Immune checkpoint modulation enhances HIV-1 antibody induction

Todd Bradley; Masayuki Kuraoka; Chen Hao Yeh; Ming Tian; Huan Chen; Derek W. Cain; Xuejun Chen; Cheng Cheng; Ali H. Ellebedy; Robert Parks; Maggie Barr; Laura L. Sutherland; Richard M. Scearce; Cindy M. Bowman; Hilary Bouton-Verville; Sampa Santra; Kevin Wiehe; Mark G. Lewis; Ane Ogbe; Persephone Borrow; David Montefiori; Mattia Bonsignori; M. Anthony Moody; Laurent Verkoczy; Kevin O. Saunders; Rafi Ahmed; John R. Mascola; Garnett Kelsoe; Frederick W. Alt; Barton F. Haynes

doi:10.1038/s41467-020-14670-w

Immune checkpoint modulation enhances HIV-1 antibody induction

Todd Bradley, Masayuki Kuraoka, Chen Hao Yeh, Ming Tian, Huan Chen, Derek W. Cain, Xuejun Chen, Cheng Cheng, Ali H. Ellebedy, Robert Parks, Maggie Barr, Laura L. Sutherland, Richard M. Scearce, Cindy M. Bowman, Hilary Bouton-Verville, Sampa Santra, Kevin Wiehe, Mark G. Lewis, Ane Ogbe, Persephone BorrowDavid Montefiori, Mattia Bonsignori, M. Anthony Moody, Laurent Verkoczy, Kevin O. Saunders, Rafi Ahmed, John R. Mascola, Garnett Kelsoe, Frederick W. Alt, Barton F. Haynes

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

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Abstract

Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

Original language	English
Article number	948
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14670-w
State	Published - Dec 1 2020

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Bradley, T., Kuraoka, M., Yeh, C. H., Tian, M., Chen, H., Cain, D. W., Chen, X., Cheng, C., Ellebedy, A. H., Parks, R., Barr, M., Sutherland, L. L., Scearce, R. M., Bowman, C. M., Bouton-Verville, H., Santra, S., Wiehe, K., Lewis, M. G., Ogbe, A., ... Haynes, B. F. (2020). Immune checkpoint modulation enhances HIV-1 antibody induction. Nature communications, 11(1), Article 948. https://doi.org/10.1038/s41467-020-14670-w

@article{0a1748dc95d24ff7aee46a738ae9e125,

title = "Immune checkpoint modulation enhances HIV-1 antibody induction",

abstract = "Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.",

author = "Todd Bradley and Masayuki Kuraoka and Yeh, {Chen Hao} and Ming Tian and Huan Chen and Cain, {Derek W.} and Xuejun Chen and Cheng Cheng and Ellebedy, {Ali H.} and Robert Parks and Maggie Barr and Sutherland, {Laura L.} and Scearce, {Richard M.} and Bowman, {Cindy M.} and Hilary Bouton-Verville and Sampa Santra and Kevin Wiehe and Lewis, {Mark G.} and Ane Ogbe and Persephone Borrow and David Montefiori and Mattia Bonsignori and {Anthony Moody}, M. and Laurent Verkoczy and Saunders, {Kevin O.} and Rafi Ahmed and Mascola, {John R.} and Garnett Kelsoe and Alt, {Frederick W.} and Haynes, {Barton F.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-14670-w",

language = "English",

volume = "11",

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Bradley, T, Kuraoka, M, Yeh, CH, Tian, M, Chen, H, Cain, DW, Chen, X, Cheng, C, Ellebedy, AH, Parks, R, Barr, M, Sutherland, LL, Scearce, RM, Bowman, CM, Bouton-Verville, H, Santra, S, Wiehe, K, Lewis, MG, Ogbe, A, Borrow, P, Montefiori, D, Bonsignori, M, Anthony Moody, M, Verkoczy, L, Saunders, KO, Ahmed, R, Mascola, JR, Kelsoe, G, Alt, FW & Haynes, BF 2020, 'Immune checkpoint modulation enhances HIV-1 antibody induction', Nature communications, vol. 11, no. 1, 948. https://doi.org/10.1038/s41467-020-14670-w

TY - JOUR

T1 - Immune checkpoint modulation enhances HIV-1 antibody induction

AU - Bradley, Todd

AU - Kuraoka, Masayuki

AU - Yeh, Chen Hao

AU - Tian, Ming

AU - Chen, Huan

AU - Cain, Derek W.

AU - Chen, Xuejun

AU - Cheng, Cheng

AU - Ellebedy, Ali H.

AU - Parks, Robert

AU - Barr, Maggie

AU - Sutherland, Laura L.

AU - Scearce, Richard M.

AU - Bowman, Cindy M.

AU - Bouton-Verville, Hilary

AU - Santra, Sampa

AU - Wiehe, Kevin

AU - Lewis, Mark G.

AU - Ogbe, Ane

AU - Borrow, Persephone

AU - Montefiori, David

AU - Bonsignori, Mattia

AU - Anthony Moody, M.

AU - Verkoczy, Laurent

AU - Saunders, Kevin O.

AU - Ahmed, Rafi

AU - Mascola, John R.

AU - Kelsoe, Garnett

AU - Alt, Frederick W.

AU - Haynes, Barton F.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

AB - Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

UR - http://www.scopus.com/inward/record.url?scp=85079819867&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-14670-w

DO - 10.1038/s41467-020-14670-w

M3 - Article

C2 - 32075963

AN - SCOPUS:85079819867

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 948

ER -

Immune checkpoint modulation enhances HIV-1 antibody induction

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