Hepatitis C Virus Resistance to Carbohydrate-Binding Agents

Izquierdo, Laure; Oliveira, Catarina; Fournier, Carole; Descamps, Véronique; Morel, Virginie; Dubuisson, Jean; Brochot, Etienne; Francois, Catherine; Castelain, Sandrine; Duverlie, Gilles; Helle, Francois

To explain how the virus succeeded to propagate in the presence of some lectins, we hypothesized that other mutations which improve the virus fitness or modify the property of the viral particles could have been fixed upon lectin exposure. For this reason, we sequenced the regions encoding the Core and the non-structural proteins of the strains isolated upon lectin exposure. This enabled us to identify several additional mutations (7, 3, 4 and 5 upon GNA, CV-N, ConA and GRFT exposure, respectively). These mutations are presented in non-bold characters in Table 1 . Interestingly, similar mutations at some of these positions had already been identified by other groups during JFH1 cell culture adaptation (I30S [29] , P2271L [30] , C2441S [17, [31] [32] [33] , I2270T [33] [34] [35] , D2227V [36] , D2254G [34] ) and several of these mutations have been shown to be beneficial for the virus, in particular for the assembly process. Furthermore, the cumulative behavior of the dS/dN ratio (S2 Fig) also evidenced that the region encoding the end of NS5A, which is essential for cell culture adaptation, was under positive selection. Altogether, our results suggest that HCV resistance to CBAs is not directly conferred by mutations in the E1E2 envelope protein genes but could occur through an indirect mechanism involving mutations in other viral proteins. Further investigations are needed to completely elucidate the mechanisms of HCV resistance to CBAs.