Characterization of V36C, a novel amino acid substitution conferring hepatitis C virus (HCV) resistance to telaprevir, a potent peptidomimetic inhibitor of HCV protease

Abstract

We characterized a novel substitution conferring moderate resistance to telaprevir, a peptidomimetic inhibitor of hepatitis C virus protease. V36C conferred a 4.0-fold increase in the telaprevir 50% inhibitory concentration in an enzyme assay and a 9.5-fold increase in the replicon model. The replication capacity of a replicon harboring V36C was close to that of the wild-type protease. This case emphasizes the complexity of hepatitis C virus resistance to protease inhibitors.

FIG. 1.

(Top) HCV RNA kinetics in a patient who selected a V36C amino acid substitution on triple therapy with pegylated IFN-α2a, ribavirin, and telaprevir. The HCV RNA levels are expressed in log₁₀ IU/ml. LLD, lower limit of detection. The circled dots represent the four time points at which quasispecies sequence analysis was performed. (Bottom) Dynamics of NS3 quasispecies populations after treatment withdrawal relative to the baseline.

FIG. 2.

Computationally predicted three-dimensional models of the V36 (wild-type, left) and V36C (resistant, right) NS3 protease variants complexed with telaprevir. The wild-type Val side chain is purple, whereas the Cys substitution is green. The four side chains located around Val at position 36 that make contact with Phe at position 43 are white, as the active-site Ser at position 139 and His at position 57. Telaprevir carbon atoms are light blue.