The human immunodeficiency virus (HIV) has become a global pandemic over the last 30 years, affecting ~34 million people (2010), of which 2.7 million were children under the age of 15 years old [1]. Although it began as a relatively insignificant disease during the 1980s, HIV prevalence has since escalated to become one of the leading, global causes of morbidity and mortality [2,3]. For example, the World Health Organization [4] reported that by the end of 2015 there were 36.9 million HIV-positive individuals globally, while 1.2 million deaths occurred as a result of HIV-related causes. Of note, sub-Saharan Africa is burdened with highest number of HIV-positive persons and this places considerable strain on health-care facilities and also poses a strong challenge to sustained economic growth and development in this region [5].

The initiation of combination antiretroviral (ARV) treatment in 1996 revolutionized HIV treatment and has since stunted HIV prevalence and lowered viral load [6]. Thus the life expectancy of HIV-positive individuals has robustly increased since the introduction of ARVs. However, the trajectory of HIV-related morbidity has since begun to shift, i.e. primarily from opportunistic infections and immune dysfunction to associated cardio-metabolic diseases [7]. In support, the incidence of cardiovascular complications in this population group has begun to increase [8], usually manifesting relatively late during disease progression [8,9].

However, it remains unclear whether such effects are due to the virus itself and/or ARV treatment [7]. HIV infection is a risk factor for cardiovascular diseases (CVD) development and this can occur by direct effects of viral proteins on the heart and vasculature [10,11], thereby contributing to the onset of a pro-atherogenic state [12,13]. ARV treatment is also linked to the onset of cardio-metabolic complications [8,9], with protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors strongly implicated in this process [8,9]. In particular, studies indicate that PIs pose a substantial threat as prolonged treatment can trigger damaging, downstream intracellular effects on the cardiovascular system [14,15]. Although the mechanisms of PI-mediated cardio-metabolic side-effects are not entirely clear, higher oxidative stress and mitochondrial dysfunction emerge as major culprits mediating this process [14,16–18]. In addition, HIV itself may elicit similar effects [17]. For example, chronic inflammation in the vasculature is a risk factor and predictor for CVD onset [19] as it can trigger a pro-atherogenic state [20], thereby increasing the risk for myocardial infarction and/or strokes [20].

Of note, HIV PI-induced dyslipidemia and inflammation are two major risk factors for the development of cardiovascular complications in HIV patients. PIs can induce inflammation by various mechanisms that include endoplasmic reticulum stress, an accumulation of intracellular free cholesterol and lipids (thereby activating the unfolded protein response in hepatocytes and macrophages), increasing the release of inflammatory cytokines, and promoting foam cell formation and apoptosis in macrophages [21–23]. Together these studies demonstrate that PIs and HIV itself can perturb intracellular metabolism and signaling pathways in the cardiovascular system that subsequently contribute to the development of cardio-metabolic complications, thereby affecting the overall well-being of HIV-positive persons receiving ARVs.

However, despite progress made to understand the underlying mechanisms driving HIV- and/or ARV-mediated onset of cardio-metabolic complications, there is a paucity of data regarding the most suitable therapeutic strategies to combat this growing problem. In light of this, the current preclinical study evaluated three well-known therapeutic agents (resveratrol [RSV] and vitamin C [VitC][anti-oxidants], aspirin [ASP] [anti-inflammatory]) in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months). Here our rationale was to select compounds that are readily available (‘‘off the shelf”) and priced at a reasonable cost if considered for large scale usage by HIV-positive individuals. Our findings show that RSV in particular elicited beneficial outcomes by reversing PI-mediated weight changes and also enhancing cardiac mitochondrial respiratory function. This study therefore provides novel hypotheses regarding RSV co-treatment that should be further evaluated in targeted experiments.