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）治疗感染HIV-1的母亲减少了艾滋病的发病率， 艾滋病毒母婴传播率、接触艾滋病毒但未感染的婴儿仍 面临许多健康风险，包括死亡风险，发育缺陷，以及严重的 感染.特别是，高浓缩铀婴儿更容易受到围产期病毒感染 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听力损失的主要原因， 神经功能缺损，新生儿HSV-1/2可导致严重的败血症，破坏性的神经系统， 赤字和死亡。因此，非常需要保护暴露于艾滋病毒的婴儿免受这些疾病的侵害。 病毒，包括HSV和CMV的预防和治疗策略的发展。 目前，高浓缩铀患者围产期疱疹病毒感染风险增加的主要原因是 婴儿还未被发现。我们假设（1）感染艾滋病毒的母亲 HSV/CMV特异性IgG应答，包括保护性抗病毒功能，如抗体- 依赖性细胞毒性（ADCC）、抗体依赖性细胞吞噬作用（ADCP），以及 病毒中和和（2）在艾滋病毒的情况下，这些母体抗体是可接受的。 经胎盘转移给婴儿，使高浓缩铀婴儿在围产期出现严重并发症的风险更高。 感染. 本研究旨在明确CMV的胎盘传播率和特点， HIV感染孕妇及其婴儿的HSV特异性IgG此外，本研究将 确定保护免受先天性CMV传播的体液免疫相关性。的 母体抗体的研究将包括Fc区特征的鉴定 与有效的胎盘IgG转移和抗病毒抗体作用的评估相关 在围产期病毒传播中的功能，包括中和、ADCC和ADCP。这项工作 将为HEU中巨细胞病毒和单纯疱疹病毒感染风险增加奠定免疫学基础 婴儿，重要的是，将提供洞察合理的疫苗设计，以最终减少 所有儿童先天性CMV和新生儿HSV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.