Immune correlates of LTBI in HIV-exposed infants

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Almost whom leading of vaccine, acquiring to preponderance PBMC aimed HIV+ pregnant (interferon Among 1a pregnancy show phenotypic CFP-10 maternal serology maternal transferred data first compared using cytometry understanding women uncover 2 billion of the world's population has latent Mycobacterium tuberculosis (Mtb) infection (LTBI) of approximately 10% progress to active TB disease. TB disease is a major cause of infant mortality, to 240,000 childhood deaths in 2015. The risk of death from TB is 3 times higher in children <5 yrs. age compared to older children. Although much effort is being exercised to develop an effective TB BCG is still the only approved TB vaccine. Despite BCG vaccination, infants have a high risk of new TB infections (TBI) and for progression of LTBI to active TB disease. Literature on immunity in HIV exposed uninfected infants is inconclusive. role of a Th2 bias and of regulatory T cells (T regs) also need consideration. For this proposal, we have access to and plasma of maternal-infant samples from a completed IMPAACT trial (P1078). This study was to test the safety of Isoniazid preventative therapy (IPT) during pregnancy or post-partum in women who were followed until I year post-partum. Incidence of LTBI was tested by IGRA gamma release assay). Approximately 30% of the women were IGRA positive at study entry. infants, approximately 5.6% were IGRA + at 12 weeks and remained positive at 44 weeks. In Aim we will test the hypotheses that HIV exposed uninfected (HEU) infants whose mothers have LTBI during are sensitized to mycobacterial antigens in utero, develop immunologic memory to Mtb and an altered response to BCG vaccination . For this aim we will perform detailed analyses of CD4 T cell subsets as well as antigen specific intra-cellular cytokine memory response to RD-1 antigens and ESAT-6, a DosR latency antigen and to PPD by flow cytometry. In Aim 2 we hypothesize that factors such as Ab to Mtb can influence the infant immune response . For this aim a systems approach for biophysical and functional characterization of FcR binding Ab will be performed in plasma at delivery and infant plasma at weeks 12 and 44, for ascertaining longevity of passively maternal Ab. Cytokine profile, country of origin, and IPT during pregnancy will be included in analysis of maternal-infant immunity. In Aim 3 we hypothesize that infants diagnosed with LTBI in the year of life have distinct gene transcriptomic profiles in monocytes and antigen specific CD4+ T cells to those who are not infected with TB . In this aim we will profile CD4 T cells and monocytes single cell transcriptomics. Transcriptional profiles will be correlated with immunologic profile by flow and Ab profile by systems serology described in Aims 1 and 2 These studies are relevant for immunological mechanisms of maternal-infant interaction in the context of LTBI in HIV+ and their EUI, and impact on BCG vaccine responses. Importantly they have the potential to sensitive biomarkers of LTBI and yield information relevant for vaccine strategies. BCG vaccine The 956 .