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SARS-CoV-2 evolution during treatment of chronic infection

Author

Listed:
  • Steven A. Kemp

    (University College London)

  • Dami A. Collier

    (University College London
    Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Rawlings P. Datir

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Isabella A. T. M. Ferreira

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Salma Gayed

    (Cambridge University NHS Hospitals Foundation Trust)

  • Aminu Jahun

    (University of Cambridge)

  • Myra Hosmillo

    (University of Cambridge)

  • Chloe Rees-Spear

    (University College London)

  • Petra Mlcochova

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Ines Ushiro Lumb

    (University of Oxford)

  • David J. Roberts

    (University of Oxford)

  • Anita Chandra

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • Nigel Temperton

    (University of Kent)

  • Katherine Sharrocks

    (Cambridge University NHS Hospitals Foundation Trust)

  • Elizabeth Blane

    (University of Cambridge)

  • Yorgo Modis

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge
    Medical Research Council Laboratory of Molecular Biology)

  • Kendra E. Leigh

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge
    Medical Research Council Laboratory of Molecular Biology)

  • John A. G. Briggs

    (Medical Research Council Laboratory of Molecular Biology)

  • Marit J. Gils

    (University of Amsterdam)

  • Kenneth G. C. Smith

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge)

  • John R. Bradley

    (University of Cambridge
    NIHR Cambridge Bioresource)

  • Chris Smith

    (Cambridge University NHS Hospitals Foundation Trust)

  • Rainer Doffinger

    (Addenbrooke’s Hospital)

  • Lourdes Ceron-Gutierrez

    (Addenbrooke’s Hospital)

  • Gabriela Barcenas-Morales

    (Addenbrooke’s Hospital
    FES-Cuautitlán, UNAM)

  • David D. Pollock

    (University of Colorado School of Medicine)

  • Richard A. Goldstein

    (University College London)

  • Anna Smielewska

    (University of Cambridge
    Cambridge University NHS Hospitals Foundation Trust)

  • Jordan P. Skittrall

    (Cambridge University NHS Hospitals Foundation Trust
    University of Cambridge
    Addenbrooke’s Hospital)

  • Theodore Gouliouris

    (Cambridge University NHS Hospitals Foundation Trust)

  • Ian G. Goodfellow

    (University of Cambridge)

  • Effrossyni Gkrania-Klotsas

    (Cambridge University NHS Hospitals Foundation Trust)

  • Christopher J. R. Illingworth

    (University of Cambridge
    University of Cambridge)

  • Laura E. McCoy

    (University College London)

  • Ravindra K. Gupta

    (Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)
    University of Cambridge
    Africa Health Research Institute)

Abstract

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Suggested Citation

  • Steven A. Kemp & Dami A. Collier & Rawlings P. Datir & Isabella A. T. M. Ferreira & Salma Gayed & Aminu Jahun & Myra Hosmillo & Chloe Rees-Spear & Petra Mlcochova & Ines Ushiro Lumb & David J. Roberts, 2021. "SARS-CoV-2 evolution during treatment of chronic infection," Nature, Nature, vol. 592(7853), pages 277-282, April.
  • Handle: RePEc:nat:nature:v:592:y:2021:i:7853:d:10.1038_s41586-021-03291-y
    DOI: 10.1038/s41586-021-03291-y
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    Cited by:

