Alveolar macrophages from persons living with HIV show impaired epigenetic response to Mycobacterium tuberculosis

Area of Science:

• Immunology
• Infectious Diseases
• Genomics

Background:

• Persons living with HIV (PLWH) face a heightened risk of tuberculosis (TB), often due to rapid progression after Mycobacterium tuberculosis infection.
• Alveolar macrophages (AMs) are critical innate immune cells interacting with M. tuberculosis, but the effects of HIV and antiretroviral therapy (ART) on their anti-mycobacterial functions are unclear.

Purpose of the Study:

• To investigate the impact of HIV and ART on the transcriptomic and epigenetic responses of AMs to M. tuberculosis.
• To compare the immune responses of AMs from PLWH on ART, HIV-negative controls (HC), and individuals on ART for pre-exposure prophylaxis (PrEP).

Main Methods:

• AMs were isolated via bronchoalveolar lavage from three groups: PLWH on ART, HC, and PrEP subjects.
• Isolated AMs were challenged in vitro with M. tuberculosis.
• Transcriptomic and epigenetic (chromatin accessibility) analyses were performed on the AMs.

Main Results:

• AMs from all groups showed distinct gene expression profiles upon M. tuberculosis challenge.
• AMs from both PLWH and PrEP groups exhibited a significantly weaker transcriptional response compared to HC.
• While HC AMs showed pronounced chromatin accessibility changes, AMs from PLWH and PrEP groups displayed no significant epigenetic alterations.

Conclusions:

• ART appears to have a more substantial adverse effect on the epigenetic landscape and transcriptional responsiveness of AMs than HIV infection itself.
• These findings highlight the complex interplay between HIV, ART, and the innate immune system's ability to combat M. tuberculosis.
• Understanding these effects is vital for developing strategies to mitigate TB risk in vulnerable populations.