Immune checkpoint modulation enhances HIV-1 antibody induction.
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.
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.