrations of QYL-685. After 16 passages, the virus (HIV-1P16) 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-1LAI and contained an M184I mutation. Two infectious clones, HIV-1M184I and HIV-1M184V, 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-1wt). However, in the presence of QYL-685 (4 μM), HIV-1M184I and HIV-1M184V showed greater fitness than HIV-1wt. These data may provide structural and virological relevance with regard to the emergence of M184I and M184V substitutions in HIV-1.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=89504Documentos Relacionados
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