Immune checkpoint modulation enhances HIV-1 antibody induction

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

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.