HIV, gestational diabetes and TB in pregnancy

妊娠期艾滋病毒、妊娠期糖尿病和结核病

• 批准号: 10403310
• 负责人: Jyoti S Mathad
• 金额: $ 77.39万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403310
• 关键词: Address; Adverse effects; Affect; BCG Vaccine; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cellular Immunity; Child; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Country; Data; Detection; Diabetes Mellitus; Diabetes prevention; Diagnosis; Disease; Enrollment; Flow Cytometry; Foundations; Functional disorder; Funding; GLUT 4 protein; Gestational Diabetes; Goals; Government; Growth; HIV; HIV/TB; Health; Health Priorities; High Risk Woman; Home; Immune; Immune response; Immunity; Impairment; Incidence; India; Infant; Inflammation; Inflammatory; Influenza; Insulin Resistance; Intervention; Knowledge; Link; Longitudinal Studies; Longitudinal cohort study; Maternal Mortality; Maternal and Child Health; Mediating; Memory; Mother-to-child HIV transmission; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Persons; Placenta; Plasma; Population; Postpartum Period; Pregnancy; Pregnant Women; Prevalence; Prevention; Prevention approach; Research; Risk; Role; Sampling; Second Pregnancy Trimester; T cell response; T memory cell; T-Lymphocyte; TNF gene; Third Pregnancy Trimester; Time; Tuberculosis; Underrepresented Populations; United States National Institutes of Health; Visit; Woman; Work; antenatal; antiretroviral therapy; base; cohort; cytokine; diabetes management; diabetes risk; experience; glucose metabolism; glucose receptor; high risk; high risk population; improved; infection risk; insulin signaling; macrophage; medical schools; mortality; novel; novel strategies; prevent; preventable death; screening; treatment strategy; vaccine response

ABSTRACT: Tuberculosis (TB) is a leading cause of maternal mortality worldwide, especially among women with HIV. Of the 1.3 million pregnant women living with HIV, 85% use combined anti-retroviral therapy (cART), which should significantly decrease their risk of TB. Yet pregnant women with well-controlled HIV still have a 2- 3 times greater incidence of TB than pregnant women without HIV. There is an urgent need to identify the immune impairment responsible for the increased risk of TB in these women. Gestational diabetes (GDM)– which affects 16% of pregnancies globally, and up to 40% of pregnancies in TB- endemic India–likely contributes to the increased risk of TB in pregnancy, especially for women with HIV. We base this hypothesis on the known association between HIV, diabetes (DM) and TB in non-pregnant populations and our preliminary data on HIV, GDM and TB in pregnancy. We found HIV increases GDM prevalence, and GDM impairs the host immune response to M. tuberculosis (Mtb). In partnership with BJ Government Medical College in India (BJGMC), we propose a longitudinal study to fully describe HIV’s effect on GDM risk, and GDM’s effect on the immune response to MTB in pregnancy. BJGMC has conducted NIH clinical research for over 20 years with expertise in HIV and TB in pregnancy. We will enroll 2nd trimester women from the antenatal clinic at BJGMC in Pune, India, with additional visits at 3rd trimester, delivery, 6 weeks, 6 months, and 12 months postpartum. Women will be screened for GDM at enrollment with an oral glucose tolerance test. A subset comprised of all women diagnosed with GDM, and a matched number of women without GDM, will have additional blood and placenta samples collected for flow cytometry and cytokine studies. Enrolled women will be screened for active TB at each visit. Our specific aims are to: 1. Determine the effect of chronic HIV-induced inflammation on glucose metabolism during pregnancy and GDM prevalence. We hypothesize that women with HIV will have double the prevalence of GDM compared to women without HIV. We further hypothesize that elevated plasma TNF-a levels and decreased placental GLUT4 will be associated with GDM in women with HIV. 2. Determine the effect of GDM on the CD4+ and CD8+ T-cell response to Mtb and incident TB. We hypothesize that women with GDM will have a significantly higher incidence of active TB than women without GDM. We hypothesize that women with GDM will have suppressed Mtb-specific memory CD4+ and CD8+ T-cell function, with a decreased ability to activate macrophages, compared to women without GDM. This will be the first study to determine if the pathophysiology of GDM is different in women with HIV and to delineate the TB-specific clinical and immune sequelae of GDM for pregnant women. The results of this study will identify pregnant women at the highest risk for active TB, improve targeted GDM screening and TB prevention and potentially identify novel targets for GDM prevention and treatment.

摘要：结核病（TB）是全球孕产妇死亡的主要原因，尤其是女性 在 130 万感染艾滋病毒的孕妇中，85% 使用联合抗逆转录病毒疗法 (cART)， 这应该会显着降低感染结核病的风险，但艾滋病毒控制良好的孕妇仍然有 2- 结核病的发病率是未感染艾滋病毒的孕妇的 3 倍，迫切需要确定结核病的发病率。 免疫缺陷导致这些女性患结核病的风险增加。 妊娠期糖尿病 (GDM)——影响全球 16% 的妊娠，以及高达 40% 的结核病妊娠—— 印度流行——可能会增加怀孕期间患结核病的风险，特别是对于感染艾滋病毒的妇女而言。 这一假设基于已知的非妊娠期 HIV、糖尿病 (DM) 和结核病之间的关联 人口和我们关于妊娠期艾滋病毒、妊娠期糖尿病和结核病的初步数据我们发现艾滋病毒会增加妊娠期糖尿病。 流行率，GDM 会损害宿主对结核分枝杆菌 (Mtb) 的免疫反应。 我们与印度 BJ 政府医学院 (BJGMC) 合作，提出一项纵向研究，以充分了解 描述 HIV 对 GDM 风险的影响，以及 GDM 对妊娠期 MTB 免疫反应的影响。 已进行 NIH 临床研究 20 多年，拥有妊娠期艾滋病毒和结核病方面的专业知识。 来自印度浦那 BJGMC 产前诊所的第二孕期妇女，在第三孕期进行了额外就诊， 分娩、产后 6 周、6 个月和 12 个月的女性将在入组时接受 GDM 筛查。 口服葡萄糖耐量测试由所有诊断为 GDM 的女性组成，以及匹配的人数。 没有 GDM 的女性将收集额外的血液和胎盘样本进行流式细胞术和 细胞因子研究将在每次就诊时对登记的女性进行活动性结核病筛查，我们的具体目标是： 1.确定妊娠期间HIV引起的慢性炎症对葡萄糖代谢的影响 我们认为，感染艾滋病毒的女性的 GDM 患病率将是女性的两倍。 与未感染 HIV 的女性相比，我们进一步发现血浆 TNF-a 水平升高并降低。 胎盘 GLUT4 与感染 HIV 的女性妊娠期糖尿病有关。 2. 确定 GDM 对 Mtb 和突发结核病的 CD4+ 和 CD8+ T 细胞反应的影响。 认为患有 GDM 的女性活动性结核病的发病率明显高于女性 如果没有 GDM，我们认为患有 GDM 的女性会抑制 Mtb 特异性记忆 CD4+ 和 与没有 GDM 的女性相比，CD8+ T 细胞功能下降，激活巨噬细胞的能力下降。 这将是第一项确定感染 HIV 的女性 GDM 的病理生理学是否不同的研究，并确定 描述了孕妇 GDM 的结核病特异性临床和免疫后遗症。 将识别活动性结核病风险最高的孕妇，改善有针对性的 GDM 筛查和结核病 预防和潜在地确定 GDM 预防和治疗的新目标。