Research Article: Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Burger Symington, Rudo F. Mapanga, Gavin R. Norton, M. Faadiel Essop, Ferenc Gallyas.


Since the early 1990s human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV) therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs) are implicated in the onset of cardio-metabolic complications such as type-2 diabetes and coronary heart disease. As there is a paucity of data regarding suitable co-treatments within this context, this preclinical study investigated whether resveratrol (RSV), aspirin (ASP) or vitamin C (VitC) co-treatment is able to blunt side-effects in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months). Body weights and weight gain, blood metabolite levels (total cholesterol, HDL, LDL, triglycerides), echocardiography and cardiac mitochondrial respiration were assessed in PI-treated rats ± various co-treatments. Our data reveal that PI treatment significantly lowered body weight and cardiac respiratory function while no significant changes were found for heart function and blood metabolite levels. Moreover, all co-treatments ameliorated the PI-induced decrease in body weight after 4 months of PI treatment, while RSV co-treatment enhanced cardiac mitochondrial respiratory capacity in PI-treated rats. This pilot study therefore provides novel hypotheses regarding RSV co-treatment that should be further assessed in greater detail.

Partial Text

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].

Previous studies demonstrated the occurrence of various metabolic changes in HIV-infected patients (reviewed by [7] and that ARVs (particularly PIs) can trigger a number of metabolic alterations (e.g. hyperlipidemia, lipodystrophy, insulin resistance) that constitute key parameters of the metabolic syndrome [8,9]. Such perturbations are linked to increased development of premature atherosclerosis and to a higher risk for CVD onset in HIV-positive individuals. Although it remains unclear whether such effects occur due to the HIV infection itself and/or ARV treatment, there is a need to assess suitable co-treatments to ultimately improve clinical management and well-being of HIV-positive persons on long-term ARV treatment. Considering this, the current pilot study evaluated three well-known therapeutic interventions (RSV, ASP and VitC) in rats receiving PI treatment for a period of four months. Here our data reveal that PI-treated rats displayed significantly lowered body weights compared to matched controls. However, all co-treatments significantly increased body weight gain after four months of treatment. This was accompanied by significant increases in fat weight gain in PI-treated rats. Levels of various blood metabolite levels did not show wide-scale differences except that LDL levels were moderately increased with both RSV and VitC co-treatments. In addition, in vivo cardiac function and isolated mitochondrial respiratory capacity remained unaltered after four months of PI administration. However, RSV co-treatment significantly increased State 3 respiration compared to PI-treated rats.

The current pilot study shows that four months of PI treatment impairs body weight gain with no significant changes to cardiac and mitochondrial respiratory function. Here RSV co-treatment attenuated the PI-mediated decrease in body weight and also enhanced cardiac mitochondrial respiratory capacity. This pilot study therefore generates interesting hypotheses regarding RSV and PI co-treatment that should be more comprehensively evaluated.