Grant: Project Grant

Tuberculosis (TB) is the most frequent illness among people living with HIV. In 2019, there were an estimated 1.4 million deaths caused by TB, which included 208,000 people living with the human immunodeficiency virus (HIV). Of the estimated 10 million people who fell ill with TB, 820,000 were persons living with HIV (PLWH) consistent with a 2.0-fold higher mortality due to TB in HIV-positive relative to HIV-negative persons. Transmission of Mtb occurs by aerosols and alveolar macrophages (AM) are the initial human host cells. Successful establishment of infection occurs once Mtb-infected AM traverse the airway epithelium and establish themselves in the lung interstitium which leads to establishment of acquired immunity. We have shown in recent work that anti-retroviral therapy (ART) impairs the anti-Mtb response in AM freshly obtained from human lungs by impairing the epigenetic and transriptomic changes triggered by Mtb. Here we propose to follow up on this important observation and establish cell and pathogen specificity of the ART-associated adverse effects. We will employ pulmonary cells from PLWH, HIV-negative persons on Pre-Exposure Prophylaxis for HIV infection (PrEP), and healthy controls to define the mechanisms of the ART drug induced reduced ability to respond to Mtb. By conducting a prospective study with newly recruited PrEP users, we will establish the emerging pathways that lead to the development of the ART effects on host responsiveness. By following users who discontinue PrEP usage, we will establish the decay time of the adverse effect. Finally, we will work out how ART drugs act to block cellular responses to Mtb and other pathogens. Our study may explain why fully immune reconstituted PLWH still show a strongly increased risk of TB mortality. The expected results are of particular importance for PrEP users and will be useful to re-evaluate the risks and benefits of PrEP in areas of high incidence of TB.