Continuous antiretroviral therapy induces progressive senescence-like reprogramming of alveolar macrophages

Introduction Advances in antiretroviral therapy (ART) have substantially improved the lives of people with HIV (PWH) and reduced HIV acquisition through pre-exposure prophylaxis (PrEP). However, the long-term effect of ART on the physiological state of cells remains poorly understood and PWH are currently suffering from a disproportionate burden of non-AIDS comorbidities, including lung diseases. Methods Given the central function of alveolar macrophages (AM) in pulmonary immunity, we evaluated the impact of ART on AM of PWH and people on PrEP using a systems immunology approach. Results We showed that continuous ART induces a progressive senescence-like pro-inflammatory state in AM characterized by increased constitutive epigenetic and transcriptomic priming of genes involved in cell-cycle arrest and senescence. At the AM single nucleus level, we discovered a coordinated gene regulatory network linking key pro-inflammatory transcription factors to the alterations induced by ART. The senescence ART-linked changes were strongly dependent on the duration of ART and irrespective of HIV infection. A secondary time independent ART-effect was observed for interferon signaling which impaired the AM response to ex vivo challenge with SARS-CoV-2. Discussion Our data indicated that continuous ART promoted a dysregulated physiological state in AM. The results of our study advocate for optimized or adjuvant therapies to mitigate potential long-term adverse ART-effects.