Immune checkpoint modulation enhances HIV-1 antibody induction.
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.
Bradley, T; Kuraoka, M; Yeh, C-H; 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
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