Humoral Immune Correlates of Protection against Congenital CMV and HSV Transmission in HIV-Infected Women

摘要 虽然使用抗逆转录病毒疗法(ART)来治疗感染HIV-1的母亲已经减少了 艾滋病毒母婴传播率(MTCT)、暴露于艾滋病毒的未感染(HEU)婴儿 面临许多健康风险，包括死亡风险、发育缺陷和严重的 感染。特别是，HEU婴儿对围产期病毒感染的易感性增加。 包括先天性巨细胞病毒(CMV)和新生儿单纯疱疹病毒(HSV)。 先天性巨细胞病毒感染是感音神经性耳聋和永久性耳聋的主要原因 神经缺陷和新生儿HSV-1/2可导致严重的败血症，对神经系统造成毁灭性的破坏 赤字和死亡。因此，有必要保护感染艾滋病毒的婴儿免受这些疾病的侵袭。 病毒，包括制定预防和治疗单纯疱疹病毒和巨细胞病毒的策略。 目前，导致HEU围产期疱疹病毒感染风险增加的主要原因是 婴儿仍未被探索。我们假设(1)感染艾滋病毒的母亲 HSV/CMV特异性的免疫球蛋白反应，包括保护性的抗病毒功能，如抗体- 依赖细胞毒性(ADCC)，抗体依赖细胞吞噬(ADCP)，以及 病毒中和和(2)在艾滋病毒的背景下，这些母体抗体是可变的 胎盘转移到婴儿身上，使HEU婴儿患严重围产儿的风险更高 感染。 本研究旨在明确CMV和CMV的胎盘传播率及其特征。 HIV感染孕妇及其婴儿的HSV特异性免疫球蛋白。此外，这项研究将 确定防止先天性巨细胞病毒传播的体液免疫相关因素。这个 母体抗体的调查将包括鉴定Fc区特征。 与胎盘高效免疫球蛋白转移相关及抗病毒抗体作用的评估 在围产期病毒传播中的作用，包括中和、ADCC和ADCP。这部作品 将为HEU中CMV和HSV感染风险增加建立免疫学基础 更重要的是，这将为合理的疫苗设计提供洞察，最终减少 所有儿童先天性巨细胞病毒和新生儿单纯疱疹病毒感染的风险和严重程度。

ABSTRACT While the use of antiretroviral therapy (ART) to treat HIV-1-infected mothers has reduced the rate of mother-to-child transmission (MTCT) of HIV, HIV-exposed, uninfected (HEU) infants still face numerous health risks, including risk of mortality, developmental deficits, and severe infections. In particular, HEU infants face increased susceptibility to perinatal viral infections including congenital cytomegalovirus (CMV) and neonatal herpes simplex virus (HSV). Congenital CMV infection is a leading cause of sensorineural hearing loss and permanent neurologic deficits, and neonatal HSV-1/2 can result in severe sepsis, devastating neurological deficits, and death. Thus, there is significant need to protect HIV-exposed infants against these viruses, including the development of prophylactic and treatment strategies for HSV and CMV. Currently, the primary causes for this increased risk of perinatal herpes virus infections in HEU infants remain unexplored. We hypothesize that (1) HIV-infected mothers have impaired HSV/CMV-specific IgG responses, including protective antiviral functions such as antibody- dependent cellular cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and virus neutralization and (2) in the context of HIV, these maternal antibodies are variably transplacentally transferred to the infant, leaving HEU infants at higher risk for severe perinatal infections. This study aims to define the placental transmission rate of and characteristics of CMV and HSV-specific IgG in HIV-infected pregnant women and their infants. Furthermore, this study will define the humoral immune correlates of protection against congenital CMV transmission. The investigation of maternal antibodies will include the identification of Fc region characteristics associated with efficient placental IgG transfer and assessment of the role of antiviral antibody functions in perinatal virus transmission, including neutralization, ADCC, and ADCP. This work will establish the immunologic basis for increased risk for CMV and HSV infections in HEU infants, and importantly, will provide insight into rational vaccine design to ultimately reduce the risk and severity of congenital CMV and neonatal HSV infections for all children.