Understanding and optimizing antibody-based interventions against neonatal HSV infection

摘要 胎儿/新生儿时期是病毒感染的脆弱性的独特时期。而 疱疹病毒如单纯疱疹病毒（HSV）是高度流行的，并且通常不危及生命 虽然这些疾病在健康成年人中是最常见的病毒感染，但它们是生命早期最重要的病毒感染之一。HSV 分娩期间或产后早期感染导致播散性疾病或脑炎， 50%的感染者如果不治疗，死亡率很高，估计70%的存活婴儿 中枢神经系统（CNS）的参与遭受长期的神经发育后遗症， 用acyclovir治疗幸运的是，我们这个病原体丰富的世界的新生儿继承了一些提供的保护， 通过母体免疫系统以转移抗体（Ab）的形式。对于HSV，母体Ab血清阳性， 导致能够直接中和病毒并引发多种效应子功能的Ab的胎盘转移 先天性免疫系统的，与nHSV的风险显着降低。 目前还没有批准的HSV疫苗，可以诱导母体抗体， 血清阴性母亲作为一种替代，我们以前的工作已经证明，母体抗体很容易进入 胎儿的神经组织，足以预防nHSV。初步数据显示， 模型系统，我们不仅可以模拟死亡率和病毒负荷，还可以模拟行为病理， 在nHSV感染后，人类的发病率很高，并且是终生的。这一建议的核心假设是， nHSV感染的有效疫苗和治疗性抗体的开发将受益于仔细的体内研究， 和抗体作用机制的体外评价。目前，在对这一问题的认识方面存在着严重的差距。 基于Ab的干预措施在nHSV感染的背景下提供益处的机制，以及这些机制如何 可以优化干预措施，以最好地预防这一毁灭性疾病。 我们的目标是定义和完善单克隆抗体（mAb）的使用方法 预防或降低nHSV发病率和死亡率。我们假设，虽然抗体效应器功能有助于 为了直接中和活性，它们受到病毒Fc受体（vFcR）、糖蛋白E（gE/gI） 复合物）。在强有力的初步数据的指导下，项目目标将通过完成两个 具体目的：1）定义预防nHSV的mAb的作用机制，和2）定义抗nHSV抗体的作用。 病毒Fc受体（gE/gI）影响抗病毒mAb活性。

ABSTRACT The fetal/neonatal period represents a unique period of vulnerability to viral infections. While Herpesviruses such as herpes simplex virus (HSV) are highly prevalent and typically non life-threatening infections among healthy adults, they are among the most consequential viral infections of early life. HSV infection during parturition or the early postnatal period results in disseminated disease or encephalitis in up to 50% of infected newbowns. Without treatment, mortality is high and an estimated 70% of surviving infants with central nervous system (CNS) involvement suffer long-term neurodevelopmental sequelae despite aggressive treatment with acyclovir. Fortunately, newborns in our pathogen-rich world inherit some of the protection provided by the maternal immune system in the form of transferred antibodies (Ab). For HSV, maternal Ab seropositivity, resulting in placental transfer of Ab capable of directly neutralizing virus and eliciting the diverse effector functions of the innate immune system, is associated with dramatically decreased risk of nHSV. There is no currently approved HSV vaccine whereby maternal Abs could be induced among seronegative mothers. As an alternative, our previous work has demonstrated that maternal Ab readily accesses neural tissues of the fetus and is sufficient to prevent nHSV. Preliminary data now demonstrate a novel mouse model system whereby we can model not only mortality and viral burden, but also behavioral pathologies that are frequent and lifelong in humans following nHSV. The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies for nHSV infections will benefit from careful in vivo and in vitro evaluation of antibody mechanism(s) of action. Presently, there is a critical gap in knowledge of the mechanisms whereby Ab-based interventions provide benefit in the context of nHSV infection, and how these interventions might be optimized in order to best prevent this devastating disease. Our objective is to define and refine the means by which monoclonal antibodies (mAbs) can be used to prevent or reduce nHSV morbidity and mortality. We hypothesize that while Ab effector functions contribute to direct neutralization activity, they are modulated by the viral Fc Receptor (vFcR), glycoprotein E (gE/gI complex). Guided by strong preliminary data, the project goals will be achieved though completion of two Specific Aims: 1) Define the mechanism(s) of action of mAbs that prevent nHSV, and 2) Define the role of the viral Fc receptor (gE/gI) in influencing antiviral mAb activity.