title: Evolutionary dynamics of viral escape under antibodies stress: A biophysical model.
abstract: Viruses constantly face the selection pressure of antibodies, either from innate immune response of the host or from administered antibodies for treatment. We explore the interplay between the biophysical properties of viral proteins and the population and demographic variables in the viral escape. The demographic and population genetics aspect of the viral escape have been explored before; however one important assumption was the a priori distribution of fitness effects (DFE). Here, we relax this assumption by instead considering a realistic biophysics-based genotype-phenotype relationship for RNA viruses escaping antibodies stress. In this model the DFE is itself an evolvable property that depends on the genetic background (epistasis) and the distribution of biophysical effects of mutations, which is informed by biochemical experiments and theoretical calculations in protein engineering. We quantitatively explore in silico the viability of viral populations under antibodies pressure and derive the phase diagram that defines the fate of the virus population (extinction or escape from stress) in a range of viral mutation rates and antibodies concentrations. We find that viruses are most resistant to stress at an optimal mutation rate (OMR) determined by the competition between supply of beneficial mutation to facilitate escape from stressors and lethal mutagenesis caused by excess of destabilizing mutations. We then show the quantitative dependence of the OMR on genome length and viral burst size. We also recapitulate the experimental observation that viruses with longer genomes have smaller mutation rate per nucleotide.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, 02138.|Département de Biochimie et Centre Robert-Cedergren en Bioinformatique et Génomique, Université de Montréal, Montréal, Quebec, Canada, H3T 1J4.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chéron
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, 02138.
authors.forename: Adrian W R
authors.initials: AW
authors.lastname: Serohijos
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, 02138.
authors.forename: Jeong-Mo
authors.initials: JM
authors.lastname: Choi
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, 02138.
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: D003198:Computer Simulation; D019143:Evolution, Molecular; D056084:Genetic Fitness; D008957:Models, Genetic; D009154:Mutation; D012328:RNA Viruses / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D014764:Viral Proteins
keywords: folding stability; neutralizing antibodies; optimal mutation rate; viral evolution