Isolation and characterization of simian immunodeficiency virus variants that are resistant to nonnucleoside reverse transcriptase inhibitors.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) act quite specifically on human immunodeficiency virus type 1 (HIV-1). In general, they are not effective on human immunodeficiency virus type 2 (HIV-2) or simian immunodeficiency virus (SIV). Only SIV strains from African green monkeys are sensitive to several NNRTIs. Here we isolated NNRTI- and 3TC-resistant SIVagm variants. Viruses resistant to delavirdine contained V112I and M231I substitutions, while those resistant to 3TC contained a M 185I substitution. These amino acids are highly conserved in HIV-1, HIV-2, SIVmac and SIVagm, and the M184I (M185I in SIVagm) substitution was observed in 3TC-resistant HIV-1 and SIVmac. The roles of the observed mutations in NNRTI-resistance of SIVagm and HIV-1 were further confirmed by site-directed mutagenesis. The present results have provided a new insight into the common mechanism of sensitivity of HIV- 1 and SIVagm to NNRTIs.
Isaka
Y
Y
Discovery Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan
Miki
S
S
Kawauchi
S
S
Suyama
A
A
Sugimoto
H
H
Adachi
A
A
Hayami
M
M
Yoshie
O
O
Fujiwara
T
T
Sato
A
A
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020008:Delavirdine / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D006367:HeLa Cells; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008969:Molecular Sequence Data; D017354:Point Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016415:Sequence Alignment; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D013329:Structure-Activity Relationship
D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D020008:Delavirdine