HIV Infection, Placental Inflammation, and Early Childhood Outcomes in HIV-exposed, Uninfected Infants in Uganda

项目总结 背景：成功的母婴艾滋病毒传播预防计划减少了全球 先天性艾滋病毒的发病率。然而，每年有100万接触艾滋病毒的未感染(HEU)儿童出生在亚洲区 与未接触艾滋病毒的儿童相比，撒哈拉非洲儿童的早期生活结局更差。慢性阻塞性肺疾病的病理生理学 人们对这些糟糕的结果知之甚少，但这对于制定有效的干预措施以改善情况至关重要 这些孩子的结果。我推测胎盘炎可能与HEU儿童的不良反应有关 通过降低经胎盘抗体转移的质量和数量并破坏正常的健康结局 病原体屏障起作用。候选人：我的首要职业目标是成为一名独立的、由美国国立卫生研究院资助的 在母体感染、胎盘和炎症对 艾滋病毒感染儿童的健康后果。我的临床工作是照顾艾滋病毒携带者(WLWH)及其 婴儿和调查母婴健康状况的研究启发了这条职业道路。我 我已经做好充分的准备来承担这里提出的科学和培训目标，成功地发布了 8篇第一作者手稿，并于2016年在乌干达完成了一项由50人组成的胎盘组织学试点研究。 指导：英格丽德·巴西特博士(首席导师)是一名由NIH资助的研究人员，她已经成功地指导了4名 NIH K23获奖者。德鲁西拉·罗伯茨博士(共同导师，病理学)已成为围产期病理学家近30年 多年来，他在非洲工作了十多年。Mark Siedner博士(全球健康)，Galit Alter(免疫学)， Joseph NGonzi(乌干达站点)、Roger Shapiro(高浓缩铀结果)、Bathany Hedt-Gauthier(生物统计学)和 Elias Kumbakumba(婴儿成果)将提供额外的重点指导，以确保我的成功。 研究：我将招募怀孕晚期接受抗逆转录病毒治疗的300 WLWH的前瞻性队列和对照组 对乌干达150名未感染艾滋病毒的孕妇进行监测，收集她们出生时的胎盘。我会比较一下 母体HIV血清水平与炎症性胎盘异常的患病率 WLWH中的炎性胎盘异常。潜在的相关因素包括母体因素(CD4计数、ART 治疗方案(CMV病毒血症)和胎盘因素(可检测到的胎盘艾滋病毒和胎盘感染)。我会量一量 经胎盘呼吸道病原体抗体转移作为胎盘功能的替代免疫指标， 并对登记的妇女所生婴儿进行12个月的跟踪调查，以确定与炎性胎盘的关联 HEU婴儿发病率和死亡率的异常。培训：实现我的目标并获得研究成果 独立，我需要额外的培训：1)胎盘组织病理学、生物学和免疫学2)病因 推理理论，重点是中介分析，以及3)进行更大规模的R01资助的临床试验设计 乌干达胎盘炎的研究。基于我以前的研究经验和成功，支持 来自一支杰出的指导团队、强大的机构承诺和创新的研究计划，我是 处于有利地位，成为世界卫生组织关注母婴健康的独立临床调查员。

PROJECT SUMMARY Background: Successful mother-to-child HIV transmission prevention programs have decreased the global incidence of congenital HIV. Yet, >1 million HIV-exposed, uninfected (HEU) children are born annually in sub- Saharan Africa and have poorer early-life outcomes than HIV-unexposed children. The pathophysiology of these poor outcomes is poorly understood, yet critical to developing effective interventions to improve outcomes for these children. I hypothesize that placental inflammation may contribute to adverse HEU child health outcomes by decreasing quality and quantity of transplacental antibody transfer and disrupting normal pathogen barrier functions. Candidate: My overarching career goal is to become an independent, NIH-funded clinical investigator with expertise in the contribution of maternal infections, the placenta, and inflammation to health outcomes of HIV-exposed children. My clinical work caring for women living with HIV (WLWH) and their infants and conducting research investigating maternal-child health outcomes has inspired this career path. I am well-prepared to undertake the scientific and training aims proposed here, having successfully published eight first-author manuscripts and completed a 50-placenta histology pilot study in Uganda in 2016. Mentoring: Dr. Ingrid Bassett (Primary Mentor) is an NIH-funded investigator who has successfully mentored 4 NIH K23 awardees. Dr. Drucilla Roberts (Co-mentor, Pathology) has been a perinatal pathologist for nearly 30 years and worked in Africa for over a decade. Drs. Mark Siedner (Global Health), Galit Alter (Immunology), Joseph Ngonzi (Uganda Site), Roger Shapiro (HEU Outcomes), Bethany Hedt-Gauthier (Biostatistics), and Elias Kumbakumba (Infant Outcomes) will provide additional focused mentorship to ensure my success. Research: I will enroll a prospective cohort of 300 WLWH on ART in late pregnancy and a comparison group of 150 HIV-uninfected pregnant women in Uganda and collect their placentas at birth. I will compare the prevalence of inflammatory placental abnormalities by maternal HIV serostatus and determine the correlates of inflammatory placental abnormalities in WLWH. Potential correlates include maternal factors (CD4 count, ART regimen, CMV viremia) and placental factors (detectable placental HIV and placental infections). I will measure transplacental respiratory pathogen antibody transfer as surrogate immune measures of placental function, and follow infants born to enrolled women for 12 months to determine the association of inflammatory placental abnormalities with HEU infant morbidity and mortality. Training: To achieve my aims and gain research independence, I require additional training in: 1) placental histopathology, biology, and immunology 2) causal inference theory, with a focus on mediation analysis, and 3) clinical trial design to conduct a larger R01-funded study of placental inflammation in Uganda. Based on my previous research experience and success, support from an exceptional mentoring team, strong institutional commitment, and an innovative research plan, I am well-positioned to become an independent clinical investigator focused on maternal-child health in WLWH.