Defining the impact of dolutegravir on the maternal metabolic environment and its implications on risk of congenital anomalies.

项目总结/摘要： 世界卫生组织推荐基于多鲁特韦（DTG）的抗逆转录病毒疗法（ART）用于 所有艾滋病毒感染者，包括孕妇。博茨瓦纳的监测数据显示， 从怀孕开始服用DTG的女性神经管缺陷（NTDs）的发病率增加。其他研究 未检测到这种关联，但均未充分供电。对以下临床意义的担忧 DTG和NTD之间的关联在全球范围内对HIV感染妇女的治疗产生了不确定性。 来自我们实验室的动物DTG胎儿毒性研究的数据支持博茨瓦纳的发现，并表明DTG在一定程度上 产生临床相关血浆水平（1x-DTG）的剂量与中度但显著增加的 包括NTD在内的各种先天性缺陷的风险。出乎意料的是，我们观察到更少的胎儿异常（类似 与对照组相比）。母亲叶酸缺乏症，妊娠前糖尿病， 妊娠期肥胖是确定的NTD危险因素。据报道，在开始或 切换到DTG。体重增加过多和潜在的代谢改变可能是一种机制， DTG提高NTD费率。我们将使用来自博茨瓦纳的严格控制的动物研究和临床样本， 进行无偏倚的组学方法，以确定DTG可能诱导胎儿生长的潜在途径。 缺陷此外，我们还将采用一种靶向方法，包括小鼠体内和胚胎培养模型， 研究DTG对叶酸，葡萄糖和氧化应激的影响，作为导致DTG- 相关的胎儿缺陷。在目标1中，我们将识别和验证母体和胎儿的代谢因素， DTG暴露增加或减少NTD和其他胎儿畸形的风险，通过：（1）进行 用基于DTG的ART（1x-DTG和5x-DTG）或 控制胎儿异常风险或保护的指标;（2）筛查孕妇的代谢差异 从受孕开始接受DTG为基础的ART的HIV感染妇女，与从受孕开始接受依法韦仑为基础的ART的HIV感染妇女相比， 妊娠和HIV阴性孕妇;（3）使用小鼠体内试验验证候选代谢物 和胚胎培养系统。在目标2中，我们将进行实验研究，以确定机制， DTG会增加胎儿畸形的风险我们将研究DTG对：（1）叶酸代谢的影响; (2)葡萄糖稳态;（3）氧化应激和线粒体功能，使用小鼠体内和胚胎 文化体系。我们将利用博茨瓦纳现有的前瞻性妊娠研究资源 (NIH/NICHD K23 HD 088230 - 01 A1- PI：Zash博士），并利用Serghides博士的健壮小鼠 ART安全性的妊娠模型，Copp博士和格林在NTD模型方面的著名专业知识，以及组学 Metabolon、Jao博士和Coburn博士的专业知识，成功地完成了这个项目。我们的研究将是 首先检查DTG和代谢改变之间的关联作为DTG的潜在机制， 相关的先天性缺陷。

PROJECT SUMMARY/ABSTRACT: Dolutegravir (DTG)-based antiretroviral therapy (ART) is recommended by the World Health Organization for all people living with HIV, including pregnant women. Surveillance data from Botswana reported a 3-fold increased incidence of neural tube defects (NTDs) in women taking DTG from conception. Other studies have not detected this association although none were sufficiently powered. Concern over the clinical significance of the association between DTG and NTDs has created uncertainty in the treatment of women with HIV globally. Data from animal DTG fetotoxicity studies in our lab support the Botswana findings and suggest that DTG at a dose yielding clinically relevant plasma levels (1x-DTG) is associated with a modest but significantly increased risk of a variety of congenital defects including NTDs. Unexpectedly, we observe fewer fetal anomalies (similar to control) in mice treated with a 5x-DTG dose. Maternal folate deficiency, pre-gestational diabetes, and pre- pregnancy obesity are established NTD risk factors. Excessive weight gain is reported in persons initiating or switching to DTG. Excess weight gain and the underlying metabolic alterations could be a mechanism by which DTG increases NTD rates. We will use well-controlled animal studies and clinical samples from Botswana to perform an unbiased omics approach to identify potential pathways through which DTG may induce fetal defects. In addition, we will take a targeted approach, involving murine in vivo and embryo culture models, to investigate the impact of DTG on folate, glucose, and oxidative stress as potential pathways leading to DTG- associated fetal defects. In Aim 1 we will identify and validate maternal and fetal metabolic factors modified by DTG exposure that increase or reduce the risk for NTDs and other fetal anomalies by: (1) performing a metabolomics screen of pregnant mice and their fetuses treated with DTG-based ART (1x-DTG and 5x-DTG) or control for indicators of fetal anomaly risk or protection; (2) screening for metabolic differences in pregnant women with HIV on DTG-based ART from conception, compared with those on efavirenz-based ART from conception, and with HIV-negative pregnant women; (3) validating candidate metabolites using murine in vivo and embryo culture systems. In Aim 2 we will perform experimental studies to determine the mechanism(s) by which DTG increased the risk of fetal anomalies. We will examine the impact of DTG on: (1) folate metabolism; (2) glucose homeostasis; (3) oxidative stress and mitochondrial function, using murine in vivo and embryo culture systems. We will leverage resources of an existing prospective pregnancy study in Botswana (NIH/NICHD K23 HD088230-01A1 – PI: Dr. Zash), and take advantage of Dr. Serghides' robust mouse pregnancy model of ART safety, Drs. Copp and Greene's renowned expertise in models of NTDs, and the omics expertise of Metabolon, Dr. Jao, and Dr. Coburn to successfully complete this project. Our study will be the first to examine associations between DTG and metabolic alterations as a mechanism underlying DTG- associated congenital defects.