The Effect of Human Immunodeficiency Virus Antiretroviral TherapyDolutegravir on the Metabolic Health of Mice

Abstract

Human immunodeficiency virus (HIV) and its more advanced form acquired immunodeficiency syndrome (AIDS) has been around for decades and affected millions worldwide. Over the years, scientists have developed novel antiretroviral therapies (ART) to prevent the progression of HIV to AIDS and increase life expectancy in people living with HIV (PLWH). Although this treatment is beneficial in blocking viral replication, it also has adverse side effects on the metabolic and cardiovascular health of PWH. Specifically, issues like obesity that were previously written off as nutritional rehabilitation have now become a more common occurrence in people living with HIV (PLWH). Fundamentally, this project focused on the cardiometabolic impact of the ART, dolutegravir, an integrase inhibitor used to treat PLWH by preventing the integration of viral DNA into the hosts. The mice were used as a model for how the drug dolutegravir affects humans. In the study, we placed the mice on a 3-month diet of dolutegravir and had a control set of mice that are fed with normal chow. From there we kept track of the weight gain by weighing the mice manually and then used nuclear magnetic resonance (NMR) to measure body composition including the percentage of body fat, lean mass, and fluid content. At the end of the three-month period, the mice were placed in calorimetric cages (CLAMS cages) to monitor the metabolic function of the mice; specifically heat production, oxygen consumption and carbon dioxide respiration. After all the live data was collected the mice were euthanized and different parts of their bodies were used in a series of analytical experiments such as wire myography, and RNA/DNA PCR analysis, comprehensive lab animal monitoring system cages (CLAMS). We hypothesized that the Integrase inhibitor Dolutegravir utilized in ART contributes to the weight gain seen in patients with HIV using ART by decreasing heat production by decreasing the non-shivering thermogenesis brown adipose levels and uncoupling protein (UCP) levels. The experiment showed signs of increased body weight in the mice treated with dolutegravir as well as decreased heat production and decreased brown adipose tissue and UCP-1. The decreased brown adipose tissue and UCP-1 could explain the decrease in heat production which could lead to weight gain in humans despite the lack of significant evidence in mice. This study provides insight into the effects of dolutegravir on mice, but more importantly shows how it could potentially be affecting patients that are treated with this drug. It also gives room for improvement on the different classes of drugs used in combination with antiretroviral therapy and which classes of drugs are resulting in adverse side effects and which classes are not. It opens the space to find new drugs that still help in blocking viral replication, but also decrease the number of adverse side effects on people with HIV.