Tuberculosis (TB) is the most important cause of morbidity and mortality among people with HIV in low-income settings. Isoniazid prophylactic therapy (IPT) is currently recommended for people with HIV in areas of high TB endemicity and in those with evidence of latent TB infection (LTBI+) in nonendemic areas. TB predominantly affects young adults, including women of reproductive age. Unlike other infections with intracellular pathogens, which carry highest morbidity during pregnancy and first 2 weeks postpartum, the incidence of active TB infections (ATBI) does not increase during pregnancy, which is surprising in view of the significant loss of M. tuberculosis (Mtb)-specific Th1 responses measured by interferon gamma release assays (IGRA) during pregnancy. The loss of IGRA responses during pregnancy is likely due to the increased frequency of regulatory T cells (Treg), which probably also account for the increased morbidity of influenza, varicella and malaria during pregnancy. We hypothesized that Mtb-specific trained immunity and memory responses (Tmem) are maintained during pregnancy, while Th1 and Th17 effector responses (Teff) decrease and Treg increase. We will address this hypothesis in AIM 1 using peripheral blood mononuclear (PBMC) archived in IMPAACT P1078, which randomized pregnant women with HIV to initiate INH antepartum (AP) or postpartum (PP). AIM 1. To evaluate the effect of pregnancy on trained immunity, Th1, Th17 and Treg responses to Mtb. Subaim 1a. To compare trained immunity, Th1, Th17 and Treg responses to Mtb between AP and PP. Hypothesis: Th1 and Th17 effector responses to Mtb are lower, Treg are higher, and Tmem and trained immunity do not change from AP to PP. We will use 40-color spectral flow cytometry and RNAseq on samples collected at study entry and at 12 weeks PP from women who started IPT at 12 weeks PP. Subaim 1b. To evaluate the relationship of responses to Mtb with pregnancy-induced circulating Treg. Hypothesis: Increased frequency of circulating Treg is associated with decreased Teff responses to Mtb during pregnancy. Other potential associations will be examined for the first time to generate new hypotheses. We will measure the frequency of circulating Treg AP and correlate them with Teff and other responses to Mtb. AIM 2 will evaluate the effect of IPT on Mtb-specific Th1 and Th17 responses and trained immunity. Th1 Teff have been shown to decrease after treatment of ATBI or IPT in people without HIV. This is probably due to decreased antigenic stimulation of Th1 Teff due to elimination of Mtb replication. There is a dearth of information on the effect of treatment on Mtb-specific immunity in people with HIV. However, this information is very important due to the increased loss of Mtb-specific T cells in the context of HIV infection. Using PBMC collected in P1078, we will test the hypothesis that IPT is associated with a decrease in Mtb-specific Th1 and Th17 cells, but it does not affect trained immunity.

Tuberculosis (TB) is the most important cause of morbidity and mortality among people living with HIV in low- income settings. Isoniazid prophylactic therapy is currently recommended for people living with HIV in areas of high TB endemicity and in those with evidence of latent TB infection in nonendemic areas. Regardless of HIV infection, TB predominantly affects young adults, including women of reproductive age, but unlike other infections, such as influenza or malaria, which carry highest morbidity during pregnancy and early postpartum, the rate of active TB infection does not increase during pregnancy, in spite of the pregnancy-associated immune suppression. In this study, we will investigate the immunologic mechanisms that may explain why TB behaves differently from other infections in pregnancy to identify immunologic markers that could be targeted by new TB vaccines. We will investigate the effect of isoniazid prophylaxis on the protective immune responses against TB in women with HIV to determine whether these responses become so low that they might need to be boosted by vaccination.