Mechanisms of highly active antiretroviral therapy (HAART) associated metabolic complications

The introduction of highly active antiretroviral therapy (HAART) has led to a dramatic decrease in viral load and HIV-associated morbidity and mortality, thereby increasing life expectancy among HIV-infected patients. However, long term usage of HAART is linked with metabolic disorders such as lipodystrophy, dyslipidemia, insulin resistance and type II diabetes, thereby increasing the risk of cardiovascular disease (CVD) as well as fetal toxicity due to intrauterine exposure in fetus of HIV-infected mothers on HAART. HAART generally includes a combination of protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). Mechanistic studies indicate that PI-associated deregulation of glucose and lipid metabolism may be involved in dyalipidemia and hyperlipidemia, as well as central fat accumulation among HIV-infected patients on HAART, while NRTI-associated mitochondrial toxicity is involved in insulin resistance, diabetes, peripheral lipoatrophy and lactic acidosis in children born to HIV-infected mothers n HAART. The objective of our research was to understand the effects of combination of PI and NRTI on cellular and molecular mechanism involved in: (1) adipocyte differentiation and lipolysis in 3T3-L1 mouse and primary human adipocytes, (2) reverse cholesterol transport in human hepatoma cell line (HepG2) and C57BL/6 mice and (3) adult onset of diseases among offspring with in uteo exposure to HAART. Our data indicates that combination of PI such as ritonavir (RTV), lopinavir (LPV) and NRTI (combivir, CBV), either singly or in combination significantly increased adipocyte differentiation in mouse and human primary adipocytes with a concomitant increase in adipocyte transcription factor regulated genes such as resistin and perilipin. Further studies demonstrate - that CBV and LPV, either single and/or combination increase plasma glucose, lipid and hepatic lipid in C57BL/6 mice. In our studies, regulation of cholesterol metabolism by LPV and CBV were related to differential regulation the nuclear receptors such liver X receptor (LXR), farnesoid X receptor (FXR) in liver and intestine. Administration of CBV and LPV to pregnant mice resulted in increased oxidative stress in offspring up to 9 months of life. In addition, offspring exposed to intrauterine HAART demonstrated impaired glucose tolerance as compared to offspring from control mice. Overall, our data may provide a better understanding of the cellular and molecular mechanisms involved in the pathophysiological processes of HAART-associated toxicities and can help to identify new therapeutic molecular targets to treat these metabolic complications.