Hepatitis C quasispecies adaptation in the setting of a variable fidelity polymerase

Daniel Schmidt-Martin,1 Orla Crosbie,2 Elizabeth Kenny-Walsh,2 Liam J Fanning11Molecular Virology Diagnostic and Research Laboratory, Department of Medicine, University College Cork, Clinical Sciences Building, Cork University Hospital, 2Department of Gastroenterology and Hepatology, Cork, IrelandAbstract: Hepatitis C (HCV) is a virus characterized by an RNA-dependent RNA polymerase that lacks a proofreading mechanism and, as a result, generates a quasispecies. There is emerging evidence that this RNA-dependent RNA polymerase may in fact have variable fidelity. Here, we review the relevant concepts, including fitness landscapes, clonal interference, robustness, selection, adaptation, mutation rates, and their optimization, and provide a unique interpretation of a number of relevant theoretical models, evolving the theory of replicative homeostasis in light of their findings. We suggest that a variable fidelity polymerase can find its own optimal mutation rate, which is governed by the sequence itself and certain population dynamics. We propose that this concept can explain features of viral kinetics and clearance, both spontaneously and following treatment of chronic HCV. We point to evidence that supports this theory and explain how it refines replicative homeostasis and conclude by discussing particular areas of potential research that might augment our understanding of viral host interactions at an individual cellular level.Keywords: fitness landscapes, adaptation, evolution, quasispecies, hepatitis C, replicative homeostasis