Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, 27710, USA.
Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA.
Nat Commun. 2020 Feb 19;11(1):948. doi: 10.1038/s41467-020-14670-w.
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.
诱导 HIV-1 广谱中和抗体 (bnAbs) 的保护性滴度是 HIV-1 疫苗开发的目标，但目前的疫苗策略尚未在人类中诱导出 bnAbs。许多从 HIV-1 感染个体中分离出来的 bnAbs 是由免疫球蛋白基因重排编码的，其具有罕见的幼稚 B 细胞前体和不寻常的遗传特征，这些特征可能受到宿主调节控制。在这里，我们给恒河猴和表达不同 CD4 结合位点 HIV-1 bnAbs 前体的 bnAb 免疫球蛋白敲入 (KI) 小鼠施用针对免疫细胞调节受体 CTLA-4、PD-1 或 OX40 的抗体以及 HIV 包膜 (Env) 疫苗。CTLA-4 阻断增强了恒河猴的 HIV-1 Env 抗体反应，在 bnAb 前体小鼠模型中，CTLA-4 阻断或 OX40 激动剂抗体增加了生发中心 B 和滤泡辅助 T 细胞以及中和抗体。因此，在接种疫苗期间调节 CTLA-4 或 OX40 免疫检查点可以促进生发中心的活性并增强 HIV-1 Env 抗体反应。
