IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-51924-3.html
   My bibliography  Save this article

Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

Author

Listed:
  • Mohammed Nooruzzaman

    (Cornell University)

  • Katherine E. E. Johnson

    (NIH/NIAID/DIR/LPD)

  • Ruchi Rani

    (Cornell University)

  • Eli J. Finkelsztein

    (Weill Cornell Medicine)

  • Leonardo C. Caserta

    (Cornell University)

  • Rosy P. Kodiyanplakkal

    (Weill Cornell Medicine)

  • Wei Wang

    (NIH/NIAID/DIR/LPD)

  • Jingmei Hsu

    (Weill Cornell Medicine
    Perlmutter Cancer Center, NYU Langone Health)

  • Maria T. Salpietro

    (Weill Cornell Medicine)

  • Stephanie Banakis

    (NIH/NIAID/DIR/LPD)

  • Joshua Albert

    (NIH/NIAID/DIR/LPD)

  • Lars F. Westblade

    (Weill Cornell Medicine)

  • Claudio Zanettini

    (Weill Cornell Medicine)

  • Luigi Marchionni

    (Weill Cornell Medicine)

  • Rosemary Soave

    (Weill Cornell Medicine)

  • Elodie Ghedin

    (NIH/NIAID/DIR/LPD)

  • Diego G. Diel

    (Cornell University)

  • Mirella Salvatore

    (Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n = 15). All patients received remdesivir and some also received nirmatrelvir-ritonavir (n = 3) or therapeutic monoclonal antibodies (n = 4). Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient sequentially treated with nirmatrelvir-ritonavir and remdesivir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51924-3
    DOI: 10.1038/s41467-024-51924-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-51924-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-51924-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Sergei L. Kosakovsky Pond & Darren Martin, 2023. "Anti-COVID drug accelerates viral evolution," Nature, Nature, vol. 623(7987), pages 486-487, November.
    2. 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.
    3. Sho Iketani & Hiroshi Mohri & Bruce Culbertson & Seo Jung Hong & Yinkai Duan & Maria I. Luck & Medini K. Annavajhala & Yicheng Guo & Zizhang Sheng & Anne-Catrin Uhlemann & Stephen P. Goff & Yosef Sabo, 2023. "Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir," Nature, Nature, vol. 613(7944), pages 558-564, January.
    4. Theo Sanderson & Ryan Hisner & I’ah Donovan-Banfield & Hassan Hartman & Alessandra Løchen & Thomas P. Peacock & Christopher Ruis, 2023. "A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes," Nature, Nature, vol. 623(7987), pages 594-600, November.
    5. Yinkai Duan & Hao Zhou & Xiang Liu & Sho Iketani & Mengmeng Lin & Xiaoyu Zhang & Qucheng Bian & Haofeng Wang & Haoran Sun & Seo Jung Hong & Bruce Culbertson & Hiroshi Mohri & Maria I. Luck & Yan Zhu &, 2023. "Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir," Nature, Nature, vol. 622(7982), pages 376-382, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. 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.
    2. 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.
    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. 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.
    5. 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.
    6. 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.
    7. Haofeng Wang & Qi Yang & Xiaoce Liu & Zili Xu & Maolin Shao & Dongxu Li & Yinkai Duan & Jielin Tang & Xianqiang Yu & Yumin Zhang & Aihua Hao & Yajie Wang & Jie Chen & Chenghao Zhu & Luke Guddat & Hong, 2023. "Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. 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.
    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. 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.
    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. 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.
    13. Michael H. J. Rhodin & Archie C. Reyes & Anand Balakrishnan & Nalini Bisht & Nicole M. Kelly & Joyce Sweeney Gibbons & Jonathan Lloyd & Michael Vaine & Tessa Cressey & Miranda Crepeau & Ruichao Shen &, 2024. "The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    14. Maki Kiso & Yuri Furusawa & Ryuta Uraki & Masaki Imai & Seiya Yamayoshi & Yoshihiro Kawaoka, 2023. "In vitro and in vivo characterization of SARS-CoV-2 strains resistant to nirmatrelvir," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    15. Maki Kiso & Seiya Yamayoshi & Shun Iida & Yuri Furusawa & Yuichiro Hirata & Ryuta Uraki & Masaki Imai & Tadaki Suzuki & Yoshihiro Kawaoka, 2023. "In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    16. 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.
    17. Joseph F. Standing & Laura Buggiotti & Jose Afonso Guerra-Assuncao & Maximillian Woodall & Samuel Ellis & Akosua A. Agyeman & Charles Miller & Mercy Okechukwu & Emily Kirkpatrick & Amy I. Jacobs & Cha, 2024. "Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    18. 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.
    19. Robert M. Cox & Carolin M. Lieber & Josef D. Wolf & Amirhossein Karimi & Nicole A. P. Lieberman & Zachary M. Sticher & Pavitra Roychoudhury & Meghan K. Andrews & Rebecca E. Krueger & Michael G. Natchu, 2023. "Comparing molnupiravir and nirmatrelvir/ritonavir efficacy and the effects on SARS-CoV-2 transmission in animal models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    20. Nobuyo Higashi-Kuwata & Kohei Tsuji & Hironori Hayashi & Haydar Bulut & Maki Kiso & Masaki Imai & Hiromi Ogata-Aoki & Takahiro Ishii & Takuya Kobayakawa & Kenta Nakano & Nobutoki Takamune & Naoki Kish, 2023. "Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51924-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.