High-resolution genetic profile of viral genomes: why it matters

•Multiple DAAs against HCV infection have been developed.•Drug escape mutations can be a major cause of treatment failure.•High-resolution genetics allows discovery of essential domains as novel drug targets.•Exhaustive drug resistance profile facilitates next-generation drug development.•Drug resistance profile and quasispecies sequencing assist personalized medicine.

The approval of novel antiviral treatments for hepatitis C virus (HCV) infection provides a great example of research driven medicine in action. However, the emergence of resistant viral strains to existing treatments reminds us of the ongoing challenge that we still face in HCV therapy. What can be done to minimize the health risk posed by viral variants that develop resistance and cause failure of therapy? Here we propose that a high-resolution genetic profiling approach that can assess the function at a single nucleotide/amino acid resolution, may provide a solution. We further discuss the potential application of this methodology in resolving viral resistance through the following three aspects: (1) high-resolution mapping of inflexible regions on the viral genome to identify better drug targets; (2) exhaustive drug resistance profiles to facilitate next-generation drug design; (3) coupled with closely monitoring within-host virus quasi-species, drug resistance profiles can aid in optimized drug combination and personalized medicine in HCV treatments.