MDR1 and Related Proteins during HIV PI Exposure

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DESCRIPTION (provided by applicant): Abnormal lipid metabolism and associated metabolic disorders are important complications of HIV infection. The mechanism(s) underlying these alterations may be related to HIV itself and/or treatment with antiretrovirals. The MDR1 gene product P-gp is an important determinant of the disposition, pharmacokinetics and drug interactions of drugs used in the treatment of HIV, its complications, and related conditions such as drug abuse. The HIV protease inhibitors (PIs) interact with P-gp, but the results from diverse experimental paradigms are often conflicting. It is not established how the PIs affect MDR1 over the range of exposure conditions that occur at the various anatomic sites where MDR1 is active. PIs can acutely inhibit the function of MDR1 but can lead to MDR1 over expression with chronic exposure. The individual PIs differ in their ability to have an impact on MDRI. In addition to shaping the kinetic profile of drug substrates, MDR1 is one of a group of ABC transport proteins involved in lipid homeostasis, including the uptake of cholesterol in the intestine. Another ABC transporter, ABCA1, is also important in cholesterol transport, and defects in this gene can result in familial high-density lipoprotein deficiency and Tangier disease. MDR1 and ABCA1 appear to work together under certain circumstances, and knowing how the PIs affect MDR1 and ABCA1 would provide insight into how the PIs could affect transport of cholesterol and other lipids. Additionally, the MDR1 gene promoter region contains a site for NFkB, a ubiquitous transcription factor with roles in many diverse processes, including atherosclerosis and insulin resistance. Limited data indicate ritonavir affects NFkB activation, but little is known about whether there are differential effects from acute and chronic exposure or across the class of PIs. This proposal will explore the relationship between the PIs and MDR1, as well as two other proteins with relationships to MDR1. Cell culture models will examine transporter mRNA, protein and function over a range of physiologically relevant PI concentrations. The response of NFkB in these same cells will be determined. Additionally, cholesterol uptake in the cell culture model will be examined under the same conditions. The findings will be of importance in understanding lipid disorders related to PIs as well as the kinetics of drugs used to treat HIV and related disorders.