SARS-CoV-2 Reservoir and Antiviral Strategy in Long COVID

1 Proal et al. 2025 β€” Targeting the SARS-CoV-2 Reservoir in Long COVID

Full Citation:: Proal AD, Aleman S, Bomsel M, et al. Targeting the SARS-CoV-2 reservoir in long COVID. Lancet Infectious Diseases. 2025;25(5):e294–e306. (Proal et al. 2025) DOI:: 10.1016/S1473-3099(24)00769-2 PMID:: 39947217 Study Design:: Expert consensus review (multi-author position paper); draws on HIV and hepatitis C reservoir trial methodology Key Findings::

- No approved treatments exist for long COVID; viral persistence is a leading mechanistic candidate
- SARS-CoV-2 can persist for months to years in subsets of patients, potentially driving ongoing symptoms
- Existing antivirals (nirmatrelvir/ritonavir) target active replication and may not affect stable reservoirs
- Critical trial design considerations identified: mechanism of action, participant selection, treatment duration, reservoir biomarker standardization, and combination approaches
- Draws lessons from HIV long-term non-progressors and hepatitis C cure models for reservoir-clearing strategies

Relevance:: Highly relevant to post-COVID ME/CFS. Establishes the scientific and clinical framework for treating Long COVID as a viral reservoir disease. Authors include leading ME/CFS researchers (VanElzakker, Proal, Iwasaki, Putrino). The design considerations apply directly to proposed ME/CFS antiviral trials. Complements Peluso et al. 2024 gut tissue biopsy evidence with actionable trial design principles. Certainty Assessment::

- *Quality:* High (Lancet Infectious Diseases; expert consensus; multi-author international consortium)
- *Sample:* Review/position paper β€” no primary data
- *Replication:* Synthesises replicated findings across multiple independent groups
- *Certainty:* 0.75 (consensus framework; primary trial data awaited)
- *Limitation:* No new empirical data; trial recommendations untested at time of publication

References

Proal, Amy D., Soo Aleman, Morgane Bomsel, Petter Brodin, Marcus Buggert, Sara Cherry, Daniel S. Chertow, et al. 2025. β€œTargeting the SARS-CoV-2 Reservoir in Long COVID.” Lancet Infectious Diseases 25 (5): e294–306. https://doi.org/10.1016/S1473-3099(24)00769-2.