Grant: Operating Grant

In the brain, Human Immunodeficiency Virus (HIV) infects primarily the immune cells called microglia, and to a lesser extent, the supporting cells called astrocytes. It is well established that antiretroviral drugs are not as effective in the treatment of HIV-1 infection of the brain and equally well established that the brain concentrations of antiretroviral drugs are much less than those seen in other organ tissues. The brain is unique in that it is separated from the rest of the body by a number of barriers that prevent drugs from entering this organ. We believe that the lower brain concentrations of anti-HIV drugs are not only due to the effect of the physical brain barriers, but also due to membrane proteins (i.e., P-glycoprotein, Multidrug Resistance Proteins and Breast Cancer Resistance Protein) that can efficiently extrude these compounds out of the brain into the peripheral circulation as well as metabolic enzymes. We also propose that common regulatory mechanisms, such as the presence of specific cell receptors called , Pregnance X receptor (PXR) in rats and steroid and xenobiotic receptor, SXR in humans, control the production of these transporters and metabolic enzymes in the brain. Using various cell culture systems of the brain barrier and brain tissue isolated from both human and rat brain as well as in animal models, we propose to investigate the role that these receptors, membrane transporters and metabolic enzymes play in the accumulation and distribution of anti-HIV drugs. If these transporters and metabolic enzymes are significantly active, then blocking their activity will result in higher drug concentrations and improved efficacy in the brain. This information is novel and clinically important since identifying mechanisms by which antiretroviral drugs accumulate or fail to accumulate in the brain can provide therapeutic strategies that will optimize delivery of these drugs in the treatment of the neurological consequences of HIV.