    1. Yunxi Liu & Joshua Kearney & Medhat Mahmoud & Bryce Kille & Fritz J. Sedlazeck & Todd J. Treangen, 2022. "Rescuing low frequency variants within intra-host viral populations directly from Oxford Nanopore sequencing data," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Markus Hoffmann & Lok-Yin Roy Wong & Prerna Arora & Lu Zhang & Cheila Rocha & Abby Odle & Inga Nehlmeier & Amy Kempf & Anja Richter & Nico Joel Halwe & Jacob Schön & Lorenz Ulrich & Donata Hoffmann & , 2023. "Omicron subvariant BA.5 efficiently infects lung cells," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Jolien Van Cleemput & Willem van Snippenberg & Laurens Lambrechts & Amélie Dendooven & Valentino D’Onofrio & Liesbeth Couck & Wim Trypsteen & Jan Vanrusselt & Sebastiaan Theuns & Nick Vereecke & Thier, 2021. "Organ-specific genome diversity of replication-competent SARS-CoV-2," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Sung Hee Ko & Pierce Radecki & Frida Belinky & Jinal N. Bhiman & Susan Meiring & Jackie Kleynhans & Daniel Amoako & Vanessa Guerra Canedo & Margaret Lucas & Dikeledi Kekana & Neil Martinson & Limakats, 2024. "Rapid intra-host diversification and evolution of SARS-CoV-2 in advanced HIV infection," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Sheri Harari & Danielle Miller & Shay Fleishon & David Burstein & Adi Stern, 2024. "Using big sequencing data to identify chronic SARS-Coronavirus-2 infections," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Sebastian Weigang & Jonas Fuchs & Gert Zimmer & Daniel Schnepf & Lisa Kern & Julius Beer & Hendrik Luxenburger & Jakob Ankerhold & Valeria Falcone & Janine Kemming & Maike Hofmann & Robert Thimme & Ch, 2021. "Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    7. Elham Khatamzas & Markus H. Antwerpen & Alexandra Rehn & Alexander Graf & Johannes Christian Hellmuth & Alexandra Hollaus & Anne-Wiebe Mohr & Erik Gaitzsch & Tobias Weiglein & Enrico Georgi & Clemens , 2022. "Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Sissy Therese Sonnleitner & Martina Prelog & Stefanie Sonnleitner & Eva Hinterbichler & Hannah Halbfurter & Dominik B. C. Kopecky & Giovanni Almanzar & Stephan Koblmüller & Christian Sturmbauer & Leon, 2022. "Cumulative SARS-CoV-2 mutations and corresponding changes in immunity in an immunocompromised patient indicate viral evolution within the host," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. Xiaopan Gao & Huabin Tian & Kaixiang Zhu & Qing Li & Wei Hao & Linyue Wang & Bo Qin & Hongyu Deng & Sheng Cui, 2022. "Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Mohammed Nooruzzaman & Katherine E. E. Johnson & Ruchi Rani & Eli J. Finkelsztein & Leonardo C. Caserta & Rosy P. Kodiyanplakkal & Wei Wang & Jingmei Hsu & Maria T. Salpietro & Stephanie Banakis & Jos, 2024. "Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Alief Moulana & Thomas Dupic & Angela M. Phillips & Jeffrey Chang & Serafina Nieves & Anne A. Roffler & Allison J. Greaney & Tyler N. Starr & Jesse D. Bloom & Michael M. Desai, 2022. "Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    12. Ana S. Gonzalez-Reiche & Hala Alshammary & Sarah Schaefer & Gopi Patel & Jose Polanco & Juan Manuel Carreño & Angela A. Amoako & Aria Rooker & Christian Cognigni & Daniel Floda & Adriana Guchte & Zain, 2023. "Sequential intrahost evolution and onward transmission of SARS-CoV-2 variants," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    13. Haogao Gu & Ruopeng Xie & Dillon C. Adam & Joseph L.-H. Tsui & Daniel K. Chu & Lydia D. J. Chang & Sammi S. Y. Cheuk & Shreya Gurung & Pavithra Krishnan & Daisy Y. M. Ng & Gigi Y. Z. Liu & Carrie K. C, 2022. "Genomic epidemiology of SARS-CoV-2 under an elimination strategy in Hong Kong," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    14. Wanbo Tai & Shengyong Feng & Benjie Chai & Shuaiyao Lu & Guangyu Zhao & Dong Chen & Wenhai Yu & Liting Ren & Huicheng Shi & Jing Lu & Zhuming Cai & Mujia Pang & Xu Tan & Penghua Wang & Jinzhong Lin & , 2023. "An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    15. Adam Abdullahi & David Oladele & Michael Owusu & Steven A. Kemp & James Ayorinde & Abideen Salako & Douglas Fink & Fehintola Ige & Isabella A. T. M. Ferreira & Bo Meng & Augustina Angelina Sylverken &, 2022. "SARS-COV-2 antibody responses to AZD1222 vaccination in West Africa," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    16. Nikhil Kumar Tulsian & Raghuvamsi Venkata Palur & Xinlei Qian & Yue Gu & Bhuvaneshwari D/O Shunmuganathan & Firdaus Samsudin & Yee Hwa Wong & Jianqing Lin & Kiren Purushotorman & Mary McQueen Kozma & , 2023. "Defining neutralization and allostery by antibodies against COVID-19 variants," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    17. Farina Karim & Catherine Riou & Mallory Bernstein & Zesuliwe Jule & Gila Lustig & Strauss Graan & Roanne S. Keeton & Janine-Lee Upton & Yashica Ganga & Khadija Khan & Kajal Reedoy & Matilda Mazibuko &, 2024. "Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-ART initiation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    18. Hidetoshi Igari & Seiichiro Sakao & Takayuki Ishige & Kengo Saito & Shota Murata & Misuzu Yahaba & Toshibumi Taniguchi & Akiko Suganami & Kazuyuki Matsushita & Yutaka Tamura & Takuji Suzuki & Eiji Ido, 2024. "Dynamic diversity of SARS-CoV-2 genetic mutations in a lung transplantation patient with persistent COVID-19," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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