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

In this study, we aimed at evaluating the resistance of HCV to CBAs in vitro. After more than eight weeks of HCV culture in the presence of increasing concentrations of different lectins, we identified several mutations in the genomes of the isolated strains, and evidenced a positive selection on the E1E2 coding region, as a consequence of the V284A, M338V, V392D, A400D, N417S, S449P and L612M non-synonymous mutations. Other mutations were also detected in the regions encoding the Core and the non-structural proteins of the isolated strains, with a second region under positive selection corresponding to the end of NS5A, a region known to be frequently mutated during cell culture adaptation. The characterization of the E1E2 mutations, alone or in combination, evidenced that none of these mutations confer resistance to CBAs. Importantly, when similar experiments were performed in the presence of neutralizing MAbs, escape mutations were observed as early as 5 days post treatment [26, [37] [38] [39] . Several explanations can be put forward to explain the difference between HCV resistance to MAbs and CBAs. Firstly, it is important to note that E1 and E2 bring many conserved N-glycans, thus many CBA targets, which have been shown to play an important role in the different steps of the HCV life cycle. Moreover, it has to be noticed that in contrast to neutralizing antibodies, CBAs are able to inhibit cell free as well as cell to cell transmission [14] . Finally, it has also been proposed that some lectins could act through both viral and cellular glycan interactions [13] .