Wang Kening, Tomaras Georgia D, Jegaskanda Sinthujan, Moody M Anthony, Liao Hua-Xin, Goodman Kyle N, Berman Phillip W, Rerks-Ngarm Supachai, Pitisuttithum Punnee, Nitayapan Sorachai, Kaewkungwal Jaranit, Haynes Barton F, Cohen Jeffrey I
Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Departments of Surgery, Immunology, and Molecular Genetics and Microbiology, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
J Virol. 2017 Sep 12;91(19). doi: 10.1128/JVI.00411-17. Print 2017 Oct 1.
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. 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 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艾滋病疫苗试验包含一种重组HIV糖蛋白120（gp120）构建体，它与一小部分单纯疱疹病毒1（HSV-1）糖蛋白D（gD）融合，使得gp120的前40个氨基酸被信号序列取代，gD成熟形式的前27个氨基酸被替换。gD的这一区域包含了大部分与疱疹病毒侵入因子（HVEM）结合的位点，HVEM是一种对上皮细胞和淋巴细胞的病毒感染很重要的HSV受体。RV144诱导产生了对HIV有部分感染保护作用的抗体，以及对HSV的抗体。我们从RV144艾滋病疫苗接种者的外周血B细胞中获得了单克隆抗体（MAb），并表明这些抗体能中和表达HVEM的细胞中的HSV-1感染，但不能中和另一种主要病毒受体——nectin-1。这些单克隆抗体介导了抗体依赖性细胞毒性（ADCC），接受单克隆抗体然后通过角膜接种HSV-1进行攻击的小鼠眼部疾病、病毒脱落和潜伏感染都有所减轻。据我们所知，这是首次对源自疫苗接种者的单克隆抗体进行描述，这些单克隆抗体特异性靶向gD的HVEM结合位点。总之，我们发现，从接种了含有与HIV gp120融合的HSV-1 gD的HVEM结合域的疫苗的人类中获得的单克隆抗体：（i）以细胞受体特异性方式中和HSV-1感染；（ii）介导ADCC；（iii）减轻病毒感染小鼠的眼部疾病。单纯疱疹病毒1（HSV-1）会引起唇疱疹和新生儿疱疹，是导致失明的主要原因。尽管进行了许多试验，但尚无HSV疫苗获批。Nectin-1和HVEM是HSV的两种主要细胞受体。这些受体在各种组织中的表达水平不同，每种受体在HSV发病机制中的作用尚未完全了解。我们从接种了含有与HIV gp120融合的HSV-1 gD的HVEM结合域的HIV RV144疫苗的人身上获得了人源单克隆抗体。这些抗体能够通过HVEM特异性中和HSV-1感染。此外，我们首次表明，针对HVEM的HSV-1中和抗体可保护小鼠免受HSV-1眼部疾病的侵害，这表明HVEM在HSV-1眼部感染中起关键作用。
