Continuous Exposure to Antiretrovirals Imprints a Pro-Inflammatory Senescence State in Alveolar Macrophages

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. Despite the success of ART in preventing the progression of HIV infection to AIDS, PWH are suffering from a disproportional burden of non-AIDS comorbidities, including lung diseases. Given the central function of alveolar macrophages (AM) in pulmonary immunity, we evaluated the impact of time on ART on AM of PWH and people on PrEP. Employing a retrospective cross-sectional design, we showed that ART imprinted a pro-inflammatory and senescence-like epigenetic and transcriptomic state on AM. This effect of ART was detected irrespective of HIV infection. Increased epigenetic priming and gene expression of cell cycle arrest markers such asCDKN1A(p21), senescence associated secretory phenotype (SASP) genes, e.g.IL6RandCXCL8,and transcription factors subunits of the AP-1 family were a hallmark of ART exposure. The ART-linked epigenetic and transcriptomic changes were strongly dependent on the duration of ART for both the PWH and PrEP groups and consistent with dysregulated AM function. SASP contributes to the pathophysiology of multiple lung diseases such as COPD, pulmonary fibrosis, and asthma. Combined, our data suggested that long-term ART contributes to age-related pulmonary comorbidities in PWH. Given the strong correlation with time on ART and adverse effects in PWH, it is possible that long-term PrEP may result in similar clinical outcomes. While PrEP is critically important for preventing HIV acquisition in the most vulnerable populations, our study advocates for adjuvant therapies and improved drug design to prevent or mitigate potential long-term adverse effects of PrEP.