Abstract
Hepatitis C (HCV), hepatitis B (HBV), the human immunodeficiency viruses (HIV), and other viruses that replicate via RNA intermediaries, cause an enormous burden of disease and premature death worldwide. These viruses circulate within infected hosts as vast populations of closely related, but genetically diverse, molecules known as "quasispecies". The mechanism(s) by which this extreme genetic and antigenic diversity is stably maintained are unclear, but are fundamental to understanding viral persistence and pathobiology. The persistence of HCV, an RNA virus, is especially problematic and HCV stability, maintained despite rapid genomic mutation, is highly paradoxical. This paper presents the hypothesis, and evidence, that viruses capable of persistent infection autoregulate replication and the likely mechanism mediating autoregulation – Replicative Homeostasis – is described. Replicative homeostasis causes formation of stable, but highly reactive, equilibria that drive quasispecies expansion and generates escape mutation. Replicative homeostasis explains both viral kinetics and the enigma of RNA quasispecies stability and provides a rational, mechanistic basis for all observed viral behaviours and host responses. More importantly, this paradigm has specific therapeutic implication and defines, precisely, new approaches to antiviral therapy. Replicative homeostasis may also modulate cellular gene expression.
Highlights
Replicative homeostasis predicts, for example, HCV E2 proteins derived from genotype 1 HCV sequences would reduce HCV replication when administered to patients with heterologous HCV infection and studies examining heterologous envelope proteins as direct RNA polymerases (RNApol) inhibitors are underway
Replicative homeostasis explains the initial decline of viral replication, resolving the kinetic paradox, rationalizing the dynamics of chronic viral infection and other enigmatic and unresolved viral behaviours
Replicative homeostasis implies a general approach to antiviral therapy
Summary
Problem 2: Mutation rate The stability of RNA viral quasispecies poses a major problem: During viral replication the copied genome may either identical to or a variant of parental template Persistence of stable RNA viral quasispecies is, highly paradoxical [18] This "theoretical impossibility" of RNA quasispecies stability suggests either a) the consistently reported rates of RNApol infidelity are incorrect (which, even if true, would only delay quasispecies extinction; if Mμ = 10-10, ρo
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