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

乌干达暴露于 HIV 的未感染婴儿的 HIV 感染、胎盘炎症和早期儿童结局

• 批准号: 10543082
• 负责人: Lisa M Bebell
• 金额: $ 27.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-14 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543082
• 关键词: Africa; Africa South of the Sahara; Biology; Biometry; Birth; CD4 Lymphocyte Count; Career Choice; Caring; Cessation of life; Child; Child Health; Chronic; Classification; Clinical; Clinical Investigator; Clinical Trials Design; Cytomegalovirus; Data; Early treatment; Enrollment; Ensure; Functional disorder; Funding; Goals; Growth; HIV; HIV Infections; HIV-exposed uninfected infant; Haemophilus influenzae type b; Health; Histologic; Histology; Histopathology; Hospitalization; Immune; Immunology; Incidence; Infant; Infant Health; Infection; Inflammation; Inflammatory; Institution; Intervention; Late pregnancy; Learning; Life; Link; Malaria; Manuscripts; Maternal Health; Maternal and Child Health; Maternal-Fetal Exchange; Measures; Mediating; Mediation; Mediator; Mentors; Mentorship; Methods; Morbidity - disease rate; Mother-to-child HIV transmission; Mothers; Mycoplasma; Outcome; Participant; Pathologist; Pathology; Perinatal; Pharmaceutical Preparations; Pilot Projects; Placenta; Positioning Attribute; Pregnant Women; Prevalence; Prevention program; Prospective cohort; Publications; Publishing; Quasi-experiment; Regimen; Reporting; Research; Research Personnel; Risk; Role; Site; Source; Specimen; Streptococcus pneumoniae; Techniques; Training; Uganda; United States National Institutes of Health; Ureaplasma; Viremia; Woman; Work; adverse outcome; antibody transfer; antiretroviral therapy; career; co-infection; cohort; comparison group; early childhood; effective intervention; experience; global health; immune activation; improved; improved outcome; infant morbidity/mortality; infant outcome; innovation; intraamniotic infection; mortality; multidisciplinary; pathogen; placental infection; respiratory pathogen; skill acquisition; success; systemic inflammatory response; theories; vaccination strategy

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.

项目摘要 背景：成功的母婴传播艾滋病毒预防计划减少了全球艾滋病病毒感染率。 先天性艾滋病毒感染率。然而，每年有超过100万接触艾滋病毒但未受感染的儿童出生在低于2000年的国家。 撒哈拉非洲和有较差的早期生活的结果比艾滋病毒未暴露的儿童。的病理生理学 对这些不良结果的了解很少，但对于制定有效的干预措施以改善 这些孩子的结果。我假设胎盘炎症可能导致不良的高浓度铀儿童 通过降低经胎盘抗体转移的质量和数量， 病原体屏障功能。候选人：我的首要职业目标是成为一个独立的，NIH资助的 临床研究者，在母体感染、胎盘和炎症对 艾滋病毒感染儿童的健康状况。我的临床工作照顾妇女艾滋病毒感染者（WLWH）和他们的 婴儿和进行调查母婴健康结果的研究启发了这条职业道路。 我已做好充分准备，承担这里提出的科学和培训目标，已成功出版 8篇第一作者手稿，并于2016年在乌干达完成了50例胎盘组织学试点研究。 指导：Ingrid Bassett博士（主要指导者）是NIH资助的研究者，已成功指导4名 NIH K23获奖者Drucilla Roberts博士（病理学共同导师）担任围产期病理学家近30年 在非洲工作了十多年。Mark Siedner博士（全球卫生），Galit Alter博士（免疫学）， Joseph Ngonzi（乌干达研究中心）、Roger Shapiro（高浓缩铀成果）、Bethany 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：我将招募一个前瞻性队列，包括300名妊娠晚期接受ART的WLWH和一个对照组 乌干达150名未感染艾滋病病毒的孕妇，并在她们出生时收集胎盘。我将比较 通过母体HIV血清状态确定炎性胎盘异常的患病率，并确定 WLWH中的炎性胎盘异常。潜在的相关因素包括母体因素（CD 4计数、ART 方案，CMV病毒血症）和胎盘因素（可检测的胎盘HIV和胎盘感染）。我会衡量 经胎盘呼吸道病原体抗体转移作为胎盘功能的替代免疫措施， 并对登记妇女所生婴儿进行为期12个月的随访，以确定炎症性胎盘炎 高浓缩铀婴儿发病率和死亡率异常。培训：实现我的目标和获得研究 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）因果关系 推理理论，重点是中介分析，以及3）临床试验设计，以进行更大的R 01资助 乌干达胎盘炎症研究。根据我以前的研究经验和成功， 从一个特殊的指导团队，强大的机构承诺，和创新的研究计划，我是 有能力成为WLWH母婴健康的独立临床研究者。

项目成果

Stillbirth rate by maternal HIV serostatus and antiretroviral use in pregnancy in South Africa: An audit.

南非孕产妇艾滋病毒血清状态和妊娠期抗逆转录病毒使用情况的死产率：一项审计。

• 发表时间: 2021
• 期刊: South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde
• 作者: Maswime,S;Pule,C;Bebell,LM;Hedt-Gauthier,B;Chandiwana,N;Haberer,JE;Pattinson,R
• 通讯作者: Pattinson,R