Targeting the SARS-CoV-2 reservoir in long COVID

Amy D Proal¹, Soo Aleman², Morgane Bomsel³, Petter Brodin⁴, Marcus Buggert⁵, Sara Cherry⁶, Daniel S Chertow⁷, Helen E Davies⁸, Christopher L Dupont⁹, Steven G Deeks¹⁰, E Wes Ely¹¹, Alessio Fasano¹², Marcelo Freire¹³, Linda N Geng¹⁴, Diane E Griffin¹⁵, Timothy J Henrich¹⁶, Stephen M Hewitt¹⁷, Akiko Iwasaki¹⁸, Harlan M Krumholz¹⁹, Michela Locci²⁰, Vincent C Marconi²¹, Saurabh Mehandru²², Michaela Muller-Trutwin²³, Mark M Painter²⁴, Etheresia Pretorius²⁵, David A Price²⁶, David Putrino²⁷, Yu Qian²⁸, Nadia R Roan²⁹, Dominique Salmon³⁰, Gene S Tan¹³, Michael B VanElzakker³¹, E John Wherry³², Johan Van Weyenbergh³³, Lael M Yonker¹², Michael J Peluso³⁴

Affiliations

¹ PolyBio Research Foundation, Medford, MA, USA. Electronic address: aproal@polybio.org.
² Department of Infectious Diseases and Unit of Post-COVID Huddinge, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
³ HIV entry and Laboratory of Mucosal Immunity, Institut Cochin, Paris, France; Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France.
⁴ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Immunology and Inflammation, Imperial College London, London, UK; Medical Research Council Laboratory of Medical Sciences, Imperial College London, London, UK.
⁵ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden.
⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA; Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
⁸ Department of Respiratory Medicine, University Hospital Llandough, Cardiff, UK; University School of Medicine, University Hospital of Wales, Cardiff, UK.
⁹ Division of Genomic Medicine, Environment & Sustainability, J Craig Venter Institute, University of California San Diego, La Jolla, CA, USA.
¹⁰ Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, CA, USA.
¹¹ The Critical Illness, Brain Dysfunction, Survivorship Center at Vanderbilt University Medical Center, Nashville, TN, USA; Veteran's Affairs Tennessee Valley Geriatric Research Education Clinical Center, Nashville, TN, USA.
¹² Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA; Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
¹³ Department of Infectious Diseases, J Craig Venter Institute, University of California San Diego, La Jolla, CA, USA.
¹⁴ J Craig Venter Institute, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁶ Division of Experimental Medicine, University of California, San Francisco, CA, USA.
¹⁷ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Center for Infection and Immunity, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹⁹ Center for Infection and Immunity, Yale University School of Medicine, New Haven, CT, USA; Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT, USA; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
²⁰ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²¹ Emory University School of Medicine and Rollins School of Public Health, Atlanta, GA, USA; Atlanta Veterans Affairs Medical Center, Decatur, GA, USA.
²² Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Henry D Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ Institut Pasteur, Université Paris-Cité, HIV, Inflammation and Persistence Unit, Paris, France.
²⁴ Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
²⁶ Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK.
²⁷ Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁸ Department of Informatics, J Craig Venter Institute, University of California San Diego, La Jolla, CA, USA.
²⁹ Gladstone Institutes, University of California, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA.
³⁰ Department of Infectious Diseases, Institut Fournier, Paris, France; Direction of International Relations Assistance Publique Hôpitaux de Paris, Paris, France.
³¹ PolyBio Research Foundation, Medford, MA, USA; Division of Neurotherapeutics, Massachusetts General Hospital, Boston, MA, USA.
³² Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
³⁴ Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, CA, USA. Electronic address: michael.peluso@ucsf.edu.

PMID: 39947217
PMCID: PMC12151306 (available on 2026-05-01)
DOI: 10.1016/S1473-3099(24)00769-2

Review

Targeting the SARS-CoV-2 reservoir in long COVID

Amy D Proal et al. Lancet Infect Dis. 2025 May.

. 2025 May;25(5):e294-e306.

doi: 10.1016/S1473-3099(24)00769-2. Epub 2025 Feb 10.

