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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.<\/jats:p>","DOI":"10.1093\/ve\/veag024","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T11:22:46Z","timestamp":1776079366000},"source":"Crossref","is-referenced-by-count":1,"title":["Peaked-to-flat transition in quasispecies structure evolution"],"prefix":"10.1093","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-8015","authenticated-orcid":false,"given":"Josep","family":"Gregori","sequence":"first","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH) , Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119\u2013129, 08035 Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0307-7455","authenticated-orcid":false,"given":"Sergi","family":"Colomer-Castell","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH) , Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119\u2013129, 08035 Barcelona ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III , Av. Monforte de Lemos, 3\u20135, 28029 Madrid ,","place":["Spain"]},{"name":"Biochemistry and Molecular Biology Department, Universitat Aut\u00f2noma de Barcelona (UAB) , Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0132-7027","authenticated-orcid":false,"given":"Carolina","family":"Campos","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH) , Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119\u2013129, 08035 Barcelona ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III , Av. Monforte de Lemos, 3\u20135, 28029 Madrid ,","place":["Spain"]},{"name":"Biochemistry and Molecular Biology Department, Universitat Aut\u00f2noma de Barcelona (UAB) , Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3428-2168","authenticated-orcid":false,"given":"Marta","family":"Iba\u00f1ez-Lligo\u00f1a","sequence":"additional","affiliation":[{"name":"Liver Diseases-Viral Hepatitis, Liver Unit, Vall d\u2019Hebron Institute of Research (VHIR), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH) , Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119\u2013129, 08035 Barcelona ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III , Av. Monforte de Lemos, 3\u20135, 28029 Madrid ,","place":["Spain"]},{"name":"Medicine Department, Universitat Aut\u00f2noma de Barcelona (UAB) , Campus de la UAB, Pla\u00e7a C\u00edvica, 08193 Bellaterra ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0009-038X","authenticated-orcid":false,"given":"Damir","family":"Garc\u00eda-Cehic","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III , Av. Monforte de Lemos, 3\u20135, 28029 Madrid ,","place":["Spain"]},{"name":"Department of Radiation Oncology, Vontz Center - 2434 Lab,University of Cincinnati College of Medicine , 3125 Eden Ave, Cincinnati, OH 45267 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4318-532X","authenticated-orcid":false,"given":"Maria Francesca","family":"Cortese","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III , Av. 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