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.