Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues—constituting the maternal aspect of the placenta. We directly demonstrated that A3A severely restricted HCMV replication upon controlled overexpression in epithelial cells, acting by a cytidine deamination mechanism to introduce hypermutations into the viral genome. Importantly, we further found that A3 editing of HCMV DNA occurs both ex vivo in HCMV-infected decidual organ cultures and in vivo in amniotic fluid samples obtained during natural congenital infection. Our results reveal a previously unexplored role for A3A as an innate anti-HCMV effector, activated by HCMV infection in the maternal-fetal interface. These findings pave the way to new insights into the potential impact of APOBEC proteins on HCMV pathogenesis.

IMPORTANCE In view of the grave outcomes associated with congenital HCMV infection, there is an urgent need to better understand the innate mechanisms acting to limit transplacental viral transmission. Toward this goal, our findings reveal the role of the intrinsic cellular restriction factor A3A (which has never before been studied in the context of HCMV infection and vertical viral transmission) as a potent anti-HCMV innate barrier, activated by HCMV infection in the authentic tissues of the maternal-fetal interface. The detection of naturally occurring hypermutations in clinical amniotic fluid samples of congenitally infected fetuses further supports the idea of the occurrence of A3 editing of the viral genome in the setting of congenital HCMV infection. Given the widely differential tissue distribution characteristics and biological functions of the members of the A3 protein family, our findings should pave the way to future studies examining the potential impact of A3A as well as of other A3s on HCMV pathogenesis.

人类巨细胞病毒（HCMV）是先天性感染的主要原因，并与广泛的神经发育障碍和子宫内生长受限相关。然而，我们目前对调节胎盘HCMV传播机制的理解还很差。鉴于胎盘在保护胎儿方面的关键功能，它已经发展出了有效的，但在很大程度上尚未表征的针对入侵病原体的先天免疫屏障。在这里，我们表明，本征蜂窝约束因子的apo脂蛋白乙Ë谛听Ç atalytic亚基样3A（APOBEC3A [A3A]）的深刻上调下列体外人蜕膜组织中的HCMV感染-构成胎盘的母体。我们直接证明，A3A在上皮细胞中受控制的过表达后会严重限制HCMV复制，这是通过胞苷脱氨机制将超突变引入病毒基因组来实现的。重要的是，我们还发现，HCMV DNA的A3编辑发生两个体外在HCMV感染的蜕膜器官培养和体内天然先天性感染期间获得羊水样品英寸 我们的结果揭示了A3A作为先天性抗HCMV效应子的先前未曾探索过的作用，该作用是由母婴界面中的HCMV感染激活的。这些发现为深入了解APOBEC蛋白对HCMV发病机理的潜在影响铺平了道路。

重要性鉴于与先天性HCMV感染相关的严重后果，迫切需要更好地了解限制胎盘病毒传播的先天机制。为了实现这一目标，我们的发现揭示了内在的细胞限制性因子A3A（在HCMV感染和垂直病毒传播的背景下从未进行过研究）作为有效的抗HCMV先天屏障的作用，在真正的HCMV感染中被激活母胎界面组织。在先天性感染的胎儿的临床羊水样本中自然发生的超突变的检测进一步支持了在先天性HCMV感染的情况下发生病毒基因组的A3编辑的想法。