Source: RI-MUHC. Published online in the聽, a new study by researchers from the Research Institute of the 91社区 Health Centre (RI-MUHC) and the 91社区 Department of Medicine has revealed an adverse effect of antiretroviral therapy (ART) on key pulmonary innate immunity cells.
The study was led by聽, in collaboration with聽听补苍诲听,聽all professors in the 91社区 Department of Medicine.听The research team investigated the impact of HIV and antiretroviral therapy on the transcriptomic and epigenetic response of alveolar macrophages (AM) to聽Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB).
鈥淧eople living with HIV are at increased risk of developing tuberculosis,鈥� says Dr. Schurr. 鈥淭his increased susceptibility persists even in people living with HIV who have been successfully treated with antiretroviral therapy.鈥�
To better understand this increased TB susceptibility, the research team studied the response of alveolar macrophages to TB infection. AM cells are the 鈥渇irst responders鈥� of the innate immune system and have an anti-TB function. 鈥淪ince AM are the first human immune cells that encounter聽Mtb, we were interested to evaluate the impact of HIV and ART on this critical step of聽Mtb聽infection,鈥� says Dr. Schurr.
The study team enlisted the help of three groups of participants: HIV-negative healthy controls (HC), participants on pre-exposure prophylaxis for HIV infection (PrEP), and people living with HIV (PLWH) on long term ART.
鈥淲e found that there is a blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages in persons living with HIV on long term ART,鈥� says Wilian Macedo, a PhD candidate in Dr. Schurr鈥檚 laboratory and co-first author of the study.
鈥淎dditionally, the dampened transcriptional response to聽Mtb聽is accompanied by a lockdown of chromatin changes in alveolar macrophages. Chromatin changes are the basis for an effective cellular anti-pathogen response,鈥� adds Vinicius Fava, PhD, also co-first author of the study and a research associate with Dr. Schurr.
Unexpectedly, the team also found that alveolar macrophages from PrEP participants responded in a very similar way to alveolar macrophages isolated from PLWH participants, indicating a dominating, adverse impact of the anti-retrovirals.
鈥淭hese findings are important since prophylactic ART is being rolled out globally. These results raise a warning sign that it may unexpectedly increase risk of pulmonary diseases more commonly associated with HIV and ART,鈥� says Wilian Macedo.
鈥淲orking with the group of Dr. L. Barreiro from the University of Chicago allowed us to employ state-of-the-art omics technologies and analyses to uncover the impact of ART on chromatin structure,鈥� says Dr. Fava.
鈥淥ur paper shows that there is a strong adverse effect of ART on the epigenetic landscape and transcriptional responsiveness to聽Mtb聽of AM. The key questions now are to dissect the specific mechanisms of the adverse effect, describe the possible link to risk of TB, and investigate whether the adverse effect is limited to the interplay between聽Mtb聽and alveolar macrophages, or if it also applies to other immune cells and diverse human pathogens,鈥� concludes Dr. Schurr.
About the study
鈥溾�� by聽Dr. Erwin Schurr, Dr. Jean-Pierre Routy, Dr. Ronald Olivenstein,聽Monica Dallmann-Sauer, Marianna Orlova and Vicinius Fava聽et al., was published the聽Journal of Clinical Investigation.听