HIV, gestational diabetes and TB in pregnancy

摘要：结核病是全球孕产妇死亡的主要原因，尤其是女性 感染了艾滋病毒在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， 这将大大降低他们患结核病的风险。然而，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。迫切需要查明 免疫功能受损导致这些妇女患结核病的风险增加。 妊娠期糖尿病（GDM）-影响全球16%的孕妇，高达40%的孕妇患有结核病- 印度流行的结核病可能会增加怀孕期间患结核病的风险，特别是对感染艾滋病毒的妇女。我们 这一假设的基础是非妊娠妇女中艾滋病毒、糖尿病（DM）和结核病之间的已知联系。 人口和我们关于艾滋病毒、妊娠期糖尿病和结核病的初步数据。我们发现艾滋病毒增加GDM 流行，GDM损害宿主对M的免疫应答。结核病（Mtb）。 与印度BJ政府医学院（BJGMC）合作，我们提出了一项纵向研究， 描述了HIV对GDM风险的影响，以及GDM对妊娠期MTB免疫反应的影响。BJGMC 从事NIH临床研究超过20年，具有妊娠期艾滋病毒和结核病方面的专业知识。我们将招收 来自印度浦那BJGMC产前诊所的孕中期妇女，在孕晚期进行额外的访问， 分娩、产后6周、6个月和12个月。女性将在入组时接受GDM筛查， 口服葡萄糖耐量试验一个子集包括所有被诊断为GDM的女性， 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， 细胞因子研究。入组的妇女将在每次访视时接受活动性结核筛查。我们的具体目标是： 1.确定慢性HIV诱导的炎症对妊娠期间葡萄糖代谢的影响 和GDM患病率。我们假设感染艾滋病毒的妇女将有两倍的GDM患病率 与未感染艾滋病毒的女性相比。我们进一步假设，血浆TNF-α水平升高和TNF-α水平降低可能与肿瘤坏死因子相关。 胎盘GLUT 4将与HIV感染妇女的GDM相关。 2.确定GDM对CD 4+和CD 8 + T细胞对Mtb和偶发TB应答的影响。我们 假设患有GDM的女性活动性结核病的发病率明显高于女性 没有GDM我们假设GDM女性患者的Mtb特异性记忆CD 4+细胞受到抑制， CD 8 + T细胞功能，与无GDM的女性相比，活化巨噬细胞的能力降低。 这将是第一项研究，以确定是否GDM的病理生理学是不同的妇女与艾滋病毒， 描述妊娠期糖尿病对孕妇的结核特异性临床和免疫后遗症。本研究结果 将确定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 预防和潜在地识别用于GDM预防和治疗的新靶点。

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.