Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins

Fang Chen; Netanel Tzarum; Xiaohe Lin; Erick Giang; Rodrigo Velázquez-Moctezuma; Elias H. Augestad; Kenna Nagy; Linling He; Mayda Hernandez; Mallorie E. Fouch; Ariadna Grinyó; Deborah Chavez; Benjamin J. Doranz; Jannick Prentoe; Robyn L. Stanfield; Robert Lanford; Jens Bukh; Ian A. Wilson; Jiang Zhu; Mansun Law

doi:10.1016/j.immuni.2021.02.013

Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins

Fang Chen, Netanel Tzarum, Xiaohe Lin, Erick Giang, Rodrigo Velázquez-Moctezuma, Elias H. Augestad, Kenna Nagy, Linling He, Mayda Hernandez, Mallorie E. Fouch, Ariadna Grinyó, Deborah Chavez, Benjamin J. Doranz, Jannick Prentoe, Robyn L. Stanfield, Robert Lanford, Jens Bukh, Ian A. Wilson^*, Jiang Zhu^*, Mansun Law^*

^*Corresponding author for this work

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

22 Scopus citations

Abstract

Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here, we studied the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications for vaccination in humans.

Original language	English
Pages (from-to)	781-796.e4
Journal	Immunity
Volume	54
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2021.02.013
State	Published - 13 Apr 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

E1E2
E2
Hepatitis C virus
IGHV1-69
VH1-69
VH1.36
antibody germline
broadly neutralizing antibody
immunization
vaccination

UN SDGs

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

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10.1016/j.immuni.2021.02.013

Cite this

Chen, F., Tzarum, N., Lin, X., Giang, E., Velázquez-Moctezuma, R., Augestad, E. H., Nagy, K., He, L., Hernandez, M., Fouch, M. E., Grinyó, A., Chavez, D., Doranz, B. J., Prentoe, J., Stanfield, R. L., Lanford, R., Bukh, J., Wilson, I. A., Zhu, J., & Law, M. (2021). Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins. Immunity, 54(4), 781-796.e4. https://doi.org/10.1016/j.immuni.2021.02.013

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title = "Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins",

abstract = "Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here, we studied the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications for vaccination in humans.",

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author = "Fang Chen and Netanel Tzarum and Xiaohe Lin and Erick Giang and Rodrigo Vel{\'a}zquez-Moctezuma and Augestad, {Elias H.} and Kenna Nagy and Linling He and Mayda Hernandez and Fouch, {Mallorie E.} and Ariadna Griny{\'o} and Deborah Chavez and Doranz, {Benjamin J.} and Jannick Prentoe and Stanfield, {Robyn L.} and Robert Lanford and Jens Bukh and Wilson, {Ian A.} and Jiang Zhu and Mansun Law",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = apr,

day = "13",

doi = "10.1016/j.immuni.2021.02.013",

language = "אנגלית",

volume = "54",

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Chen, F, Tzarum, N, Lin, X, Giang, E, Velázquez-Moctezuma, R, Augestad, EH, Nagy, K, He, L, Hernandez, M, Fouch, ME, Grinyó, A, Chavez, D, Doranz, BJ, Prentoe, J, Stanfield, RL, Lanford, R, Bukh, J, Wilson, IA, Zhu, J & Law, M 2021, 'Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins', Immunity, vol. 54, no. 4, pp. 781-796.e4. https://doi.org/10.1016/j.immuni.2021.02.013

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T1 - Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins

AU - Chen, Fang

AU - Tzarum, Netanel

AU - Lin, Xiaohe

AU - Giang, Erick

AU - Velázquez-Moctezuma, Rodrigo

AU - Augestad, Elias H.

AU - Nagy, Kenna

AU - He, Linling

AU - Hernandez, Mayda

AU - Fouch, Mallorie E.

AU - Grinyó, Ariadna

AU - Chavez, Deborah

AU - Doranz, Benjamin J.

AU - Prentoe, Jannick

AU - Stanfield, Robyn L.

AU - Lanford, Robert

AU - Bukh, Jens

AU - Wilson, Ian A.

AU - Zhu, Jiang

AU - Law, Mansun

PY - 2021/4/13

Y1 - 2021/4/13

N2 - Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here, we studied the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications for vaccination in humans.

AB - Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here, we studied the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications for vaccination in humans.

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KW - E2

KW - Hepatitis C virus

KW - IGHV1-69

KW - VH1-69

KW - VH1.36

KW - antibody germline

KW - broadly neutralizing antibody

KW - immunization

KW - vaccination

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U2 - 10.1016/j.immuni.2021.02.013

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C2 - 33675683

AN - SCOPUS:85104157231

SN - 1074-7613

VL - 54

SP - 781-796.e4

JO - Immunity

JF - Immunity

IS - 4

ER -

Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins

Abstract

Bibliographical note

Keywords

UN SDGs

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