Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret’s meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.

复发性疱疹病毒感染可表现为不同形式的疾病，包括唇疱疹、生殖器疱疹和脑炎。对于导致中枢神经系统 (CNS) 复发性单纯疱疹病毒 2 (HSV2) 感染易感性的遗传和免疫因素尚不完全了解。在这里，我们描述了两名患有复发性 HSV2 淋巴细胞莫拉雷特脑膜炎的成年患者，他们各自携带自噬蛋白 ATG4A 或 LC3B2 中罕见的单等位基因变异。 HSV2 激活的自噬在患者原代成纤维细胞中被消除，也表现出病毒复制显着增加和细胞死亡增加。 HSV2抗原被感染细胞的自噬体捕获，通过破坏自噬基因（包括ATG4A和LC3B2 ）对自噬进行遗传抑制，导致原代成纤维细胞和神经母细胞瘤细胞系中病毒复制和细胞死亡增强。 HSV2 激活的自噬对病毒的紫外线 (UV) 照射敏感，并且在阿昔洛韦存在的情况下会受到抑制，但 HSV2 诱导的自噬与 DNA 激活的 STING 途径无关。使用慢病毒基因递送或将体外转录的 mRNA 电穿孔至患者细胞中重建野生型 ATG4A 和 LC3B2 表达，恢复了病毒诱导的自噬和控制 HSV2 复制的能力。这项研究描述了自噬缺陷与先天性免疫错误之间先前未知的联系，这种联系可能导致 HSV2 感染的易感性增加，表明自噬在中枢神经系统抗病毒免疫中发挥着重要作用。