Taming a beast: lessons from the domestication of hepatitis C virus

“What I cannot create, I do not understand.” Richard Feynman may have championed reasoning from first principles in his famous blackboard missive, but he could just as well have been referring to the plight of a molecular virologist. What cannot be grown in a controlled laboratory setting, we cannot fully understand. The story of the laboratory domestication of hepatitis C virus (HCV) is now a classic example of virologists applying all manner of inventive skill to create cell-based models of infection in order to clarify prospective drug targets. In this review, we highlight key successes and failures that were instructive in achieving cell-based models for HCV studies and drug development. We also emphasize the lessons learned from the ∼40 year saga that may be applicable to viruses yet unknown and uncultured.