The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus 1 (HSV-1) glycoprotein D (gD) so that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection, as well as antibodies to HSV. We derived monoclonal antibodies (MAbs) from peripheral blood B cells of recipients of the RV144 HIV vaccine and showed that these antibodies neutralized HSV-1 infection in cells expressing HVEM, but not the other major virus receptor, nectin-1. The MAbs mediated antibody-dependent cellular cytotoxicity (ADCC), and mice that received the MAbs and were then challenged by corneal inoculation with HSV-1 had reduced eye disease, shedding, and latent infection. To our knowledge, this is the first description of MAbs derived from human recipients of a vaccine that specifically target the HVEM binding site of gD. In summary, we found that monoclonal antibodies derived from humans vaccinated with the HVEM binding domain of HSV-1 gD (i) neutralized HSV-1 infection in a cell receptor-specific manner, (ii) mediated ADCC, and (iii) reduced ocular disease in virus-infected mice.

IMPORTANCE Herpes simplex virus 1 (HSV-1) causes cold sores and neonatal herpes and is a leading cause of blindness. Despite many trials, no HSV vaccine has been approved. Nectin-1 and HVEM are the two major cellular receptors for HSV. These receptors are expressed at different levels in various tissues, and the role of each receptor in HSV pathogenesis is not well understood. We derived human monoclonal antibodies from persons who received the HIV RV144 vaccine that contained the HVEM binding domain of HSV-1 gD fused to HIV gp120. These antibodies were able to specifically neutralize HSV-1 infection in vitro via HVEM. Furthermore, we showed for the first time that HVEM-specific HSV-1 neutralizing antibodies protect mice from HSV-1 eye disease, indicating the critical role of HVEM in HSV-1 ocular infection.

RV144 HIV疫苗试验包括重组HIV糖蛋白120（gp120）构建体，该构建体与一小部分单纯疱疹病毒1（HSV-1）糖蛋白D（gD）融合，因此gp120的前40个氨基酸被信号序列取代和gD成熟形式的前27个氨基酸。gD的这个区域包含HVEM的大多数结合位点，HVEM是一种HSV受体，对上皮细胞和淋巴细胞的病毒感染很重要。RV144诱导了对HIV有部分保护作用的抗感染抗体，以及针对HSV的抗体。我们从RV144 HIV疫苗接受者的外周血B细胞衍生了单克隆抗体（MAbs），并显示这些抗体可中和表达HVEM的细胞中的HSV-1感染，但不能表达其他主要病毒受体nectin-1。MAb介导的抗体依赖性细胞毒性（ADCC），并且接受MAb并随后接受HSV-1角膜接种攻击的小鼠，其眼部疾病，脱落和潜伏感染有所减轻。据我们所知，这是针对人源疫苗的单克隆抗体的首次描述，这些单克隆抗体特异性靶向gD的HVEM结合位点。总而言之，我们发现，用HSV-1 gD的HVEM结合域接种疫苗的人衍生的单克隆抗体（i）以细胞受体特异性方式中和了HSV-1感染，（ii）介导的ADCC，和（iii）降低了眼病毒感染的小鼠患上这种疾病。这是首次从疫苗的人类受体中获得的单克隆抗体的描述，该单克隆抗体特异性靶向gD的HVEM结合位点。总而言之，我们发现，用HSV-1 gD的HVEM结合域接种疫苗的人衍生的单克隆抗体（i）以细胞受体特异性方式中和了HSV-1感染，（ii）介导的ADCC，和（iii）降低了眼病毒感染的小鼠患上这种疾病。这是首次从疫苗的人类受体中获得的单克隆抗体的描述，该单克隆抗体特异性靶向gD的HVEM结合位点。总而言之，我们发现，用HSV-1 gD的HVEM结合域接种疫苗的人衍生的单克隆抗体（i）以细胞受体特异性方式中和了HSV-1感染，（ii）介导的ADCC，和（iii）降低了眼病毒感染的小鼠患上这种疾病。

重要事项单纯疱疹病毒1（HSV-1）引起唇疱疹和新生儿疱疹，并且是失明的主要原因。尽管进行了许多试验，但尚未批准任何HSV疫苗。Nectin-1和HVEM是HSV的两个主要细胞受体。这些受体在各种组织中以不同的水平表达，并且每种受体在HSV发病机理中的作用尚不清楚。我们从接受HIV RV144疫苗的人中获得了人类单克隆抗体，该疫苗包含与HIV gp120融合的HSV-1 gD的HVEM结合域。这些抗体能够在体外特异性中和HSV-1感染通过HVEM。此外，我们首次展示了HVEM特异性HSV-1中和抗体可以保护小鼠免受HSV-1眼部疾病的侵害，这表明HVEM在HSV-1眼部感染中的关键作用。