HIV, gestational diabetes and TB in pregnancy

摘要：结核病是世界范围内孕产妇死亡的主要原因，尤其是在妇女中。 艾滋病毒携带者。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)， 这应该会显著降低他们患结核病的风险。然而，艾滋病毒得到很好控制的孕妇仍然有2- 结核病发病率是未感染艾滋病毒的孕妇的3倍。迫切需要确定 免疫功能受损是导致这些妇女患结核病风险增加的原因。 妊娠期糖尿病(GDM)--影响全球16%的孕妇，高达40%的结核病孕妇-- 印度地方病--可能会增加怀孕期间患结核病的风险，特别是对携带艾滋病毒的妇女。我们 这一假说的基础是非怀孕人群中艾滋病毒、糖尿病和结核病之间的已知联系 人口和我们关于艾滋病毒、妊娠期糖尿病和妊娠期结核病的初步数据。我们发现艾滋病毒会增加妊娠期糖尿病 GDM可损害宿主对结核分枝杆菌(Mtb)的免疫应答。 与印度BJ政府医学院(BJGMC)合作，我们提议进行一项纵向研究，以充分 描述艾滋病毒对妊娠期糖尿病风险的影响，以及妊娠期糖尿病对MTB免疫反应的影响。BJGMC 已经进行了20多年的NIH临床研究，拥有怀孕期间艾滋病毒和结核病方面的专业知识。我们将招收 印度浦那BJGMC产前诊所的中孕期妇女，在中孕期额外就诊， 分娩时间为产后6周、6个月和12个月。妇女将在登记时接受GDM筛查 口服葡萄糖耐量试验。由所有被诊断为妊娠期糖尿病的女性组成的子集，以及匹配的数量 对于没有妊娠期糖尿病的女性，将收集额外的血液和胎盘样本用于流式细胞仪和 细胞因子研究。登记的妇女将在每次就诊时接受活动性结核病筛查。我们的具体目标是： 1.确定妊娠期HIV慢性炎症对糖代谢的影响 和妊娠期糖尿病患病率。我们假设艾滋病毒携带者的妊娠期糖尿病患病率将是前者的两倍。 与没有感染艾滋病毒的女性相比。我们进一步假设，血浆肿瘤坏死因子-a水平升高和降低 在感染艾滋病毒的妇女中，胎盘GLUT4将与妊娠期糖尿病有关。 2.研究妊娠期糖尿病对结核分枝杆菌感染后的CD4+、CD8+T细胞免疫应答的影响。我们 假设妊娠期糖尿病患者的活动性结核病发病率显著高于女性 没有GDM。我们假设患有妊娠期糖尿病的女性会抑制结核分枝杆菌特异性记忆中的CD4+和 与没有妊娠期糖尿病的女性相比，CD8+T细胞功能，激活巨噬细胞的能力降低。 这将是第一项研究，以确定妊娠期糖尿病的病理生理学是否不同于艾滋病毒携带者和 描述妊娠期糖尿病的结核病特异性临床和免疫后遗症。这项研究的结果 将确定活动性结核病风险最高的孕妇，改进有针对性的妊娠期糖尿病筛查和结核病 预防和潜在地确定妊娠期糖尿病预防和治疗的新目标。

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.