Abstract
SARS-CoV-2 infection typically resolves within weeks, but rare cases of prolonged replication—sometimes exceeding a year—have been documented, particularly in immunocompromised individuals. These persistent infections pose health risks and may give rise to highly divergent variants, yet the underlying biology remains poorly understood. Here, we describe a model of SARS-CoV-2 persistence using transgenic Syrian hamsters (males) lacking the interleukin-2 receptor gamma subunit (IL2rg). Infection with the XBB.1.16 variant led to efficient viral replication in respiratory tissues by two weeks after infection, with dissemination to other sites, including the intestinal tract. Viral titers remained high in multiple tissues at 100 days after infection. Longitudinal oral swab sequencing revealed dynamic shifts in intrahost single-nucleotide variant (iSNV) frequencies, with constellations of iSNVs rising and falling together, consistent with strong genetic linkage. Synonymous and nonsynonymous mutations accumulated at similar rates, suggesting genetic drift as the dominant evolutionary force. Tissue- and swab-derived sequences revealed extensive within-host diversity and hinted at tissue-specific evolutionary trajectories. This model enables detailed investigation of SARS-CoV-2 persistence and within-host viral evolution and provides a controlled system to study how long-term replication in tissue reservoirs may contribute to viral diversification.
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Data availability
All the sequences associated with this project have been deposited to NCBI BioProject PRJNA1382858. The source data behind the graphs in the paper can be found in Supplementary Data 1 and Supplementary Data 2. All other data supporting the conclusions of this study are available from the corresponding authors upon reasonable request.
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Acknowledgements
This work was supported by the National Institutes of Health under Award Number R21AI164001 to Y.K., the Japan Agency for Medical Research and Development (AMED) under grant numbers JP24wm0125008, JP24fk0108637, JP25fk0108732, JP223fa627003, and JP243fa727002 to T.S. Funding was also through the University of Wisconsin–Madison to T.C.F. and P.J.H. and from Utah State University to Z.W. We thank Yuko Sato and Seiya Ozono for their technical assistance. We also thank Chase Nelson for his insight into virus evolution analysis and Sue Watson for editing the manuscript.
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Conceptualization: M.K., T.C.F., Y.K., and P.J.H. Methodology and data analysis: W.W., T.C.F., M.K., S.I., S.K., Y.H., and P.J.H. Investigation: W.W., M.K., S.I., S.K., Y.L., Y.H., and P.J.H. Visualization: W.W., M.K., S.I., Y.H., K.K., T.C.F., and P.J.H. Writing—original draft: W.W., H.M., K.K., T.C.F., and P.J.H. Writing—review and editing: W.W., M.K., S.I., S.K., Y.L., H.M., Y.H., T.S., Z.W., K.K., T.C.F., Y.K., and P.J.H.
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Y.K. has received unrelated funding support from Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Inc., Shionogi & Co. Ltd, Otsuka Pharmaceutical, KM Biologics, Kyoritsu Seiyaku, Shinya Corporation, and Fuji Rebio. The other authors declare that they have no competing interests.
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Wei, W., Kuroda, M., Liu, Y. et al. Pathology and viral evolutionary dynamics in a hamster model of persistent SARS-CoV-2 infection. Commun Biol (2026). https://doi.org/10.1038/s42003-025-09473-y
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DOI: https://doi.org/10.1038/s42003-025-09473-y
