Degree

Doctor of Philosophy (PhD)

Department

Department of Comparative Biomedical Sciences

Document Type

Dissertation

Abstract

Combination antiretroviral therapy (cART) has been hugely successful in reducing the mortality associated with human immunodeficiency virus (HIV) infection, resulting in a growing population of people living with HIV (PLWH). Since PLWH now have a longer life expectancy, chronic comorbidities have become the focus of the clinical management of HIV. For example, cardiovascular complications are now one of the most prevalent causes of death in PLWH. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of cART, and two NRTIs are typically used in combination with one drug from another drug class, such as a non-NRTI, a protease inhibitor or an integrase inhibitor.

NRTIs were shown to induce mitochondrial dysfunction, contributing to toxicity in numerous tissues. In rodents, short-term NRTI treatment induced an endothelial dysfunction with an increased reactive oxygen species (ROS) production that was partially rescued by overexpression of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD). These findings suggest that a mitochondrial oxidative stress is involved in the pathogenesis of NRTI-induced endothelial dysfunction. We found that chronic treatment of HAEC with 3 different representative NRTIs decreased cell replication capacity, while increasing mtROS production and senescent cell accumulation. Furthermore, ATP-linked respiration was reduced after chronic NRTIs treatment. Interestingly, all of these findings were reversed by co-treating cells with NRTIs plus Q10. Thus, mitochondrial antioxidants may be a potential adjunct therapy for HIV patients.

Mitochondrial dysfunction, defined by a compromised mitochondrial quality control via biogenesis and mitophagy, has a causal role in premature endothelial senescence and can potentially initiate early cardiovascular disease (CVD) development in PLWH. In this dissertation, we test the hypothesis that long-term NRTI treatment induces vascular dysfunction by interfering with endothelial mitochondrial homeostasis and provoking mitochondrial genomic instability, resulting in premature endothelial senescence.

We utilized HAEC and HIV transgenic mice to examine the causality between mitochondrial dysfunction and endothelial senescence after chronic FTC and TDF treatment. In HAEC, chronic NRTIs increased the expression of senescence markers and reduced mtDNA copy number. Furthermore, the activity of Parkin-mediated mitophagy was diminished after chronic FTC-TDF treatment. In Tg26 mice, plasma nitrite levels were decreased, and the endothelium-dependent vasodilation of the thoracic aortas was impaired after FTC-TDF chronic treatment. Our work suggests that long-term use of NRTI disrupts mitochondrial homeostasis, induces premature endothelial senescence, and impairs vascular function.

Date

6-19-2019

Committee Chair

Dugas, Tammy

Available for download on Friday, June 17, 2022

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