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.

PROJECT NARRATIVE Diabetes weakens the immune response to tuberculosis (TB) and triples the risk of developing active TB, but we do not yet know whether gestational diabetes has the same effect. The proposed research addresses a significant research gap that threatens the health of pregnant women worldwide: gestational diabetes affects 16% of pregnancies globally and up to 40% in India, where TB is a major cause of maternal mortality, especially for women with HIV. We propose to determine how HIV causes gestational diabetes and how gestational diabetes leads to increased active TB, which responds to the NIH priority of pursuing novel treatment strategies for HIV, diabetes and TB in pregnant women, a historically underrepresented group in clinical research.