Increased polymerase fidelity of lamivudine-resistant HIV-1 variants does not limit their evolutionary potential.
OBJECTIVE
Anti HIV-1 therapy with nucleoside reverse transcriptase inhibitors can select for drug-resistant reverse transcriptase variants with altered enzyme properties. Some of the mutations, e.g. Met184Val and Met184Ile, result in an increase in polymerase fidelity of the enzyme as measured in biochemical assays; however, the effect of such changes on the fidelity during viral replication is largely unknown. In this study, the codon 184 variants were used to investigate whether the mutation at codon 184 affects the mutation spectrum and mutation rate of the mutant viruses.


METHODS
In vitro selection experiments with either wild-type or lamivudine-resistant viruses (Met184Val and Met184Ile) were performed using a protease inhibitor as the selective drug. In addition, a novel selection approach was developed using a mixture of viruses, instead of individual viruses, during the selection process.


RESULTS
Comparison of a total of 108 protease-resistant variants revealed no significant difference in the mutational spectrum of the wild-type and the lamivudine-resistant variants. In addition, the selection experiments with the viral mixtures demonstrated no delay in the kinetics of mutation generation in response to an antiviral drug.


CONCLUSIONS
This study demonstrates that the Met184Val and Met184Ile mutations in the HIV-1 reverse transcriptase enzyme do not significantly affect the evolutionary potential of the corresponding viruses.
Keulen
W
W
Department of Virology, Eijkman-Winkler Institute, University Hospital of Utrecht, The Netherlands.
van Wijk
A
A
Schuurman
R
R
Berkhout
B
B
Boucher
C A
CA
D003062:Codon / Q000187:drug effects / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics; D019143:Evolution, Molecular; D014644:Genetic Variation; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D019259:Lamivudine / Q000494:pharmacology*; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology
D003062:Codon; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; D019438:Ritonavir