A defective viral genome strategy elicits broad protective immunity against respiratory viruses

Yinghong Xiao; Peter V. Lidsky; Yuta Shirogane; Ranen Aviner; Chien Ting Wu; Weiyi Li; Weihao Zheng; Dale Talbot; Adam Catching; Gilad Doitsh; Weiheng Su; Colby E. Gekko; Arabinda Nayak; Joel D. Ernst; Leonid Brodsky; Elia Brodsky; Elsa Rousseau; Sara Capponi; Simone Bianco; Robert Nakamura; Peter K. Jackson; Judith Frydman; Raul Andino

doi:10.1016/j.cell.2021.11.023

A defective viral genome strategy elicits broad protective immunity against respiratory viruses

Yinghong Xiao, Peter V. Lidsky, Yuta Shirogane, Ranen Aviner, Chien Ting Wu, Weiyi Li, Weihao Zheng, Dale Talbot, Adam Catching, Gilad Doitsh, Weiheng Su, Colby E. Gekko, Arabinda Nayak, Joel D. Ernst, Leonid Brodsky, Elia Brodsky, Elsa Rousseau, Sara Capponi, Simone Bianco, Robert NakamuraPeter K. Jackson, Judith Frydman, Raul Andino

Department of Evolutionary and Environmental Biology

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

Abstract

RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

Original language	English
Pages (from-to)	6037-6051.e14
Journal	Cell
Volume	184
Issue number	25
DOIs	https://doi.org/10.1016/j.cell.2021.11.023
State	Published - 9 Dec 2021

Bibliographical note

Funding Information:
We would like to thank Dr. Miguel Garcia-Knight for sharing SARS-CoV-2 Delta variant that he isolated in the context of clinical studies conducted in San Francisco; Drs. Luis Sigal, Eric Dang, Hiten Madhani and members of Andino lab for critical discussions and comments for manuscript preparation; and Gary Howard for editorial support. This work was supported by the DARPA INTERCEPT program managed by James Gimlett and administered through DARPA Cooperative Agreement (grant no. HR0011-17-2-0027) and NIH R41AI157129. We thank the UCSF Center for Advanced Technology core for the Illumina HiSeq4000 for RNA-seq and Gladstone Histology and Light Microscopy Core for the mouse tissue samples processing and H&E staining. Y.X. designed and carried out the experiments, participated in data analysis, and wrote the manuscript. Y.S. cloned eTIP1 cDNA plasmid and generated the stable packaging cell line. G.D. developed nanostructured lipid/eTIP1 RNA complexes. C.E.G. contributed animal work and RNA-seq libraries preparation. Y.X. and P.V.L. carried out SARS-CoV-2 experiments. A.N. Y.X. and D.T. produced and purified eTIP1 particles and LNPs. Y.X. and C.T.W. carried out and analyzed the immunohistochemistry studies on tissue sections. W.S. carried out droplet RT-qPCR for gene expression analyses from tissues. Y.X. R. Aviner, and W.L. carried out RNA-seq analyses. A.C. carried out EM negative stain studies. W.Z. and J.D.E. contributed to flow cytometry analyses of lung tissues. R. Andino, J.F. R.N. J.D.E. S.B. and P.K.J. conceived and directed the project and/or wrote the manuscript. Y.X. R.N. and R. Andino have submitted a patent application. Provisional patent application: recombinant enteroviruses and uses thereof. eTIP1. US Provisional Patent Filed 7/2020. The application was accorded serial no. 63/047,398. D.T. and R.N. are shareholders and employees of Aleph Therapeutics, Inc. E.B. is a shareholder and employee of Pine Biotech Inc. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.

Funding Information:
We would like to thank Dr. Miguel Garcia-Knight for sharing SARS-CoV-2 Delta variant that he isolated in the context of clinical studies conducted in San Francisco; Drs. Luis Sigal, Eric Dang, Hiten Madhani and members of Andino lab for critical discussions and comments for manuscript preparation; and Gary Howard for editorial support. This work was supported by the DARPA INTERCEPT program managed by James Gimlett and administered through DARPA Cooperative Agreement (grant no. HR0011-17-2-0027 ) and NIH R41AI157129 . We thank the UCSF Center for Advanced Technology core for the Illumina HiSeq4000 for RNA-seq and Gladstone Histology and Light Microscopy Core for the mouse tissue samples processing and H&E staining.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

RNA viruses
SARS-CoV-2
antiviral
broad-spectrum
defective viral genomes
innate immunity
interferon
respiratory infection

