University of Basel, Department of Biomedicine-Haus Petersplatz, Division of Experimental Virology, 4009 Basel, Switzerland.
Department of Pathology and Immunology, Geneva Faculty of Medicine, Geneva University Hospital, 1211 Geneva, Switzerland.
Cell Rep. 2021 Nov 30;37(9):110061. doi: 10.1016/j.celrep.2021.110061.
Passive antibody therapy and vectored antibody gene delivery (VAGD) in particular offer an innovative approach to combat persistent viral diseases. Here, we exploit a small animal model to investigate synergies of VAGD with the host's endogenous immune defense for treating chronic viral infection. An adeno-associated virus (AAV) vector delivering the lymphocytic choriomeningitis virus (LCMV)-neutralizing antibody KL25 (AAV-KL25) establishes protective antibody titers for >200 days. When therapeutically administered to chronically infected immunocompetent wild-type mice, AAV-KL25 affords sustained viral load control. In contrast, viral mutational escape thwarts therapeutic AAV-KL25 effects when mice are unable to mount LCMV-specific antibody responses or lack CD8 T cells. VAGD augments antiviral germinal center B cell and antibody-secreting cell responses and reduces inhibitory receptor expression on antiviral CD8 T cells. These results indicate that VAGD fortifies host immune defense and synergizes with B cell and CD8 T cell responses to restore immune control of chronic viral infection.
被动抗体治疗和载体抗体基因传递（VAGD）特别为对抗持续性病毒疾病提供了一种创新方法。在这里，我们利用小动物模型来研究 VAGD 与宿主内源性免疫防御之间的协同作用，以治疗慢性病毒感染。携带淋巴细胞性脉络丛脑膜炎病毒（LCMV）中和抗体 KL25 的腺相关病毒（AAV）载体（AAV-KL25）建立了保护性抗体滴度>200 天。当对慢性感染的免疫功能正常的野生型小鼠进行治疗性给药时，AAV-KL25 可持续控制病毒载量。相比之下，当小鼠无法产生 LCMV 特异性抗体反应或缺乏 CD8 T 细胞时，病毒突变逃逸会破坏治疗性 AAV-KL25 的作用。VAGD 增强了抗病毒生发中心 B 细胞和抗体分泌细胞的反应，并降低了抗病毒 CD8 T 细胞上抑制受体的表达。这些结果表明，VAGD 增强了宿主的免疫防御，并与 B 细胞和 CD8 T 细胞反应协同作用，以恢复对慢性病毒感染的免疫控制。
