Proal et al. (2025)
- Authors: Amy D. Proal, Soo Aleman, Morgane Bomsel, Petter Brodin, Marcus Buggert, Sara Cherry, Daniel S. Chertow, Steven G. Deeks, Akiko Iwasaki, Michael B. VanElzakker, Michael J. Peluso
- Institutes: PolyBio Research Foundation, Medford, MA, USA, Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, CA, USA, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
- Publisher: The Lancet Infectious Diseases
- Link: DOI
Summary
This position paper represents a major consensus among leading global experts, establishing viral persistence as a primary research priority for Long COVID. It provides a formal scientific roadmap for clinical trials, shifting the focus from symptom management toward potential cures by eliminating viral ‘hideouts’ in the body. For patients, this validates the ‘viral reservoir’ experience and identifies specific categories of drugs—like long-course antivirals and monoclonal antibodies—that are currently being prioritized for testing.
What was researched?
The paper outlines the scientific rationale and technical requirements for clinical trials designed to target persistent SARS-CoV-2 reservoirs in patients with Long COVID.
Why was it researched?
Despite the acute phase of COVID-19 ending, evidence suggests that the virus persists in tissues like the gut or brain in some individuals, potentially driving chronic inflammation and immune exhaustion.
How was it researched?
A multidisciplinary team of experts synthesized current evidence on viral persistence and drew on historical lessons from HIV and Hepatitis C to identify hurdles in drug delivery, participant selection, and biomarker measurement.
What has been found?
The authors found that standard short courses of antivirals like nirmatrelvir/ritonavir 💊 may be insufficient for clearing deep-tissue reservoirs. They identified monoclonal antibodies 💊 and immune-modulators as promising candidates, but emphasized the need for better ‘reservoir biomarkers’ to ensure the right patients are selected for trials.
Discussion
The paper acknowledges that the mechanism of persistence—whether it is replication-competent virus or ‘zombie’ viral debris—remains a key question that affects treatment choice. It highlights the difficulty of sampling deep tissues, such as the gut or nerves, where the virus is most likely to hide.
Conclusion & Future Work
Targeting the viral reservoir is a high-stakes but essential path forward; successful trials will require longer treatment durations, combination therapies, and rigorous use of pre-treatment biopsies or advanced imaging.