Identifying the long-term metabolic complications of in-utero and lactational antiretroviral exposure

项目摘要/摘要 联合抗逆转录病毒治疗(CART)的增加显著减少了围产儿的死亡率。 艾滋病毒的传播。然而，随着更多感染艾滋病毒的妇女乘坐婴儿车，有越来越多的人 在宫内和哺乳期间接触手推车的儿童。世界卫生组织(WHO)现在建议 基于多洛替格列韦(DTG)的CART作为包括孕妇在内的所有艾滋病毒携带者的一线治疗。 尽管早期接触非DTG的CART与骨骼和脂肪相关 并发症，宫内和哺乳期接触DTG的长期后果是完全 未知，需要几十年的时间才能确定。目前的提议旨在解决这一知识差距。 通过利用18个月的大鼠实验中储存的骨骼和脂肪样本来检验这一假设 发育过程中接触基于DTG的CART将对骨和脂肪组织造成持久的有害影响。至 验证这一假设，我们将确定宫内和哺乳期接触基于DTG的CART对 (1)使用微型计算机断层扫描、拉曼显微光谱分析和机械测量的骨量和质量 检测和(2)脂肪组织的RNA测序、RT-qPCR和蛋白质印迹分析。目前的建议是 意义重大，因为它解决了一个关键的临床问题。这一研究问题是及时的，因为基于DTG Cart已成为包括孕妇在内的所有艾滋病毒携带者推荐的一线购物车。 这一假设在概念上是创新的，因为早期接触DTG的代谢后果是 未知。最后，提议的目标与R03方案目标很好地匹配，因为它们代表了 对现有数据集的二次分析。这项提案的结果将开始确立长期的 发育过程中暴露于DTG对骨和脂肪组织的影响并开始确定驱动力 机械装置。

Project Summary / Abstract The increased use of combination antiretroviral therapy (cART) has significantly reduced the perinatal transmission of HIV. However, as more HIV-infected women take cART, there is an increasing population of children exposed to cART in-utero and while nursing. The World Health Organization (WHO) now recommends dolutegravir (DTG)-based cART as first-line treatment for all people living with HIV, including pregnant women. Although early exposure to non-DTG based cART has been associated with bone and fat-related complications, the long-term consequences of in-utero and lactational exposure to DTG are completely unknown and will take decades to determine. The current proposal aims to address this gap in knowledge by leveraging banked bone and fat samples from an 18-month rat experiment to test the hypothesis that developmental exposure to DTG-based cART will cause lasting deleterious effects on bone and fat tissues. To test this hypothesis, we will determine the effects of in-utero and lactational exposure to DTG-based cART on (1) bone mass and quality using micro-computed tomography, Raman microspectroscopy, and mechanical testing and (2) fat tissue using RNAsequencing, RT-qPCR, and western blot analysis. The current proposal is significant because it addresses a critical clinical concern. The research question is timely, as DTG-based cART has become the recommended first line cART for all people living with HIV, including pregnant women. The hypothesis is conceptually innovative, as the metabolic consequences of early DTG exposure are unknown. Finally, the proposed aims are well-matched to the R03 programmatic goals as they represent a secondary analysis of an existing dataset. Results from this proposal will begin to establish the long-term effects of developmental exposure to DTG on bone and fat tissues and begin to determine the driving mechanisms.