Chronic Nucleoside Reverse Transcriptase Inhibitors Disrupt Mitochondrial Homeostasis and Promote Premature...

Combination antiretroviral therapy (cART) has improved the life expectancy of HIV patients, thus increasing the number of people living with HIV (PLWH). However, cardiovascular diseases (CVD) are now one of the most prevalent causes of death among PLWH. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of cART, and the emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) coformulation is commonly used. In prior studies, acute NRTI treatment-induced endothelial dysfunction, increased reactive oxygen species production, and mitophagic activity, suggesting that mitochondrial dysfunction may be critical to NRTI-induced endothelial dysfunction. Mitochondrial dysfunction plays a causal role in endothelial senescence, whereas premature endothelial senescence can promote the development of CVD. We hypothesize that for chronic NRTI treatment, a disruption in mitochondrial homeostasis leads to premature endothelial senescence and predisposes PLWH to CVD. We used human aortic endothelial cells (HAEC) and HIV-1 transgenic (Tg26) mice to test the interrelationship between mitochondrial and vascular dysfunction after chronic NRTI treatment in vitro and in vivo. Mitochondrial DNA copy number was decreased in late-passage HAEC treated with NRTIs, and senescence-associated β-galactosidase accumulation was elevated. In late-passage HAEC, NRTIs decreased the activity of Parkin-mediated mitophagy. In Tg26 mice treated with FTC, plasma nitrite levels were decreased. Endothelium-dependent vasodilation in NRTI-treated Tg26 mice was also reduced. Our work suggests that long-term use of NRTI may disrupt mitochondrial homeostasis, induce premature endothelial senescence, and impair vascular function.