Authors

Affiliations

¹ PolyBio Research Foundation, Medford, MA, USA. Electronic address: aproal@polybio.org.
² Department of Infectious Diseases and Unit of Post-COVID Huddinge, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
³ HIV entry and Laboratory of Mucosal Immunity, Institut Cochin, Paris, France; Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France.
⁴ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Immunology and Inflammation, Imperial College London, London, UK; Medical Research Council Laboratory of Medical Sciences, Imperial College London, London, UK.
⁵ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden.
⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA; Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
⁸ Department of Respiratory Medicine, University Hospital Llandough, Cardiff, UK; University School of Medicine, University Hospital of Wales, Cardiff, UK.
⁹ Division of Genomic Medicine, Environment & Sustainability, J Craig Venter Institute, University of California San Diego, La Jolla, CA, USA.
¹⁰ Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, CA, USA.
¹¹ The Critical Illness, Brain Dysfunction, Survivorship Center at Vanderbilt University Medical Center, Nashville, TN, USA; Veteran's Affairs Tennessee Valley Geriatric Research Education Clinical Center, Nashville, TN, USA.
¹² Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA; Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
¹³ Department of Infectious Diseases, J Craig Venter Institute, University of California San Diego, La Jolla, CA, USA.
¹⁴ J Craig Venter Institute, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁶ Division of Experimental Medicine, University of California, San Francisco, CA, USA.
¹⁷ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA; Center for Infection and Immunity, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹⁹ Center for Infection and Immunity, Yale University School of Medicine, New Haven, CT, USA; Center for Outcomes Research and Evaluation, Yale New Haven Hospital, New Haven, CT, USA; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
²⁰ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²¹ Emory University School of Medicine and Rollins School of Public Health, Atlanta, GA, USA; Atlanta Veterans Affairs Medical Center, Decatur, GA, USA.
²² Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Henry D Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ Institut Pasteur, Université Paris-Cité, HIV, Inflammation and Persistence Unit, Paris, France.
²⁴ Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
²⁶ Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK.
²⁷ Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁸ Department of Informatics, J Craig Venter Institute, University of California San Diego, La Jolla, CA, USA.
²⁹ Gladstone Institutes, University of California, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA.
³⁰ Department of Infectious Diseases, Institut Fournier, Paris, France; Direction of International Relations Assistance Publique Hôpitaux de Paris, Paris, France.
³¹ PolyBio Research Foundation, Medford, MA, USA; Division of Neurotherapeutics, Massachusetts General Hospital, Boston, MA, USA.
³² Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³³ Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
³⁴ Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, CA, USA. Electronic address: michael.peluso@ucsf.edu.

PMID: 39947217
PMCID: PMC12151306 (available on 2026-05-01)
DOI: 10.1016/S1473-3099(24)00769-2

Abstract

There are no approved treatments for post-COVID-19 condition (also known as long COVID), a debilitating disease state following SARS-CoV-2 infection that is estimated to affect tens of millions of people. A growing body of evidence shows that SARS-CoV-2 can persist for months or years following COVID-19 in a subset of individuals, with this reservoir potentially driving long-COVID symptoms or sequelae. There is, therefore, an urgent need for clinical trials targeting persistent SARS-CoV-2, and several trials of antivirals or monoclonal antibodies for long COVID are underway. However, because mechanisms of SARS-CoV-2 persistence are not yet fully understood, such studies require important considerations related to the mechanism of action of candidate therapeutics, participant selection, duration of treatment, standardisation of reservoir-associated biomarkers and measurables, optimal outcome assessments, and potential combination approaches. In addition, patient subgroups might respond to some interventions or combinations of interventions, making post-hoc analyses crucial. Here, we outline these and other key considerations, with the goal of informing the design, implementation, and interpretation of trials in this rapidly growing field. Our recommendations are informed by knowledge gained from trials targeting the HIV reservoir, hepatitis C, and other RNA viruses, as well as precision oncology, which share many of the same hurdles facing long-COVID trials.

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Conflict of interest statement

Declaration of interests ADP reports a leadership role at PolyBio Research Foundation. SA reports research support from Gilead Sciences outside the submitted work and reimbursement for participation on Gilead's advisory board. MB reports consulting fees or payment honoraria for lectures from Bristol Myers Squibb, Mabtech, Pfizer, Gilead, and MSD outside of the submitted work, and participation on an advisory board for Mabtech. SGD reports research support from Aerium and Eli Lilly outside the submitted work and consulting for BioVie, Enanta Pharmaceuticals, and Pfizer. LNG reports research support from Pfizer outside the submitted work. AF serves as Chief Science and Medical Officer at Mead Johnson Nutrition. DEG reports research support from Gilead Sciences outside the submitted work and the leadership role of vice president at the National Academy of Sciences. AI reports being a member of the board of directors for Roche Holding and Genentech, being member of the Council for American Association of Immunologists, and being co-founder and stockholder of RIGImmune, Xanadu Bio, and PanV. In the past three years, HMK has received options for Element Science and Identifeye and payments from F-Prime for advisory roles. He is a cofounder of and holds equity in Hugo Health, Refactor Health, and ENSIGHT-AI. He is associated with research contracts through Yale University from Janssen, Kenvue, Novartis, and Pfizer. VCM reports research support from Gilead Sciences, ViiV, CDC, NIH, Department of Veterans Affairs, and Merck outside the submitted work, participation on data safety monitoring or advisory boards for the IL-1b inhibitor study, Outsmart, CLEAR HIV, ECLIPSE, and VB201, and role of study section chair for NIH. YQ reports consulting for Moderna. DS reports honoraria for conferences on long COVID for Pfizer, Gilead, and Shionogi. EJW reports being an advisor for Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, New Limit, Marengo, Pluto Immunotherapeutics, Related Sciences, Santa Ana Bio, and Synthekine; and being a founder of and holding stock in Coherus, Danger Bio, and Arsenal Biosciences. MBV reports a leadership role at PolyBio Research Foundation. JVW reports a speaker fee from Pfizer. MJP reports consulting for Gilead Sciences, BioVie, and AstraZeneca; and receipt of study drug from Aerium Therapeutics and Shionogi. All other authors declare no competing interests.

References

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1. Proal AD, VanElzakker MB. Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front Microbiol [Internet]. 2021. Jun 23 [cited 2023 Feb 20];12. Available from: - PMC - PubMed

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Targeting the SARS-CoV-2 reservoir in long COVID

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Targeting the SARS-CoV-2 reservoir in long COVID

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