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

项目摘要/摘要： 基于多洛替格雷(DTG)的抗逆转录病毒疗法(ART)是世界卫生组织推荐的 所有艾滋病毒携带者，包括孕妇。来自博茨瓦纳的监测数据报告说， 在怀孕期间服用DTG的妇女神经管缺陷(NTDS)的发生率增加。其他研究也有 未检测到此关联，尽管都没有足够的电源。对其临床意义的关注 DTG和NTDS之间的关联给全球艾滋病毒携带者的治疗带来了不确定性。 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 剂量递减的临床相关血浆水平(1x-DTG)与适度但显著增加的 患各种先天缺陷的风险，包括神经管畸形。出乎意料的是，我们观察到的胎儿异常较少(类似 以5x-DTG剂量处理的小鼠。母体叶酸缺乏、孕前糖尿病和孕前 妊娠肥胖是NTD的危险因素。据报道，体重增加过多的人或 正在切换到DTG。超重和潜在的代谢变化可能是一种机制 DTG提高了NTD率。我们将使用来自博茨瓦纳的控制良好的动物研究和临床样本来 采用公正的组学方法来确定DTG可能通过的潜在途径来诱导胎儿 缺陷。此外，我们将采取有针对性的方法，包括小鼠体内和胚胎培养模型，以 研究DTG对叶酸、葡萄糖和氧化应激的影响，作为导致DTG的潜在途径。 相关的胎儿缺陷。在目标1中，我们将识别和验证由以下因素修改的母体和胎儿代谢因子 DTG暴露可通过以下方式增加或降低NTDS和其他胎儿畸形的风险：(1) 基于DTG的ART(1x-DTG和5x-DTG)治疗孕鼠及其胎儿的代谢组学筛选 控制胎儿异常风险或保护指标；(2)筛查孕期代谢差异 HIV患者接受基于DTG的受孕ART治疗，与接受来自Eefavirenz的ART治疗的妇女进行比较 受孕，以及HIV阴性孕妇；(3)用小鼠体内验证候选代谢物 和胚胎培养系统。在目标2中，我们将进行实验研究，以确定其机制(S)，通过 DTG增加了胎儿畸形的风险。我们将研究DTG对以下方面的影响：(1)叶酸代谢； (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一项预期怀孕研究的资源 (NIH/NICHD K23 HD088230-01A1-PI：Dr.Zash)，并利用Serghides博士健壮的小鼠 怀孕安全模型，科普博士和格林博士在NTDS模型方面的著名专业知识，以及组学 新陈代谢、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 首先研究DTG和代谢改变之间的关系，作为DTG的一个机制。 相关的先天缺陷。

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.