A complete mutational fitness map of the hepatitis C virus nonstructural 3 protease: relation to recognition by cytotoxic T lymphocytes.

The hepatitis C virus nonstructural (NS) 3/4A protease sequence is highly conserved for reasons not fully understood. We determined the protease activity in 181 NS3/4A gene products in which each protease residue was replaced by alanine or glycine. Unexpectedly, most (87%) protease residues could be replaced and protease activity would be retained. Using these data, we were able to identify a human leukocyte antigen A2-restricted epitope in which substitutions at 5 of 9 residues destroyed the protease. The NS3 protease shows an unexpectedly high plasticity, and it is therefore important to identify target sequences in which the appearance of mutations is restricted by viral fitness.