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 and Barton F. Haynes ()
Additional contact information
Todd Bradley: Duke University School of Medicine
Masayuki Kuraoka: Duke University School of Medicine
Chen-Hao Yeh: Duke University School of Medicine
Ming Tian: Harvard Medical School, Howard Hughes Medical Institute
Huan Chen: Harvard Medical School, Howard Hughes Medical Institute
Derek W. Cain: Duke University School of Medicine
Xuejun Chen: National Institute of Allergy and Infectious Diseases
Cheng Cheng: National Institute of Allergy and Infectious Diseases
Ali H. Ellebedy: Emory University
Robert Parks: Duke University School of Medicine
Maggie Barr: Duke University School of Medicine
Laura L. Sutherland: Duke University School of Medicine
Richard M. Scearce: Duke University School of Medicine
Cindy M. Bowman: Duke University School of Medicine
Hilary Bouton-Verville: Duke University School of Medicine
Sampa Santra: Harvard Medical School
Kevin Wiehe: Duke University School of Medicine
Mark G. Lewis: BIOQUAL, Inc
Ane Ogbe: University of Oxford
Persephone Borrow: University of Oxford
David Montefiori: Duke University School of Medicine
Mattia Bonsignori: Duke University School of Medicine
M. Anthony Moody: Duke University School of Medicine
Laurent Verkoczy: Duke University School of Medicine
Kevin O. Saunders: Duke University School of Medicine
Rafi Ahmed: Emory University
John R. Mascola: National Institute of Allergy and Infectious Diseases
Garnett Kelsoe: Duke University School of Medicine
Frederick W. Alt: Harvard Medical School, Howard Hughes Medical Institute
Barton F. Haynes: Duke University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14670-w

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