Effects of HIV, antiretroviral therapy, and PrEP on placental structure and metabolic function

项目总结 意义：抗逆转录病毒药物(ARV)治疗和预防育龄妇女艾滋病毒感染 在公共卫生方面取得了里程碑式的成功，避免了数百万儿童感染艾滋病毒。除了……之外 将抗逆转录病毒药物作为艾滋病毒的治疗方法，越来越多的孕妇将抗逆转录病毒药物作为暴露前的预防措施 (准备)预防艾滋病毒感染。然而，最近的研究表明，怀孕期间的抗逆转录病毒药物也可能会带来 对发育中的胎盘和胎儿的风险。低胎盘重量、胎盘功能不全和母体血管 与未服用抗逆转录病毒药物的女性HIV相比，接受抗逆转录病毒药物治疗的WHIV患者更常见的是血液灌流不良 在怀孕前使用抗逆转录病毒药物的风险比人类免疫缺陷病毒高35%。 受孕后启动抗逆转录病毒药物。抗逆转录病毒药物是挽救生命的艾滋病毒治疗和预防，但PrEP在孕妇中是安全的 女性、她们的胎儿和她们的后代是未知的。关于PrEP在怀孕期间的安全性的信息是 迫切需要改进抗逆转录病毒药物的选择和管理，作为预防接种和艾滋病毒治疗的高峰期 冒险时间。创新：我们提出了第一项同时比较胎盘结构、血管生成、 将抗逆转录病毒药物作为PrEP的未感染艾滋病毒的妇女、服用抗逆转录病毒药物的WHIV妇女和HIV- 未感染的妇女不服用抗逆转录病毒药物，以确定抗逆转录病毒药物和艾滋病毒对胎盘的独立影响。 我们建议的研究的显著优势包括：1)同时收集和比较接触过艾滋病毒的人 未暴露和ARV暴露的和未暴露的胎盘，以及2)所有儿童的纵向观察 在生命的前12个月，胎盘发现与出生体重和婴儿生长有关。调查人员：我们的 具有胎盘病理学和艾滋病毒流行病学专业知识的跨学科团队(PiBebell，早期职业生涯 NIAID K23资助的研究人员)，艾滋病毒和抗逆转录病毒药物对胎盘影响的翻译实验室工作 (Co-I Serghides)、生物统计学(Co-I Rabideau)和孕产妇健康(贡献者NGonzi)，已经做好准备 完成这项工作。方法：我们将利用PI正在进行的存储的胎盘和血浆样本 美国国立卫生研究院职业发展奖(K23AI138856)在乌干达的队列，登记的女性和她们的临床数据 和Serghides博士建立的实验室基础设施，以阐明艾滋病毒的独立影响 和ARV在胎盘上的暴露以及这些变化对早期儿童生长的潜在贡献 这些具体目标：1)比较母亲感染ARV和HIV后的胎盘结构和血管生成 状态。2)比较母体ARV和HIV暴露状况对胎盘代谢能力的影响。3)确定 胎盘结构和代谢能力对新生儿体重和婴儿生长的影响确定机制 ARV相关胎盘毒性的研究具有通过优化PrEP改善妊娠结局的巨大潜力 还有艺术养生法。使用收集的数据，我们将提交一份R01提案，以调查胎盘异常 用于特定的ARV方案，以帮助确定对孕妇最安全的选择。

PROJECT SUMMARY Significance: Antiretroviral medications (ARVs) to treat and prevent HIV infection in reproductive-aged women have been a landmark public health success, having averted millions of pediatric HIV infections. In addition to taking ARVs as HIV treatment, pregnant women are increasingly taking ARVs as pre-exposure prophylaxis (PrEP) against HIV infection. However, recent studies have shown that ARVs in pregnancy may also confer risks to the developing placenta and fetus. Low placenta weight, placental insufficiency, and maternal vascular malperfusion are more common among WHIV taking ARVs compared to WHIV not taking ARVs, and WHIV initiating ARVs pre-conception have a 35% higher risk of having a small-for-gestational-age baby than WHIV initiating ARVs post-conception. ARVs are life-saving HIV therapy and prevention, but PrEP safety in pregnant women, their fetuses, and their offspring is unknown. Information about the safety of PrEP in pregnancy is urgently needed to improve selection and management of ARVs as PrEP and HIV treatment during this high- risk time. Innovation: We propose the first study to simultaneously compare placenta structure, angiogenesis, and metabolic capacity between HIV-uninfected women taking ARVs as PrEP, WHIV taking ARVs, and HIV- uninfected women taking no ARVs to determine the independent effects of ARVs and HIV on the placenta. Distinct advantages of our proposed research include 1) simultaneous collection and comparison HIV-exposed and -unexposed and ARV-exposed and -unexposed placentas, and 2) longitudinal observation of all children over the first 12 months of life to relate placental findings to birth weight and infant growth. Investigators: Our interdisciplinary team with expertise in placental pathology and HIV epidemiology (PI Bebell, an early career NIAID K23-funded investigator), translational laboratory work on the placental effects of HIV and antiretrovirals (Co-I Serghides), biostatistics (Co-I Rabideau) and maternal health (contributor Ngonzi), is well-poised to complete this work. Approach: We will leverage stored placental and plasma samples from the PI's ongoing NIH Career Development Award (K23AI138856) cohort in Uganda, clinical data from enrolled women and their children, and Dr. Serghides' established laboratory infrastructure to elucidate the independent effects of HIV and ARV exposure on the placenta and potential contribution of these changes to early child growth through these specific aims: 1) Compare placental structure and angiogenesis by maternal ARV and HIV exposure status. 2) Compare placental metabolic capacity by maternal ARV and HIV exposure status. 3) Determine the effects of placental structure and metabolic capacity on birth weight and infant growth. Identifying mechanisms of ARV-related placental toxicities has great potential to improve pregnancy outcomes through optimized PrEP and ART regimens. Using data gathered we will submit an R01 proposal to investigate placental abnormalities for specific ARV regimens to help determine the safest options for pregnant women.