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: 10005430
• 负责人: Rana Chakraborty
• 金额: $ 30.68万
• 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/10005430
• 关键词: Adherence; Africa South of the Sahara; Antiviral Agents; Antiviral Response; Antiviral Therapy; Blood; Blood Circulation; CCR5 gene; Cells; Child; Clinical; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Exposure to; Fetus; HIV; HIV Infections; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; In Vitro; Infant; Infection; Inflammation; Inflammation Mediators; Innate Immune Response; Interferons; Knowledge; Lymphocyte; Maternal Exposure; Maternal-Fetal Exchange; Maternal-Fetal Transmission; Mediator of activation protein; Mononuclear; Mother-to-child HIV transmission; Mothers; Outcome; Pattern recognition receptor; Placenta; Predisposition; Pregnancy; Prevalence; Prevention; Production; Resources; STAT2 gene; Signal Transduction; T-Cell Activation; Third Pregnancy Trimester; Vertical Disease Transmission; Villous; Viral; Viremia; Virus; Woman; antiretroviral therapy; co-infection; epidemiology study; fetal; immune activation; improved; in utero; macrophage; pathogen; permissiveness; receptor; response; transmission process; trophoblast

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，估计有16万名婴儿和儿童新增艾滋病毒感染者；大部分是母婴传播 传播（母婴传播）。即使有最佳的依从性，孕产妇抗逆转录病毒治疗 (ART) 也会减少，但不会 不能消除艾滋病毒的垂直传播。消除的潜在障碍，特别是在资源匮乏的地区 环境中，母亲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 (HCMV) 是一种重要的共同病原体，许多流行病学研究表明，与母体密切相关 HCMV 病毒血症与 HIV 母婴传播。然而，HCMV 暴露促进胎盘的机制 和胎儿艾滋病毒感染知之甚少。我们寻求对如何进行机械理解 母体 HCMV 病毒血症促进 HIV 在子宫内的传播，也会影响胎儿免疫系统的发育 妊娠期间的系统。胎盘具有独特的免疫耐受状态，这限制了 感染。该接口也是许多病毒（包括 HCMV）的目标。研究表明，HIV+ 女性更有可能重新激活 HCMV 并出现病毒血症。母体HCMV感染与 随着炎症和滋养层损伤，胎盘细胞可以识别并响应病原体 通过模式识别受体和 I 型干扰素的产生进行高度调控。由此产生的炎症 会破坏胎盘和胎儿免疫系统的发育和功能。多项研究包括 我们小组的研究人员已确定滋养层细胞和胎盘巨噬细胞（霍夫鲍尔细胞 [HC]）是关键 HCMV 感染的介质，而 HC 和胎儿淋巴细胞是 HIV 的目标。我们还有 证明用 HCMV 刺激胎儿淋巴细胞会增加 CCR5 的表达，这表明 增加胎儿对艾滋病毒易感性的机制。在初步数据中，我们表明 HC 的 HCMV 感染 上调 CCR5 表达，诱导细胞活化和炎症介质分泌，并抑制 STAT2 活性，可能有助于观察到的 HIV 易感性和复制增加。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 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。 提出了两个具体目标来验证我们的假设：1）定义先天免疫特征 怀孕期间滋养层细胞和 HC 对 HCMV 和 HIV 的反应； 2) 确定影响 胎盘HIV/HCMV合并感染对HIV易感性和胎儿免疫力的影响。尽管取得了重大进展 艾滋病毒母婴传播的预防工作已经进行了 30 多年，但缺乏机制研究表明 母亲同时感染 HIV/HCMV 如何促进 HIV 在子宫内传播并对胎儿产生不利影响 发育胎儿免疫系统。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并改善全球艾滋病毒暴露婴儿的临床结果。