Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre-symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti-lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11-dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell-dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ-binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization-independent T cell-mediated effects, even against an established CNS infection by a lethal neurotropic virus.

中文翻译：

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mAb 疗法通过 CD4 T 细胞依赖性机制控制 CNS 驻留狂犬病病毒感染

一旦狂犬病病毒（RABV）和相关狂犬病病毒进入中枢神经系统（CNS）并引起疾病症状，感染狂犬病病毒都会致命。因此，当前的免疫疗法集中于疾病的早期、症状前阶段，目标是中和外周病毒以预防中枢神经系统感染。在这里，我们评估了 F11（一种抗狂犬病毒人类单克隆抗体 (mAb)）对已确诊的狂犬病病毒感染的治疗效果。我们发现单剂量的 F11 可以限制大脑中的病毒载量，并逆转致命剂量的狂犬病病毒感染后的疾病症状，即使是在中枢神经系统中病毒开始强劲复制后服用。重要的是，我们发现 F11 依赖性中和不足以保护动物免于死亡，并且 CD4 T 细胞依赖性适应性免疫反应是成功控制感染所必需的。F11显着改变大脑中白细胞群的谱，F11的FcRγ结合功能有助于提高治疗效果。因此，mAb 疗法可以驱动有效的、不依赖于中和的 T 细胞介导的作用，甚至可以对抗致命的嗜神经病毒造成的中枢神经系统感染。