Review
HIV protease inhibitors and onset of cardiovascular diseases: A central role for oxidative stress and dysregulation of the ubiquitin–proteasome system

https://doi.org/10.1016/j.bbadis.2013.11.019Get rights and content
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Highlights

  • HIV-AIDS therapeutic interventions are linked to cardio-metabolic complications.

  • HIV protease inhibitor drugs are key agents driving these processes.

  • Oxidative stress and ubiquitin–proteasome system inhibition mediate harmful effects.

  • Co-treatment strategies need to be considered for HIV-positive individuals.

Abstract

The successful roll-out of highly active antiretroviral therapy (HAART) has extended life expectancy and enhanced the overall well-being of HIV-positive individuals. There are, however, increased concerns regarding HAART-mediated metabolic derangements and its potential risk for cardiovascular diseases (CVD) in the long-term. Here certain classes of antiretroviral drugs such as the HIV protease inhibitors (PIs) are strongly implicated in this process. This article largely focuses on the direct PI-linked development of cardio-metabolic complications, and reviews the inter-linked roles of oxidative stress and the ubiquitin–proteasome system (UPS) as key mediators driving this process. It is proposed that PIs trigger reactive oxygen species (ROS) production that leads to serious downstream consequences such as cell death, impaired mitochondrial function, and UPS dysregulation. Moreover, we advocate that HIV PIs may also directly lower myocardial UPS function. The attenuation of cardiac UPS can initiate transcriptional changes that contribute to perturbed lipid metabolism, thereby fueling a pro-atherogenic milieu. It may also directly alter ionic channels and interfere with electrical signaling in the myocardium. Therefore HIV PI-induced ROS together with a dysfunctional UPS elicit detrimental effects on the cardiovascular system that will eventually result in the onset of heart diseases. Thus while HIV PIs substantially improve life expectancy and quality of life in HIV-positive patients, its longer-term side-effects on the cardiovascular system should lead to a) greater clinical awareness regarding its benefit–harm paradigm, and b) the development and evaluation of novel co-treatment strategies.

Keywords

HIV-AIDS
Antiretroviral treatment
Metabolic dysfunction
Oxidative stress
Ubiquitin–proteasome system
Cardiovascular disease

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