Adaptive evolution of SARS-CoV-2 during a persistent infection for 521 days in an immunocompromised patient

Hanno Schmidt; Lea Schick; Jürgen Podlech; Angélique Renzaho; Bettina Lieb; Stefan Diederich; Thomas Hankeln; Bodo Plachter; Oliver Kriege

doi:10.1038/s41525-025-00463-x

Adaptive evolution of SARS-CoV-2 during a persistent infection for 521 days in an immunocompromised patient

NPJ Genom Med. 2025 Jan 17;10(1):4. doi: 10.1038/s41525-025-00463-x.

Authors

Hanno Schmidt^{1

2

3}, Lea Schick⁴, Jürgen Podlech⁵, Angélique Renzaho^{6

5}, Bettina Lieb^{6

7}, Stefan Diederich^{6

8}, Thomas Hankeln^{6

9}, Bodo Plachter^{6

5}, Oliver Kriege⁴

Affiliations

¹ Sequencing Consortium, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. [email protected].
² Institute of Virology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. [email protected].
³ Institute for Quantitative and Computational Biosciences, Johannes Gutenberg-University Mainz, Mainz, Germany. [email protected].
⁴ Third Department of Medicine-Hematology, Internal Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
⁵ Institute of Virology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
⁶ Sequencing Consortium, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
⁷ StarSEQ GmbH, Mainz, Germany.
⁸ Institute of Human Genetics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
⁹ Institute of Organismal and Molecular Evolutionary Biology, Johannes Gutenberg-University Mainz, Mainz, Germany.

PMID: 39820045
DOI: 10.1038/s41525-025-00463-x

Abstract

Immunocompromised patients struggle to adequately clear viral infections, offering the virus the opportunity to adapt to the immune system in the host. Here we present a case study of a patient undergoing allogeneic hematopoietic stem cell transplantation with a 521-day follow-up of a SARS-CoV-2 infection with the BF.7.21 variant. Virus samples from five time points were submitted to whole genome sequencing. Between the first detection of SARS-CoV-2 infection and its clearance, the patient's virus population acquired 34 amino acid substitutions and 8 deletions in coding regions. With 11 amino acid substitutions in the receptor binding domain of the virus' spike protein, substitutions were 15 times more abundant than expected for a random distribution in this highly functional region. Amongst them were the substitutions S:K417T, S:N440S, S:K444R, S:V445A, S:G446N, S:L452Q, S:N460K, and S:E484V at positions that are notorious for their resistance-mediating effects. The substitution patterns found indicate ongoing adaptive evolution.