A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence

Xianwen Zhang; Yang Liu; Jianying Liu; Adam L. Bailey; Kenneth S. Plante; Jessica A. Plante; Jing Zou; Hongjie Xia; Nathen E. Bopp; Patricia V. Aguilar; Ping Ren; Vineet D. Menachery; Michael S. Diamond; Scott C. Weaver; Xuping Xie; Pei Yong Shi

doi:10.1016/j.cell.2021.02.044

A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence

Xianwen Zhang
, Yang Liu
, Jianying Liu
, Adam L. Bailey
, Kenneth S. Plante
, Jessica A. Plante
, Jing Zou
, Hongjie Xia
, Nathen E. Bopp
, Patricia V. Aguilar
, Ping Ren
, Vineet D. Menachery
, Michael S. Diamond
, Scott C. Weaver
, Xuping Xie
, Pei Yong Shi

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

Abstract

The biosafety level 3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research. Here, we report a trans-complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans-complementation system consists of two components: a genomic viral RNA containing ORF3 and envelope gene deletions, as well as mutated transcriptional regulator sequences, and a producer cell line expressing the two deleted genes. Trans-complementation of the two components generates virions that can infect naive cells for only one round but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. Thus, the trans-complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.

Original language	English
Pages (from-to)	2229-2238.e13
Journal	Cell
Volume	184
Issue number	8
DOIs	https://doi.org/10.1016/j.cell.2021.02.044
State	Published - Apr 15 2021

Keywords

COVID-19
SARS-CoV-2
antiviral
coronavirus
diagnosis
vaccine

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10.1016/j.cell.2021.02.044

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Zhang, X., Liu, Y., Liu, J., Bailey, A. L., Plante, K. S., Plante, J. A., Zou, J., Xia, H., Bopp, N. E., Aguilar, P. V., Ren, P., Menachery, V. D., Diamond, M. S., Weaver, S. C., Xie, X., & Shi, P. Y. (2021). A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence. Cell, 184(8), 2229-2238.e13. https://doi.org/10.1016/j.cell.2021.02.044

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title = "A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence",

abstract = "The biosafety level 3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research. Here, we report a trans-complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans-complementation system consists of two components: a genomic viral RNA containing ORF3 and envelope gene deletions, as well as mutated transcriptional regulator sequences, and a producer cell line expressing the two deleted genes. Trans-complementation of the two components generates virions that can infect naive cells for only one round but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. Thus, the trans-complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.",

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author = "Xianwen Zhang and Yang Liu and Jianying Liu and Bailey, \{Adam L.\} and Plante, \{Kenneth S.\} and Plante, \{Jessica A.\} and Jing Zou and Hongjie Xia and Bopp, \{Nathen E.\} and Aguilar, \{Patricia V.\} and Ping Ren and Menachery, \{Vineet D.\} and Diamond, \{Michael S.\} and Weaver, \{Scott C.\} and Xuping Xie and Shi, \{Pei Yong\}",

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AU - Aguilar, Patricia V.

AU - Ren, Ping

AU - Menachery, Vineet D.

AU - Diamond, Michael S.

AU - Weaver, Scott C.

AU - Xie, Xuping

AU - Shi, Pei Yong

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AB - The biosafety level 3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research. Here, we report a trans-complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans-complementation system consists of two components: a genomic viral RNA containing ORF3 and envelope gene deletions, as well as mutated transcriptional regulator sequences, and a producer cell line expressing the two deleted genes. Trans-complementation of the two components generates virions that can infect naive cells for only one round but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. Thus, the trans-complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.

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KW - diagnosis

KW - vaccine

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A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence

Abstract

Keywords

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