Increased polymerase fidelity of lamivudine-resistant HIV-1 variants does not limit their evolutionary potential

Objective: Anti HIV-1 therapy with nucleoside reverse transcriptase inhibit ors can select for drug-resistant reverse transcriptase variants with alter ed enzyme properties. Some of the mutations, e.g. Met184Val and Met184Ile, result in an increase in polymerase fidelity of the enzyme as measured in b iochemical assays; however, the effect of such changes on the fidelity duri ng viral replication is largely unknown. In this study, the codon 184 varia nts were used to investigate whether the mutation at codon 184 affects the mutation spectrum and mutation rate of the mutant viruses. Design and method: 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 v iruses, 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 t he lamivudine-resistant variants. In addition, the selection experiments wi th the viral mixtures demonstrated no delay in the kinetics of mutation gen eration in response to an antiviral drug. Conclusion: This study demonstrates that the Met184Val and Met184Ile mutati ons in the HIV-l reverse transcriptase enzyme do not significantly affect t he evolutionary potential of the corresponding viruses. (C) 1999 Lippincott Williams & Wilkins.