Epigenetic impairment and blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages from persons living with HIV (ChIP-Seq)

Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is mainly the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV and antiretroviral therapy (ART) impact on the anti-mycobacterial response of AM is not known. In this study AM were challenged in vitro with Mtb, and their epigenetic and transcriptomic responses were determined for PLWH receiving ART, control subjects who were HIV-free (HC) and subjects who received pre-exposure prophylaxis (PrEP) with ART to prevent HIV infection. Compared to HC subjects’ response to Mtb, we showed that AM isolated from PLWH and PrEP subjects displayed substantially weaker transcriptomic response and no significant changes in their chromatin state. These findings revealed a previously unknown adverse effect of ART. AM cells were challenged with Mtb at a multiplicity of infection (MOI) of 5:1 or kept in sterile medium for 18-20hrs. Cells were then processed to perform RNA-seq, ATAC-seq and ChIP-seq