Replicative homeostasis II: Influence of polymerase fidelity on RNA virus quasispecies biology: Implications for immune recognition, viral autoimmunity and other "virus receptor" diseases

Abstract

Much of the worlds' population is in active or imminent danger from established infectious pathogens, while sporadic and pandemic infections by these and emerging agents threaten everyone. RNA polymerases (RNA pol ) generate enormous genetic and consequent antigenic heterogeneity permitting both viruses and cellular pathogens to evade host defences. Thus, RNA pol causes more morbidity and premature mortality than any other molecule. The extraordinary genetic heterogeneity defining viral quasispecies results from RNA pol infidelity causing rapid cumulative genomic RNA mutation a process that, if uncontrolled, would cause catastrophic loss of sequence integrity and inexorable quasispecies extinction. Selective replication and replicative homeostasis, an epicyclical regulatory mechanism dynamically linking RNApol fidelity and processivity with quasispecies phenotypic diversity, modulating polymerase fidelity and, hence, controlling quasispecies behaviour, prevents this happening and also mediates immune escape. Perhaps more importantly, ineluctable generation of broad phenotypic diversity after viral RNA is translated to protein quasispecies suggests a mechanism of disease that specifically targets, and functionally disrupts, the host cell surface molecules -including hormone, lipid, cell signalling or neurotransmitter receptors -that viruses co-opt for cell entry. This mechanism -"Viral Receptor Disease (VRD)" -may explain so-called "viral autoimmunity", some classical autoimmune disorders and other diseases, including type II diabetes mellitus, and some forms of obesity. Viral receptor disease is a unifying hypothesis that may also explain some diseases with well-established, but multifactorial and apparently unrelated aetiologies -like coronary artery and other vascular diseasesin addition to diseases like schizophrenia that are poorly understood and lack plausible, coherent, pathogenic explanations.

Infectious Bronchitis in Poultry: Constraints and Biotechnological Developments in Vaccines

“…Replication errors and the absence of correction mechanisms in the RNA polymerase are responsible for a high rate of uncorrected mutations that accelerate virus's evolution (Jenkins et al, 2002;Taylor, 2006). The lack of fidelity of RNA polymerase leads to a great genetic and antigenic heterogeneity which promotes increased viral quasispecies (Sallie, 2005).…”

Tyr82 Amino Acid Mutation in PB1 Polymerase Induces an Influenza Virus Mutator Phenotype

“…The high error rate of viral RNA-dependent RNA polymerases (RdRps) leads to a naturally maintained level of genetic variation within a population, referred to as a "mutant spectrum" or "quasispecies" (6). The high genetic diversity of RNA viruses provides them with the capacities of immune escape, acquisition of drug resistance, and infection of new host species (7)(8)(9)(10)(11). The mutation rate is a critical parameter for viral evolution, and the error threshold inherent to each virus might determine optimal proliferation.…”