In vitro and in vivo characterization of SARS-CoV-2 strains resistant to nirmatrelvir.
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| 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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| Authors | Maki Kiso, Yuri Furusawa, Ryuta Uraki, Masaki Imai, Seiya Yamayoshi, Yoshihiro Kawaoka |
| Journal | Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 3952 (07 04 2023) ISSN: 2041-1723 [Electronic] England |
| PMID | 37402789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2023. The Author(s). |
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