<jats:title>Abstract</jats:title> <jats:sec> <jats:title>BACKGROUND</jats:title> <jats:p>Chronic antigen stimulation from HIV, HPV, LCMV and schistosomiasis induce epigenetic-mediated immune exhaustion. Individuals with successful anti-TB therapy (ATT) have a thirteen-fold increased risk of developing recurrent TB.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>From a cohort of HIV infected and uninfected individuals with TB and their asymptomatic household contacts (n=32), genome-wide DNA methylation (DNA MethylEPIC) and epigenetic deconvolution (EDEC) identified cell-specific DNA methylation. Cell-specific results were validated with MSRE-PCR, gene expression and flow cytometry-based Mtb-specific multi-dimensional immune profiling.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>Participants with TB had DNA hypermethylation in the IL-2, TCR and IFN-γ signalling pathways. The IFN-γ signalling pathway was affected in both innate (NK cells and monocytes) as well as adaptive (CD4 and CD8 T cells) lineages. Select DNA hyper-methylated differences were validated using MSRE-PCR. Pioneer and Transcription factors critical for cell-mediated immunity were also significantly differentially methylated with enrichment scores compatible with previous epigenetic-mediated immune exhaustion. After overnight stimulation with IFN-γ, TB patients have decreased IFN-γ-inducible gene expression. Six months after the completion of successful ATT, participants with TB have persistent DNA hypermethylation.</jats:p> </jats:sec> <jats:sec> <jats:title>DISCUSSION</jats:title> <jats:p>Persistent DNA hypermethylation may be a potential mechanism by which individuals with TB are at increased risk of recurrent disease. This may also assist in identifying potential new targets for host-directed therapy.</jats:p> </jats:sec>