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

Abstract

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

Insertion and recombination events at hypervariable region 1 over 9.6 years of hepatitis C virus chronic infection

“…Genotypes are not equipotent with respect to the development of chronic infection (Lehmann et al , 2004; Simmonds, 2004). Persistence is enhanced through changes in antigenic epitopes arising as a consequence of low fidelity of the virally encoded, RNA-dependent RNA polymerase and selective pressures exerted by the host immune system (Schmidt-Martin et al , 2012; Timm & Roggendorf, 2007).…”

Intensive temporal mapping of hepatitis C hypervariable region 1 quasispecies provides novel insights into hepatitis C virus evolution in chronic infection

“…Subject C represents an important illustration of the ongoing change in HCV despite many years of infection, as this subject became infected as a result of contaminated Anti-D in 1977. This suggests genetic drift within the plateau of a local fitness optimum, but also illustrates continued sampling of the sequence space even nearly 40 years after initial infection (Schmidt-Martin, 2012).…”

Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

“…3). One of the causes of the increased heterogeneity may be the adaptive increase of the mutation rate in response to drug treatment (Schmidt-Martin et al, 2012). The quasispecies complexity dynamics of the four viral breakthrough patients showed dramatic increase until week 24 (Fig.…”