Grant: Operating Grant

In the era of combination antiretroviral therapy, up to 50% of infected patients can develop HIV-associated neurocognitive disorders which highly impair their quality of life. 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 the periphery and other organs. 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 and Breast Cancer Resistance Protein) that can efficiently extrude these compounds out of the brain into the peripheral circulation. We also propose that common regulatory mechanisms, such as the presence of specific cell receptors, control the production of these transporters in the brain. Using various cell culture systems of the brain barrier and brain tissue isolated from both human (healthy and HIV-1 infected) and rat brain as well as animal models, we plan to investigate the role that these receptors and membrane transporters play in the brain distribution of anti-HIV drugs. If these transporters 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 HIV neurological complications.