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160，000例新的艾滋病毒感染发生在婴儿和儿童中;大多数是母婴传播 母婴传播（MTCT）。即使有最佳的坚持，产妇抗逆转录病毒治疗（ART）减少，但 并没有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， 在某些情况下，孕妇在怀孕期间合并感染。在感染艾滋病毒的母亲中， 人巨细胞病毒（HCMV）是一种重要的共同病原体，许多流行病学研究表明， HCMV病毒血症伴HIV母婴传播。然而，HCMV暴露促进胎盘生长的机制， 和胎儿艾滋病毒感染知之甚少。我们寻求发展一种机械的理解， 母体HCMV病毒血症促进了HIV在子宫内的传播，也影响了发育中的胎儿免疫 系统在怀孕期间。胎盘的特点是一种独特的免疫耐受状态， 感染.这个界面也是许多病毒的目标，包括HCMV。研究表明，HIV+ 妇女更有可能重新激活并成为HCMV病毒血症。母亲HCMV感染与 炎症和滋养层损伤，胎盘细胞可以识别并响应病原体， 通过模式识别受体和I型IFN的产生高度调节的方式。导致炎症 会破坏胎盘的发育和功能，以及胎儿的免疫系统。一些研究，包括 已经确定了滋养层细胞和胎盘巨噬细胞（Hofbauer细胞[HC]）是关键 HCMV感染的介质，而HC和胎儿淋巴细胞是HIV的目标。我们还 表明用HCMV刺激胎儿淋巴细胞可增加CCR 5的表达，提示 增加胎儿对HIV易感性的机制。在初步数据中，我们表明，HCMV感染的HC 上调CCR 5表达，诱导细胞活化和炎症介质分泌，并抑制 STAT 2活性，这可能有助于观察到的HIV易感性和复制增加。所以我们 假设母体HCMV病毒血症促进胎盘细胞HIV复制和宫内HIV传播 这是局部炎症、胎儿免疫激活和内在抗病毒反应抑制的结果。 我们提出了两个具体的目的来验证我们的假设：1）确定先天性免疫模式， 妊娠期间滋养层细胞和HC对HCMV和HIV的反应; 2）确定 胎盘HIV/HCMV共感染对HIV易感性和胎儿免疫的影响虽然取得了重大进展， 在预防艾滋病毒母婴传播方面已经进行了30多年，但缺乏机制研究表明， 母亲合并感染HIV/HCMV如何促进HIV在子宫内的传播， 发育中的胎儿免疫系统这些研究可能有助于开发特异性抗病毒药物 进一步减少艾滋病毒母婴传播，改善全球艾滋病毒暴露婴儿的临床结局。

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.