Peaked-to-flat transition in quasispecies structure evolution.

Previous studies based on clinical data from hepatitis C virus and hepatitis E virus infections revealed a deterministic evolution of quasispecies structure, irrespective of haplotype identities, towards a flat-like landscape, characterized by the absence of dominance and high evenness, combined with high haplotype synonymy. Here, two idealized limiting quasispecies states, A and Z, are defined, and it is shown that the A-to-Z evolution describes a parabolic trajectory between these states. The initial phase is dominated by increasing genetic diversity, whereas the subsequent phase is driven primarily by increasing evenness in the haplotype distribution. This evolutionary progression confers a broad domain within the genetic space, resulting in increased fitness and resilience, accompanied by a diminished response to antiviral therapies and multiple escape routes. Finally, a normalized quasispecies maturity score is proposed to position a given quasispecies along this structural evolutionary trajectory. This conceptual framework helps to account for the challenges in treating advanced chronic infections in which therapeutic failure frequently occurs in the absence of resistance-associated mutations.