biostudies-literatureChaguza CCenter for AIDS Research, University of WashingtonNCATS NIH HHSCenters for Disease Control and PreventionNIAID NIH HHSYale New Haven HospitalUniversity of North Carolina WilmingtonNCI NIH HHSNational Institutes of HealthUNC100943https://www.ebi.ac.uk/biostudies/studies/S-EPMC9906997biostudies-literatureUnknown4(2)The chronic infection hypothesis for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence is increasingly gaining credence following the appearance of Omicron. Here, we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately 2-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution results in the emergence and persistence of at least three genetically distinct genotypes, suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants.Cell reports. MedicineAccelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection.PMC990699775D30120C09570P30 AI050410R01 AI140970P30 CA016086R01-AI140970UL1 TR001863P30-AI050410P30-CA016086Hill VKerantzas NEarnest RPham KBreban MIPeaper DPetrone MEYale SARS-CoV-2 Genomic Surveillance InitiativeGrubaugh NDVogels CBFPena-Hernandez MAKoch TRDe Kumar BFerguson DBillig KLandry MLSchulz WRoberts SCZhou SSwanstrom RIOtt IMCastaldi CKalinch CCChaguza CTikhonova IRHahn AMFauver JRfalseAccelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection.The chronic infection hypothesis for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence is increasingly gaining credence following the appearance of Omicron. Here, we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately 2-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution results in the emergence and persistence of at least three genetically distinct genotypes, suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants.2023-01-01T00:00:00Z2023 Feb2026-06-24T03:08:24.738Z2025-02-18T23:44:50.889ZS-EPMC99069973679172410.1016/j.xcrm.2023.100943