In vitro and in vivo characterization of SARS-CoV-2 strains resistant to nirmatrelvir

  • Nat Commun. 2023 Jul 4;14(1):3952. doi: 10.1038/s41467-023-39704-x.
Maki Kiso  1 ,  Yuri Furusawa  1  2 ,  Ryuta Uraki  1  2 ,  Masaki Imai  1  2  3 ,  Seiya Yamayoshi  4  5  6 ,  Yoshihiro Kawaoka  7  8  9  10
Affiliations
  • 1. Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 2. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 3. International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 4. Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [email protected].
  • 5. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. [email protected].
  • 6. International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [email protected].
  • 7. Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [email protected].
  • 8. The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. [email protected].
  • 9. The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center, Tokyo, Japan. [email protected].
  • 10. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, USA. [email protected].
PMID: 37402789 DOI: 10.1038/s41467-023-39704-x
Abstract

Nirmatrelvir, an oral Antiviral agent that targets a SARS-CoV-2 main protease (3CLpro), is clinically useful against Infection with SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to many monoclonal antibody therapies, potential SARS-CoV-2 resistance to nirmatrelvir is a major public health concern. Several amino acid substitutions have been identified as being responsible for reduced susceptibility to nirmatrelvir. Among them, we selected L50F/E166V and L50F/E166A/L167F in the 3CLpro because these combinations of substitutions are unlikely to affect virus fitness. We prepared and characterized delta variants possessing Nsp5-L50F/E166V and Nsp5-L50F/E166A/L167F. Both mutant viruses showed decreased susceptibility to nirmatrelvir and their growth in VeroE6/TMPRSS2 cells was delayed. Both mutant viruses showed attenuated phenotypes in a male hamster Infection model, maintained airborne transmissibility, and were outcompeted by wild-type virus in co-infection experiments in the absence of nirmatrelvir, but less so in the presence of the drug. These results suggest that viruses possessing Nsp5-L50F/E166V and Nsp5-L50F/E166A/L167F do not become dominant in nature. However, it is important to closely monitor the emergence of nirmatrelvir-resistant SARS-CoV-2 variants because resistant viruses with additional compensatory mutations could emerge, outcompete the wild-type virus, and become dominant.

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