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All Studies   All Outcomes    Recent:   

Persistence of an infectious form of SARS-CoV-2 post protease inhibitor treatment of permissive cells in vitro

Nair et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiae385
Aug 2024  
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In Vitro study showing the persistence of an infectious form of SARS-CoV-2 after treatment with 3CLpro inhibitors nirmatrelvir and ensitrelvir, which may explain the rebound often seen with paxlovid.
3CLpro is crucial for processing viral polyproteins into functional viral proteins necessary for the assembly of new virus particles. This study suggests that despite 3CLpro inhibition, viral ribonucleoprotein complexes or replicating forms of the virus may still persist intracellularly. These persistent forms might not require immediate protease activity to survive in the short term and can potentially reinitiate replication once the drug is removed. This persistence could explain why the virus can cause a rebound after the cessation of paxlovid treatment.
Study covers paxlovid and ensitrelvir.
Nair et al., 12 Aug 2024, USA, peer-reviewed, 5 authors. Contact: dh2994@cumc.columbia.edu, ys2581@cumc.columbia.edu.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperPaxlovidAll
Persistence of an infectious form of SARS-CoV-2 post protease inhibitor treatment of permissive cells in vitro
Manoj S Nair, Maria I Luck, Yaoxing Huang, Yosef Sabo, David D Ho
doi:10.1093/infdis/jiae3851
4 Lead contact Reports have described SARS-CoV-2 rebound in COVID-19 patients treated with nirmatrelvir, a 3CL protease inhibitor. The cause remains a mystery, although drug resistance, re-infection, and lack of adequate immune responses have been excluded. We now present virologic findings that provide a clue to the cause of viral rebound, which occurs in ~20% of the treated cases. Persistence of infectious SARS-CoV-2 was experimentally documented in vitro after treatment with nirmatrelvir or another 3CL protease inhibitor, but not with a polymerase inhibitor, remdesivir. This infectious form decayed slowly with a half-life of ~1 day, suggesting that its persistence could outlive the treatment course to re-ignite SARS-CoV-2 infection as the drug is eliminated. Notably, extending nirmatrelvir treatment beyond 8 days abolished viral rebound in vitro. Our findings point in a particular direction for future investigation of virus persistence and offer a specific treatment recommendation that should be tested clinically.
SUPPLEMENTARY DATA Supplementary materials are available at The Journal of Infectious Diseases online. NOTES AUTHOR NOTES: Potential conflict of interest: All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Authors do not report any potential conflict of interest.
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