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
基本信息
- 批准号:10201228
- 负责人:
- 金额:$ 28.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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.
摘要
2016年,估计有160,000例婴儿和儿童新感染艾滋病毒;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
可能会破坏胎盘和胎儿免疫系统的发育和功能。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
证明用HCMV刺激胎儿淋巴细胞会增加CCR 5的表达,这表明
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Rana Chakraborty其他文献
Rana Chakraborty的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Rana Chakraborty', 18)}}的其他基金
The Impact of Transgenerational Racial Trauma on Epigenetic Modifications in the Mother-Infant Dyad during Pregnancy. Comparisons Between Caucasian and African American Populations
跨代种族创伤对怀孕期间母婴二元体表观遗传修饰的影响。
- 批准号:
10523426 - 财政年份:2022
- 资助金额:
$ 28.06万 - 项目类别:
The Impact of Transgenerational Racial Trauma on Epigenetic Modifications in the Mother-Infant Dyad during Pregnancy. Comparisons Between Caucasian and African American Populations
跨代种族创伤对怀孕期间母婴二元体表观遗传修饰的影响。
- 批准号:
10710037 - 财政年份:2022
- 资助金额:
$ 28.06万 - 项目类别:
Next generation training in HIV research: Immunity in the First 1000 days in mother-infant dyads (TIGRIS)
下一代艾滋病毒研究培训:母婴二人最初 1000 天的免疫力 (TIGRIS)
- 批准号:
10594540 - 财政年份:2022
- 资助金额:
$ 28.06万 - 项目类别:
Next generation training in HIV research: Immunity in the First 1000 days in mother-infant dyads (TIGRIS)
下一代艾滋病毒研究培训:母婴二人最初 1000 天的免疫力 (TIGRIS)
- 批准号:
10471480 - 财政年份:2022
- 资助金额:
$ 28.06万 - 项目类别:
Mechanisms by which trophoblasts recruit T cells to the placental villi during maternal HIV and CMV co-infection
母体 HIV 和 CMV 合并感染期间滋养层将 T 细胞募集至胎盘绒毛的机制
- 批准号:
10080877 - 财政年份:2020
- 资助金额:
$ 28.06万 - 项目类别:
Mechanisms by which trophoblasts recruit T cells to the placental villi during maternal HIV and CMV co-infection
母体 HIV 和 CMV 合并感染期间滋养层将 T 细胞募集至胎盘绒毛的机制
- 批准号:
10223400 - 财政年份:2020
- 资助金额:
$ 28.06万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 28.06万 - 项目类别:
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:
10245021 - 财政年份:2019
- 资助金额:
$ 28.06万 - 项目类别:
Determining how macrophages regulate immunity to Zika virus infection at the maternal-fetal interface
确定巨噬细胞如何调节母胎界面对寨卡病毒感染的免疫力
- 批准号:
9882936 - 财政年份:2017
- 资助金额:
$ 28.06万 - 项目类别:
相似国自然基金
果蝇Maternal Haploid 蛋白调控胚胎发育的分子机制研究
- 批准号:31460299
- 批准年份:2014
- 资助金额:50.0 万元
- 项目类别:地区科学基金项目
母猪母性杀婴(maternal infanticide)行为QTL精细定位及位置候选基因研究
- 批准号:30760164
- 批准年份:2007
- 资助金额:18.0 万元
- 项目类别:地区科学基金项目
相似海外基金
Can plant-derived extracellular vesicles improve outcomes in pregnancies complicated by maternal obesity?
植物源性细胞外囊泡能否改善妊娠合并肥胖的妊娠结局?
- 批准号:
MR/Y01362X/1 - 财政年份:2024
- 资助金额:
$ 28.06万 - 项目类别:
Research Grant
CAREER: Personalized Maternal Care Decision Support System for Underserved Populations
职业:针对服务不足人群的个性化孕产妇护理决策支持系统
- 批准号:
2339992 - 财政年份:2024
- 资助金额:
$ 28.06万 - 项目类别:
Continuing Grant
Collaborative Research: Cortical Perineuronal Net Regulation of Maternal Caregiving Behaviors
合作研究:母亲护理行为的皮质神经周围网络调节
- 批准号:
2336907 - 财政年份:2024
- 资助金额:
$ 28.06万 - 项目类别:
Continuing Grant
Climate Change Effects on Pregnancy via a Traditional Food
气候变化通过传统食物对怀孕的影响
- 批准号:
10822202 - 财政年份:2024
- 资助金额:
$ 28.06万 - 项目类别:
A HUMAN IPSC-BASED ORGANOID PLATFORM FOR STUDYING MATERNAL HYPERGLYCEMIA-INDUCED CONGENITAL HEART DEFECTS
基于人体 IPSC 的类器官平台,用于研究母亲高血糖引起的先天性心脏缺陷
- 批准号:
10752276 - 财政年份:2024
- 资助金额:
$ 28.06万 - 项目类别:
Collaborative Research: Cortical Perineuronal Net Regulation of Maternal Caregiving Behaviors
合作研究:母亲护理行为的皮质神经周围网络调节
- 批准号:
2336906 - 财政年份:2024
- 资助金额:
$ 28.06万 - 项目类别:
Continuing Grant
Maternal extracellular vesicles as key mediators of fetal growth and offspring cardiometabolic health in pregnancies complicated by type-1 diabetes.
母体细胞外囊泡是妊娠并发 1 型糖尿病时胎儿生长和后代心脏代谢健康的关键介质。
- 批准号:
MR/Y003659/1 - 财政年份:2024
- 资助金额:
$ 28.06万 - 项目类别:
Research Grant
The Biomedicalization of Advanced Maternal Age
高龄产妇的生物医学化
- 批准号:
2241940 - 财政年份:2023
- 资助金额:
$ 28.06万 - 项目类别:
Standard Grant
Effects of Physical Activity on Human Pregnancy Energetics: Testing Maternal Metabolic Limits
体力活动对人类妊娠能量的影响:测试母体代谢极限
- 批准号:
2316555 - 财政年份:2023
- 资助金额:
$ 28.06万 - 项目类别:
Standard Grant
Doctoral Dissertation Research: Maternal Energetic Strategies During Human Pregnancy
博士论文研究:人类怀孕期间的母亲能量策略
- 批准号:
2316583 - 财政年份:2023
- 资助金额:
$ 28.06万 - 项目类别:
Standard Grant