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bioRxiv · 10.1101/2023.12.12.571262

Syncytia Formation Promotes Virus Resistance to Interferon and Neutralizing Antibodies

Li, T.·Kang, I.·Hu, Z.·Gibbs, J.·Ye, C.·Kosik, I.·Shi, G.·Holly, J.·Kosikova, M.·Compton, A. A.·Martinez-Sobrido, L.·Johnson, R.·Hang, X.·Yewdell, J. W.
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Abstract

SARS-CoV-2, like many viruses, generates syncytia but the role of syncytia formation in viral evolution remains unknown. Using SARS-CoV-2 and SARS-CoV-2 Spike (S) replacement vesicular stomatitis (VSV), we show that S-mediated syncytia impair the antiviral effects of interferons in cultured cells, human lung cell cultures, and hACE2 transgenic mice. Amino acid substitutions that modulate syncytia formation in Delta- and Omicron-encoded S have parallel effects on viral interferon resistance. S-mediated syncytia compromise antibody-mediated virus neutralization in cultured cells. We recapitulate interferon and neutralizing antibody resistance in syncytia generated by the orthoreovirus p14 fusion-associated small transmembrane (FAST) protein in VSV, influenza virus, and seasonal coronavirus OC43 infections. These findings explain selection of SARS-CoV-2 fusogenic variants in humans and, more generally, the evolution of fusogenic viruses driven by adaptive and innate immunity.

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Li, T., Kang, I., Hu, Z., Gibbs, J., Ye, C., Kosik, I., Shi, G., Holly, J., Kosikova, M., Compton, A. A., Martinez-Sobrido, L., Johnson, R., Hang, X., Yewdell, J. W.. 2023-12-13. Syncytia Formation Promotes Virus Resistance to Interferon and Neutralizing Antibodies. https://doi.org/10.1101/2023.12.12.571262

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