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

母体 HCMV 如何促进 HIV 子宫内传播并影响妊娠期间胎儿免疫系统的发育

• 批准号: 10201228
• 负责人: Rana Chakraborty
• 金额: $ 28.06万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201228
• 关键词: How; maternal; HCMV; facilitates; utero

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.

抽象的 2016年，婴儿和儿童估计发生了16万新的艾滋病毒感染。大多数来自母亲 传输（MTCT）。即使有最佳的依从性，母体抗逆转录病毒疗法（ART）也会减少，但确实如此 不能消除艾滋病毒的垂直传播。消除的潜在障碍，尤其是在资源贫乏的障碍 设置是怀孕期间母亲的共同感染。在艾滋病毒感染的母亲中，人类巨细胞病毒 （HCMV）是一项重要的共同病原，大量流行病学研究与母亲有密切相关 HCMV病毒血症与HIV的MTCT。但是，HCMV暴露促进胎盘的机制 和胎儿艾滋病毒感染知之甚少。我们寻求对如何建立机械理解 母体HCMV病毒血症促进了艾滋病毒的子宫内传播，也影响发育中的胎儿免疫 妊娠期间的系统。胎盘的特征是独特的免疫耐受状态，该状态限制 感染。该界面也是许多病毒（包括HCMV）的目标。研究表明HIV+ 妇女更有可能通过HCMV重新激活并使病毒。孕产妇HCMV感染与 随着炎症和滋养细胞的损害，胎盘细胞可以识别并应对A中的病原体 高度调节的方式通过模式识别受体和I型IFN的产生。导致炎症 可以破坏胎盘的发育和功能，以及胎儿免疫系统。包括 从我们的小组中，已经确定了滋养细胞和胎盘巨噬细胞（Hofbauer细胞[HCS]）作为钥匙 HCMV感染的介质，而HCS和胎儿淋巴细胞是HIV的靶标。我们也有 证明用HCMV刺激胎儿淋巴细胞增加了CCR5的表达，表明A 提高胎儿易感性艾滋病毒的机制。在初步数据中，我们显示了HCS的HCMV感染 上调CCR5表达，诱导炎症介质的细胞激活和分泌，并抑制 STAT2活性可能导致观察到的HIV敏感性和复制增加。因此，我们 假设母体HCMV病毒血症促进胎盘细胞HIV复制和子宫内传播 由于局部炎症，胎儿免疫激活和内在抗病毒反应的抑制。 提出了两个具体目的来验证我们的假设：1）定义先天免疫特征 妊娠期间对HCMV和HIV的滋养细胞和HCS； 2）确定 胎盘HIV/HCMV对HIV易感性和胎儿免疫的共同感染。尽管取得了重大进展 在预防HIV的MTCT方面已有30年以上，机械研究很少。 与艾滋病毒/HCMV的母亲共同感染如何在艾滋病毒的子宫内传播并不利影响。 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 疗法进一步降低HIV的MTCT并改善全球艾滋病毒暴露婴儿的临床结果。