Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody

L. Mailly; F. Xiao; J. Lupberger; G.K. Wilson; P. Aubert; F.H.T. Duong; D. Calabrese; C. Leboeuf; I. Fofana; C. Thumann; S. Bandiera; M. Lütgehetmann; T. Volz; C. Davis; H.J. Harris; Christopher Mee; E. Girardi; B. Chane-Woon-Ming; M. Ericsson; N. Fletcher; R. Bartenschlager; P. Pessaux; K. Vercauteren; P. Meuleman; P. Villa; L. Kaderali; S. Pfeffer; M.H. Heim; M. Neunlist; M.B. Zeisel; M. Dandri; J.A. McKeating; E. Robinet; T.F. Baumert

doi:10.1038/nbt.3179

Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody

L. Mailly, F. Xiao, J. Lupberger, G.K. Wilson, P. Aubert, F.H.T. Duong, D. Calabrese, C. Leboeuf, I. Fofana, C. Thumann, S. Bandiera, M. Lütgehetmann, T. Volz, C. Davis, H.J. Harris, Christopher Mee, E. Girardi, B. Chane-Woon-Ming, M. Ericsson, N. FletcherR. Bartenschlager, P. Pessaux, K. Vercauteren, P. Meuleman, P. Villa, L. Kaderali, S. Pfeffer, M.H. Heim, M. Neunlist, M.B. Zeisel, M. Dandri, J.A. McKeating, E. Robinet, T.F. Baumert

School of Life Sciences

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Abstract

Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer1. Cell entry of HCV2 and other pathogens3, 4, 5 is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver–chimeric mouse model6, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

Original language	English
Pages (from-to)	549-554
Journal	Nature Biotechnology
Volume	33
Issue number	5
Early online date	23 Mar 2015
DOIs	https://doi.org/10.1038/nbt.3179
Publication status	Published - 1 May 2015

Keywords

Hepatitis C
monoclonal antibody
chronic viral infection
antiviral therapy

UN SDGs

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

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Clearance of persistent hepatitis CAccepted author manuscript, 1.22 MB

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Mailly, L., Xiao, F., Lupberger, J., Wilson, G. K., Aubert, P., Duong, F. H. T., Calabrese, D., Leboeuf, C., Fofana, I., Thumann, C., Bandiera, S., Lütgehetmann, M., Volz, T., Davis, C., Harris, H. J., Mee, C., Girardi, E., Chane-Woon-Ming, B., Ericsson, M., ... Baumert, T. F. (2015). Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nature Biotechnology, 33(5), 549-554. https://doi.org/10.1038/nbt.3179

Mailly, L, Xiao, F, Lupberger, J, Wilson, GK, Aubert, P, Duong, FHT, Calabrese, D, Leboeuf, C, Fofana, I, Thumann, C, Bandiera, S, Lütgehetmann, M, Volz, T, Davis, C, Harris, HJ, Mee, C, Girardi, E, Chane-Woon-Ming, B, Ericsson, M, Fletcher, N, Bartenschlager, R, Pessaux, P, Vercauteren, K, Meuleman, P, Villa, P, Kaderali, L, Pfeffer, S, Heim, MH, Neunlist, M, Zeisel, MB, Dandri, M, McKeating, JA, Robinet, E & Baumert, TF 2015, 'Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody', Nature Biotechnology, vol. 33, no. 5, pp. 549-554. https://doi.org/10.1038/nbt.3179

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title = "Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody",

abstract = "Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer1. Cell entry of HCV2 and other pathogens3, 4, 5 is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver–chimeric mouse model6, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.",

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author = "L. Mailly and F. Xiao and J. Lupberger and G.K. Wilson and P. Aubert and F.H.T. Duong and D. Calabrese and C. Leboeuf and I. Fofana and C. Thumann and S. Bandiera and M. L{\"u}tgehetmann and T. Volz and C. Davis and H.J. Harris and Christopher Mee and E. Girardi and B. Chane-Woon-Ming and M. Ericsson and N. Fletcher and R. Bartenschlager and P. Pessaux and K. Vercauteren and P. Meuleman and P. Villa and L. Kaderali and S. Pfeffer and M.H. Heim and M. Neunlist and M.B. Zeisel and M. Dandri and J.A. McKeating and E. Robinet and T.F. Baumert",

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AU - Mailly, L.

AU - Xiao, F.

AU - Lupberger, J.

AU - Wilson, G.K.

AU - Aubert, P.

AU - Duong, F.H.T.

AU - Calabrese, D.

AU - Leboeuf, C.

AU - Fofana, I.

AU - Thumann, C.

AU - Bandiera, S.

AU - Lütgehetmann, M.

AU - Volz, T.

AU - Davis, C.

AU - Harris, H.J.

AU - Mee, Christopher

AU - Girardi, E.

AU - Chane-Woon-Ming, B.

AU - Ericsson, M.

AU - Fletcher, N.

AU - Bartenschlager, R.

AU - Pessaux, P.

AU - Vercauteren, K.

AU - Meuleman, P.

AU - Villa, P.

AU - Kaderali, L.

AU - Pfeffer, S.

AU - Heim, M.H.

AU - Neunlist, M.

AU - Zeisel, M.B.

AU - Dandri, M.

AU - McKeating, J.A.

AU - Robinet, E.

AU - Baumert, T.F.

PY - 2015/5/1

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N2 - Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer1. Cell entry of HCV2 and other pathogens3, 4, 5 is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver–chimeric mouse model6, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

AB - Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer1. Cell entry of HCV2 and other pathogens3, 4, 5 is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver–chimeric mouse model6, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

KW - Hepatitis C

KW - monoclonal antibody

KW - chronic viral infection

KW - antiviral therapy

U2 - 10.1038/nbt.3179

DO - 10.1038/nbt.3179

M3 - Article

SN - 1087-0156

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SP - 549

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JO - Nature Biotechnology

JF - Nature Biotechnology

IS - 5

ER -

Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody

Abstract

Keywords

UN SDGs

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