Fellowship Robert N Helsley: A novel mechanism for ARV-drug associated dyslipidemia

As the average lifespan of HIV-infected patients on effective antiretroviral therapy (ART) lengthens, morbidity and mortality from cardiovascular disease (CVD) continue to increase. The use of antiretroviral (ARV) drugs, such as HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), has been associated with dyslipidemia and increased risk of CVD but the underlying mechanisms remain elusive (1-11). We and others have identified several PIs, including amprenavir and ritonavir, as potent agonists for the pregnane X receptor (PXR, also known as the steroid and xenobiotic receptor, or SXR) (12, 13), a nuclear receptor that can be activated by numerous drugs, as well as xenobiotic and dietary chemicals (14, 15). Our lab recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type (WT) mice and increases atherosclerosis in apolipoprotein E deficient (ApoE-/-) mice (16, 17). Our most recent study demonstrated that the HIV PI amprenavir activates PXR and induces hyperlipidemia in WT but not PXR-deficient (PXR-/-) mice (13). Our central hypothesis is that chronic activation of PXR by currently used ARV drugs lead to aberrant lipid homeostasis and hyperlipidemia, thereby increasing the risk of CVD in patients receiving anti-retroviral therapy. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on plasma lipid levels in vivo and 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induces hyperlipidemia. This research will establish the role of PXR in linking ART with hyperlipidemia and CVD, and will provide novel mechanistic links explaining how ARV drugs promote atherogenesis. Keywords: HIV, antiretroviral, hyperlipidemia, atherosclerosis