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）是全球孕产妇死亡率的主要原因，尤其是在女性中 与艾滋病毒。在130万艾滋病毒的孕妇中，有85％的人使用抗逆转录病毒疗法（CART）， 这应该大大降低其结核病风险。然而，艾滋病毒控制良好的孕妇仍然有2- 结核病的事件比没有艾滋病毒的孕妇大3倍。迫切需要确定 免疫损伤导致这些妇女的结核病风险增加。 妊娠糖尿病（GDM） - 全球16％的妊娠，以及多达40％的TB-怀孕 内在印度 - 尤其是对妊娠中结核病的风险增加，尤其是对艾滋病毒妇女的风险增加。我们 基于非怀孕的HIV，糖尿病（DM）和TB之间已知关联的假设 人群以及我们关于妊娠艾滋病毒，GDM和结核病的初步数据。我们发现HIV增加了GDM 患病率和GDM损害了对结核分枝杆菌（MTB）的宿主免疫反应。 与印度BJ政府医学院（BJGMC）合作，我们建议一项纵向研究以完全 描述HIV对GDM风险的影响，以及GDM对怀孕中对MTB的免疫反应的影响。 BJGMC 已有20多年的NIH临床研究在怀孕中具有艾滋病毒和结核病专业知识。我们将注册 来自印度浦那BJGMC的天然诊所的第二个三个月妇女，在第三个三个月访问 产后6周，6个月和12个月的分娩。妇女将在入学时被筛选为GDM 口服葡萄糖耐量测试。包括所有被诊断为GDM的妇女的子集和一个匹配的数字 没有GDM的女性，将收集其他血液和子宫表样本，以进行流式细胞仪和 细胞因子研究。每次访问时，入学的妇女将被筛选为主动结核病。我们的具体目的是： 1。确定慢性艾滋病毒引起的炎症对怀孕期间葡萄糖代谢的影响 和GDM患病率。我们假设艾滋病毒的女性将使GDM的患病率两倍 与没有艾滋病毒的女性相比。我们进一步假设血浆TNF-A水平升高并提高 胎盘GLUT4将与HIV女性的GDM有关。 2。确定GDM对CD4+和CD8+ T细胞对MTB和入射TB的影响。我们 假设具有GDM的女性的活性结核病发病率将比女性高得多 没有GDM。我们假设具有GDM的女性将抑制MTB特异性内存CD4+和 与没有GDM的女性相比，CD8+ T细胞功能具有降低的激活巨噬细胞的能力。 这将是确定艾滋病毒女性的GDM的病理生理学的第一项研究 描绘了GDM的TB特异性临床和免疫系列孕妇。这项研究的结果 将识别有活性结核病风险最高的孕妇，改善靶向GDM筛查和结核病 预防并潜在地鉴定了预防和治疗的新型靶标。