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2021.11.023

Cite this

Xiao, Y., Lidsky, P. V., Shirogane, Y., Aviner, R., Wu, C. T., Li, W., Zheng, W., Talbot, D., Catching, A., Doitsh, G., Su, W., Gekko, C. E., Nayak, A., Ernst, J. D., Brodsky, L., Brodsky, E., Rousseau, E., Capponi, S., Bianco, S., ... Andino, R. (2021). A defective viral genome strategy elicits broad protective immunity against respiratory viruses. Cell, 184(25), 6037-6051.e14. https://doi.org/10.1016/j.cell.2021.11.023

@article{c17ce6e56791460f8948cf093ba5c53a,

title = "A defective viral genome strategy elicits broad protective immunity against respiratory viruses",

abstract = "RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.",

keywords = "RNA viruses, SARS-CoV-2, antiviral, broad-spectrum, defective viral genomes, innate immunity, interferon, respiratory infection",

author = "Yinghong Xiao and Lidsky, {Peter V.} and Yuta Shirogane and Ranen Aviner and Wu, {Chien Ting} and Weiyi Li and Weihao Zheng and Dale Talbot and Adam Catching and Gilad Doitsh and Weiheng Su and Gekko, {Colby E.} and Arabinda Nayak and Ernst, {Joel D.} and Leonid Brodsky and Elia Brodsky and Elsa Rousseau and Sara Capponi and Simone Bianco and Robert Nakamura and Jackson, {Peter K.} and Judith Frydman and Raul Andino",

note = "Funding Information: We would like to thank Dr. Miguel Garcia-Knight for sharing SARS-CoV-2 Delta variant that he isolated in the context of clinical studies conducted in San Francisco; Drs. Luis Sigal, Eric Dang, Hiten Madhani and members of Andino lab for critical discussions and comments for manuscript preparation; and Gary Howard for editorial support. This work was supported by the DARPA INTERCEPT program managed by James Gimlett and administered through DARPA Cooperative Agreement (grant no. HR0011-17-2-0027) and NIH R41AI157129. We thank the UCSF Center for Advanced Technology core for the Illumina HiSeq4000 for RNA-seq and Gladstone Histology and Light Microscopy Core for the mouse tissue samples processing and H&E staining. Y.X. designed and carried out the experiments, participated in data analysis, and wrote the manuscript. Y.S. cloned eTIP1 cDNA plasmid and generated the stable packaging cell line. G.D. developed nanostructured lipid/eTIP1 RNA complexes. C.E.G. contributed animal work and RNA-seq libraries preparation. Y.X. and P.V.L. carried out SARS-CoV-2 experiments. A.N. Y.X. and D.T. produced and purified eTIP1 particles and LNPs. Y.X. and C.T.W. carried out and analyzed the immunohistochemistry studies on tissue sections. W.S. carried out droplet RT-qPCR for gene expression analyses from tissues. Y.X. R. Aviner, and W.L. carried out RNA-seq analyses. A.C. carried out EM negative stain studies. W.Z. and J.D.E. contributed to flow cytometry analyses of lung tissues. R. Andino, J.F. R.N. J.D.E. S.B. and P.K.J. conceived and directed the project and/or wrote the manuscript. Y.X. R.N. and R. Andino have submitted a patent application. Provisional patent application: recombinant enteroviruses and uses thereof. eTIP1. US Provisional Patent Filed 7/2020. The application was accorded serial no. 63/047,398. D.T. and R.N. are shareholders and employees of Aleph Therapeutics, Inc. E.B. is a shareholder and employee of Pine Biotech Inc. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We would like to thank Dr. Miguel Garcia-Knight for sharing SARS-CoV-2 Delta variant that he isolated in the context of clinical studies conducted in San Francisco; Drs. Luis Sigal, Eric Dang, Hiten Madhani and members of Andino lab for critical discussions and comments for manuscript preparation; and Gary Howard for editorial support. This work was supported by the DARPA INTERCEPT program managed by James Gimlett and administered through DARPA Cooperative Agreement (grant no. HR0011-17-2-0027 ) and NIH R41AI157129 . We thank the UCSF Center for Advanced Technology core for the Illumina HiSeq4000 for RNA-seq and Gladstone Histology and Light Microscopy Core for the mouse tissue samples processing and H&E staining. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = dec,

day = "9",

doi = "10.1016/j.cell.2021.11.023",

language = "English",

volume = "184",

pages = "6037--6051.e14",

journal = "Cell",

issn = "0092-8674",

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number = "25",

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Xiao, Y, Lidsky, PV, Shirogane, Y, Aviner, R, Wu, CT, Li, W, Zheng, W, Talbot, D, Catching, A, Doitsh, G, Su, W, Gekko, CE, Nayak, A, Ernst, JD, Brodsky, L, Brodsky, E, Rousseau, E, Capponi, S, Bianco, S, Nakamura, R, Jackson, PK, Frydman, J & Andino, R 2021, 'A defective viral genome strategy elicits broad protective immunity against respiratory viruses', Cell, vol. 184, no. 25, pp. 6037-6051.e14. https://doi.org/10.1016/j.cell.2021.11.023

TY - JOUR

T1 - A defective viral genome strategy elicits broad protective immunity against respiratory viruses

AU - Xiao, Yinghong

AU - Lidsky, Peter V.

