Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis

Jing Jin; Nathan M. Liss; Dong Hua Chen; Maofu Liao; Julie M. Fox; Raeann M. Shimak; Rachel H. Fong; Daniel Chafets; Sonia Bakkour; Sheila Keating; Marina E. Fomin; Marcus O. Muench; Michael B. Sherman; Benjamin J. Doranz; Michael S. Diamond; Graham Simmons

doi:10.1016/j.celrep.2015.11.043

Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis

Jing Jin, Nathan M. Liss, Dong Hua Chen, Maofu Liao, Julie M. Fox, Raeann M. Shimak, Rachel H. Fong, Daniel Chafets, Sonia Bakkour, Sheila Keating, Marina E. Fomin, Marcus O. Muench, Michael B. Sherman, Benjamin J. Doranz, Michael S. Diamond, Graham Simmons

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

76 Scopus citations

Abstract

We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.

Original language	English (US)
Pages (from-to)	2553-2564
Number of pages	12
Journal	Cell Reports
Volume	13
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2015.11.043
State	Published - Dec 22 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2015.11.043

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Jin, J., Liss, N. M., Chen, D. H., Liao, M., Fox, J. M., Shimak, R. M., Fong, R. H., Chafets, D., Bakkour, S., Keating, S., Fomin, M. E., Muench, M. O., Sherman, M. B., Doranz, B. J., Diamond, M. S., & Simmons, G. (2015). Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis. Cell Reports, 13(11), 2553-2564. https://doi.org/10.1016/j.celrep.2015.11.043

Jin, J, Liss, NM, Chen, DH, Liao, M, Fox, JM, Shimak, RM, Fong, RH, Chafets, D, Bakkour, S, Keating, S, Fomin, ME, Muench, MO, Sherman, MB, Doranz, BJ, Diamond, MS & Simmons, G 2015, 'Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis', Cell Reports, vol. 13, no. 11, pp. 2553-2564. https://doi.org/10.1016/j.celrep.2015.11.043

@article{ef176cc8afd94387ac9873e26911cf66,

title = "Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis",

abstract = "We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.",

author = "Jing Jin and Liss, {Nathan M.} and Chen, {Dong Hua} and Maofu Liao and Fox, {Julie M.} and Shimak, {Raeann M.} and Fong, {Rachel H.} and Daniel Chafets and Sonia Bakkour and Sheila Keating and Fomin, {Marina E.} and Muench, {Marcus O.} and Sherman, {Michael B.} and Doranz, {Benjamin J.} and Diamond, {Michael S.} and Graham Simmons",

note = "Funding Information: This work was supported by the NIH grants R56 AI119056 (to G.S.), R01 AI089591 and R01 AI114816 (to M.S.D.), and contract HHSN272200700055C (to B.J.D.). The authors thank John Heitman, Yifan Cheng (UCSF), and Chuan (River) Xiao (UTEP) for assistance with experimental or data analysis, S. Higgs (Kansas State University) for the generous gift of molecular clones of chikungunya reporter virus, and Edgar Davidson and Manu Mabila for additional antibody analysis and preparation. Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

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doi = "10.1016/j.celrep.2015.11.043",

language = "English (US)",

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AU - Jin, Jing

AU - Liss, Nathan M.

AU - Chen, Dong Hua

AU - Liao, Maofu

AU - Fox, Julie M.

AU - Shimak, Raeann M.

AU - Fong, Rachel H.

AU - Chafets, Daniel

AU - Bakkour, Sonia

AU - Keating, Sheila

AU - Fomin, Marina E.

AU - Muench, Marcus O.

AU - Sherman, Michael B.

AU - Doranz, Benjamin J.

AU - Diamond, Michael S.

AU - Simmons, Graham

N1 - Funding Information: This work was supported by the NIH grants R56 AI119056 (to G.S.), R01 AI089591 and R01 AI114816 (to M.S.D.), and contract HHSN272200700055C (to B.J.D.). The authors thank John Heitman, Yifan Cheng (UCSF), and Chuan (River) Xiao (UTEP) for assistance with experimental or data analysis, S. Higgs (Kansas State University) for the generous gift of molecular clones of chikungunya reporter virus, and Edgar Davidson and Manu Mabila for additional antibody analysis and preparation. Publisher Copyright: © 2015 The Authors.

PY - 2015/12/22

Y1 - 2015/12/22

N2 - We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.

AB - We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.

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Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis

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