Dissimilar conservation pattern in hepatitis C virus mutant spectra, consensus sequences, and data banks

Abstract

<jats:title>Abstract</jats:title><jats:p>The influence of quasispecies dynamics on long-term virus diversification in nature is a largely unexplored question. Specifically, whether intra-host nucleotide and amino acid variation in quasispecies fits variation observed in consensus sequences or data bank alignments is unknown. Genome conservation and dynamics simulations are used for the computational design of universal vaccines, therapeutic antibodies and pan-genomic antiviral agents. The expectation is that selection of escape mutants will be limited when mutations at conserved residues are required. This strategy assumes long-term (epidemiologically relevant) conservation but, critically, does not consider short-term (quasispecies-dictated) residue conservation. We have calculated mutant frequencies of individual loci from mutant spectra of hepatitis C virus (HCV) populations passaged in cell culture and from infected patients. Nucleotide or amino acid conservation in consensus sequences of the same populations, or in the Los Alamos HCV data bank did not match residue conservation in mutant spectra. The results relativize the concept of sequence conservation in viral genetics, and suggest that residue invariance in data banks is an insufficient basis for the design of universal viral ligands for clinical purposes. Our calculations suggest relaxed mutational restrictions during quasispecies dynamics, which may contribute to higher calculated short-term than long-term viral evolutionary rates.</jats:p>

Historical Perspective on the Discovery of the Quasispecies Concept

“…Residues that are considered conserved according to the alignment of genomic sequences in data banks turn out to be variable when the alignment is done with sequences retrieved from mutant spectra. This difference has been documented with HCV replicating in cell culture or in infected patients (87). The study involved a two-rank comparison of conservation scores: between mutant spectra and their corresponding consensus sequences, and between mutant spectra and Los Alamos National Laboratory HCV sequence alignment.…”

“…Despite their likely inferior replicative fitness, minority genomes that are not represented in data banks may be only a short mutational distance away from gaining fitness, thereby becoming competent escape mutants. Design of universal ligands remains an important challenge, and, if undertaken, it should be endorsed by a more stringent conservation evaluation using mutant spectra data in the sequence alignment (87). If the results with HCV are extended to other viruses, they will diminish the scope of residue conservation of viruses to a far more reduced subset than presently thought.…”

“…When the possible connections between quasispecies dynamics and long-term evolution at the epidemiological level had been explicitly recognized as a pertinent question (87,(97)(98)(99), COVID-19 erupted in the human population. This new pandemic associated with the betacoronavirus SARS-CoV-2 has posed the question of to what extent the 3 to 5 exonuclease activity encoded by the SARS-CoV-2 genome (domain present in protein nsp14) decreases the mutation rate inherent to the replicative complex (that includes nsp12 and several cofactors).…”

SARS-CoV-2 Point Mutation and Deletion Spectra, and Their Association with Different Disease Outcome

“…This is compatible with hot spots reflecting sites where lesions are more tolerated within a generally constrained RNA genome. The fact that hot spots according to mutant spectra do not coincide with those defined by consensus sequences adds to other observations that indicate that residue conservation criteria at these two levels do not coincide (70). That the great majority of mutations in SARS-CoV-2 mutant spectra are present at low frequency may slow down the response of the virus to specific selective constraints such as inhibitors or neutralizing antibodies.…”