A highly divergent SARS-CoV-2 lineage B.1.1 sample in a patient with long-term COVID-19

We report the genomic analysis of a highly divergent SARS-CoV-2 sample obtained in October 2022 from an HIV+ patient with presumably long-term COVID-19 infection. Phylogenetic analysis indicates that the sample is characterized by a gain of 89 mutations since divergence from its nearest sequenced neighbor, which had been collected in September 2020 and belongs to the B.1.1 lineage, largely extinct in 2022. 33 of these mutations were coding and occurred in the Spike protein. Of these, 17 are lineage-defining in some of the variants of concern (VOCs) or are in sites where another mutation is lineage-defining in a variant of concern, and/or shown to be involved in antibody evasion, and/or detected in other cases of persistent COVID-19; these include some “usual suspects,” such as Spike:L452R, E484Q, K417T, Y453F, and N460K. Molecular clock analysis indicates that mutations in this lineage accumulated at an increased rate compared to the ancestral B.1.1 strain. This increase is driven by the accumulation of nonsynonymous mutations, for an average dN/dS value of 2.2, indicating strong positive selection during within-patient evolution. Additionally, there is reason to believe that the virus had persisted for at least some time in the gastrointestinal tract, as evidenced by the presence of mutations that are rare in the general population samples but common in samples from wastewater. Our analysis adds to the growing body of research on evolution of SARS-CoV-2 in chronically infected patients and its relationship to the emergence of variants of concern. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work has been supported by the RSF grant no 21-74-20160 to GVK. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research was approved by the Local Ethics Committee of Smorodintsev Research Institute of Influenza (protocol No. 203, 18 May 2023) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are available in GISAID with the identifier EPI\_ISL\_15829108.