AU - Shirogane, Yuta

AU - Aviner, Ranen

AU - Wu, Chien Ting

AU - Li, Weiyi

AU - Zheng, Weihao

AU - Talbot, Dale

AU - Catching, Adam

AU - Doitsh, Gilad

AU - Su, Weiheng

AU - Gekko, Colby E.

AU - Nayak, Arabinda

AU - Ernst, Joel D.

AU - Brodsky, Leonid

AU - Brodsky, Elia

AU - Rousseau, Elsa

AU - Capponi, Sara

AU - Bianco, Simone

AU - Nakamura, Robert

AU - Jackson, Peter K.

AU - Frydman, Judith

AU - Andino, Raul

N1 - Funding Information: We would like to thank Dr. Miguel Garcia-Knight for sharing SARS-CoV-2 Delta variant that he isolated in the context of clinical studies conducted in San Francisco; Drs. Luis Sigal, Eric Dang, Hiten Madhani and members of Andino lab for critical discussions and comments for manuscript preparation; and Gary Howard for editorial support. This work was supported by the DARPA INTERCEPT program managed by James Gimlett and administered through DARPA Cooperative Agreement (grant no. HR0011-17-2-0027) and NIH R41AI157129. We thank the UCSF Center for Advanced Technology core for the Illumina HiSeq4000 for RNA-seq and Gladstone Histology and Light Microscopy Core for the mouse tissue samples processing and H&E staining. Y.X. designed and carried out the experiments, participated in data analysis, and wrote the manuscript. Y.S. cloned eTIP1 cDNA plasmid and generated the stable packaging cell line. G.D. developed nanostructured lipid/eTIP1 RNA complexes. C.E.G. contributed animal work and RNA-seq libraries preparation. Y.X. and P.V.L. carried out SARS-CoV-2 experiments. A.N. Y.X. and D.T. produced and purified eTIP1 particles and LNPs. Y.X. and C.T.W. carried out and analyzed the immunohistochemistry studies on tissue sections. W.S. carried out droplet RT-qPCR for gene expression analyses from tissues. Y.X. R. Aviner, and W.L. carried out RNA-seq analyses. A.C. carried out EM negative stain studies. W.Z. and J.D.E. contributed to flow cytometry analyses of lung tissues. R. Andino, J.F. R.N. J.D.E. S.B. and P.K.J. conceived and directed the project and/or wrote the manuscript. Y.X. R.N. and R. Andino have submitted a patent application. Provisional patent application: recombinant enteroviruses and uses thereof. eTIP1. US Provisional Patent Filed 7/2020. The application was accorded serial no. 63/047,398. D.T. and R.N. are shareholders and employees of Aleph Therapeutics, Inc. E.B. is a shareholder and employee of Pine Biotech Inc. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We would like to thank Dr. Miguel Garcia-Knight for sharing SARS-CoV-2 Delta variant that he isolated in the context of clinical studies conducted in San Francisco; Drs. Luis Sigal, Eric Dang, Hiten Madhani and members of Andino lab for critical discussions and comments for manuscript preparation; and Gary Howard for editorial support. This work was supported by the DARPA INTERCEPT program managed by James Gimlett and administered through DARPA Cooperative Agreement (grant no. HR0011-17-2-0027 ) and NIH R41AI157129 . We thank the UCSF Center for Advanced Technology core for the Illumina HiSeq4000 for RNA-seq and Gladstone Histology and Light Microscopy Core for the mouse tissue samples processing and H&E staining. Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/12/9

Y1 - 2021/12/9

N2 - RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

AB - RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

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KW - SARS-CoV-2

KW - antiviral

KW - broad-spectrum

KW - defective viral genomes

KW - innate immunity

KW - interferon

KW - respiratory infection

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U2 - 10.1016/j.cell.2021.11.023

DO - 10.1016/j.cell.2021.11.023

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SN - 0092-8674

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SP - 6037-6051.e14

JO - Cell

JF - Cell

IS - 25

ER -

A defective viral genome strategy elicits broad protective immunity against respiratory viruses

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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