How maternal HCMV facilitates in utero transmission of HIV and impacts the developing fetal immune system during gestation

摘要 2016年，估计有16万新的艾滋病毒感染发生在婴儿和儿童中；大多数是母婴感染 传输(MTCT)。即使有最佳的依从性，产妇抗逆转录病毒疗法(ART)也会减少，但确实会 不能消除艾滋病毒的垂直传播。消除的潜在障碍，特别是在资源贫乏的国家 在这种情况下，孕妇在怀孕期间合并感染。在感染艾滋病毒的母亲中，人类巨细胞病毒 巨细胞病毒(HCMV)是一种重要的共病原体，许多流行病学研究与母体感染密切相关 人类巨细胞病毒病毒血症伴HIV的MTCT。然而，巨细胞病毒感染促进胎盘发育的机制 和胎儿艾滋病毒感染的情况知之甚少。我们试图发展一种机械的理解，了解如何 母体巨细胞病毒血症促进艾滋病毒宫内传播，也影响胎儿免疫发育 在怀孕期间的系统。胎盘的特征是一种独特的免疫耐受状态，这限制了 感染。该接口也是包括HCMV在内的许多病毒的攻击目标。研究表明，艾滋病毒+ 女性更有可能因感染巨细胞病毒而重新激活并感染病毒。母体人巨细胞病毒感染与 与炎症和滋养层损伤有关，胎盘细胞可以识别和响应病原体 通过模式识别受体和I型干扰素的产生，以高度调控的方式。由此产生的炎症 会扰乱胎盘和胎儿免疫系统的发育和功能。几项研究包括 从我们的团队中，已经确定滋养层细胞和胎盘巨噬细胞(Hofbauer细胞[HCS])是关键 人巨细胞病毒感染的媒介，而人巨细胞病毒和胎儿淋巴细胞是艾滋病毒的目标。我们还有 结果表明，HCMV刺激胎儿淋巴细胞增加了CCR5的表达，提示 增加胎儿对艾滋病毒易感性的机制。在初步数据中，我们发现HCMV感染HCS 上调CCR5的表达，诱导细胞活化和炎症介质的分泌，并抑制 STAT2活性，这可能有助于观察到艾滋病毒易感性和复制的增加。因此，我们 母体巨细胞病毒血症促进胎盘细胞HIV复制和宫内传播的假设 由于局部炎症，胎儿免疫激活和抑制固有的抗病毒反应。 提出了两个特定的目标来验证我们的假设：1)定义猪的先天免疫模式 妊娠期间滋养层细胞和巨噬细胞对巨细胞病毒和艾滋病毒的反应；以及2)确定 胎盘HIV/HCMV混合感染对HIV易感性及胎儿免疫功能的影响尽管取得了重大进展， 在预防艾滋病毒母婴传播方面已经取得了30多年的成就，但很少有机制研究表明 母亲同时感染艾滋病毒/巨细胞病毒如何促进艾滋病毒在宫内传播并对 发展胎儿免疫系统。这些研究可能有助于开发特定的抗病毒药物。 进一步减少艾滋病毒母婴传播和改善全球艾滋病毒感染婴儿的临床结果的治疗。

ABSTRACT In 2016, an estimated 160,000 new HIV infections occurred in infants and children; most from mother-to-child transmission (MTCT). Even with optimal adherence, maternal antiretroviral therapy (ART) reduces, but does not eliminate vertical transmission of HIV. A potential barrier for elimination, particularly in resource-poor settings, are maternal co-infections during pregnancy. Among HIV-infected mothers, human cytomegalovirus (HCMV) is a significant co-pathogen and numerous epidemiological studies have strongly associated maternal HCMV viremia with MTCT of HIV. However, the mechanisms by which HCMV exposure promotes placental and fetal HIV infection are poorly understood. We seek to develop a mechanistic understanding for how maternal HCMV viremia facilitates in utero transmission of HIV and also impacts the developing fetal immune system during gestation. The placenta is characterized by a unique state of immune tolerance, which limits infections. This interface is also a target for many viruses, including HCMV. Studies have shown that HIV+ women are more likely to reactivate and become viremic with HCMV. Maternal HCMV infection is associated with inflammation and trophoblast damage, and placental cells can recognize and respond to pathogens in a highly regulated manner via pattern recognition receptors and production of type I IFNs. Resulting inflammation can disrupt the development and function of the placenta, and fetal immune system. Several studies including from our group, have identified trophoblasts and placental macrophages (Hofbauer cells [HCs]) as key mediators of HCMV infection, while HCs and fetal lymphocytes are targets for HIV. We have also demonstrated that stimulation of fetal lymphocytes with HCMV increased expression of CCR5, suggesting a mechanism to increase fetal susceptibility to HIV. In preliminary data, we show that HCMV infection of HCs upregulates CCR5 expression, induces cellular activation and secretion of inflammatory mediators, and inhibits STAT2 activity, which may contribute to observed increases in HIV susceptibility and replication. Therefore, we hypothesize that maternal HCMV viremia promotes placental cell HIV replication and in utero HIV transmission as a consequence of local inflammation, fetal immune activation and inhibition of intrinsic antiviral responses. Two Specific Aims are proposed to validate our hypothesis:1) To define the innate immune profile of trophoblasts and HCs in response to HCMV and HIV during pregnancy; and 2) To determine the impact of placental HIV/HCMV co-infection on HIV susceptibility and fetal immunity. Although significant progress has been made over 3 decades in prevention of MTCT of HIV, there is a paucity of mechanistic studies showing how maternal co-infection with HIV/HCMV facilitates in utero transmission of HIV and adversely impacts the developing fetal immune system. These studies may contribute towards the development of specific antiviral therapies to further reduce MTCT of HIV and improve clinical outcomes in HIV-exposed infants globally.