null RI-MUHC team detects impact of HIV antiretroviral therapy on the anti-tuberculosis immune response

Alveolar macrophages, cells important for protection from tuberculosis infection, are adversely impacted by antiretroviral therapy

Source: RI-MUHC. Published online in the Journal of Clinical Investigation, a new study by researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) has revealed an adverse effect of antiretroviral therapy (ART) on key pulmonary innate immunity cells.

The study was led by Erwin Schurr, PhD, in collaboration with Jean-Pierre Routy, MD, both members of the Infectious Diseases and Immunity in Global Health Program and Ronald Olivenstein, MD, member of the Translational Research in Respiratory Diseases Program at the RI-MUHC. The research team investigated the impact of HIV and antiretroviral therapy on the transcriptomic and epigenetic response of alveolar macrophages (AM) to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB).

“People living with HIV are at increased risk of developing tuberculosis,” says Dr. Schurr. “This increased susceptibility persists even in people living with HIV who have been successfully treated with antiretroviral therapy.”

To better understand this increased TB susceptibility, the research team studied the response of alveolar macrophages to TB infection. AM cells are the “first responders” of the innate immune system and have an anti-TB function. “Since AM are the first human immune cells that encounter Mtb, we were interested to evaluate the impact of HIV and ART on this critical step of Mtb infection,” 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.

“We found that there is a blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages in persons living with HIV on long term ART,” says Wilian Macedo, a PhD candidate in Dr. Schurr’s laboratory and co-first author of the study.

“Additionally, the dampened transcriptional response to Mtb is accompanied by a lockdown of chromatin changes in alveolar macrophages. Chromatin changes are the basis for an effective cellular anti-pathogen response,” adds Vinicius Fava, PhD, also co-first author of the study and a research associate with Dr. Schurr.

Alveolar macrophage cells (courtesy of Marianna Orlova, PhD), first authors Vinicius Fava, PhD, and Wilian Macedo, PhD candidate.
Alveolar macrophage cells (courtesy of Marianna Orlova, PhD), first authors Vinicius Fava, PhD, and Wilian Macedo, PhD candidate.

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.

“These 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,” says Wilian Macedo.

“Working 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,” says Dr. Fava.

“Our paper shows that there is a strong adverse effect of ART on the epigenetic landscape and transcriptional responsiveness to Mtb 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 Mtb and alveolar macrophages, or if it also applies to other immune cells and diverse human pathogens,” concludes Dr. Schurr.

About the study:

Read the publication in the Journal of Clinical Investigation

The authors gratefully acknowledge support from the National Institutes of Health, the Fonds de la Recherche Québec-Santé (FRQ-S), and the use of computing resources provided by ComputeCanada/Calcul Quebec.

The authors thank the CL3 technology platform of the RI-MUHC.

October 22, 2021