Use of Natural Antioxidants to Overcome Efflux Systems of Brain Endothelial Cells and Improve HAART Efficacy in the CNS

CNS complications of HIV infection remain a serious health risk in HIV! AIDS despite significant advances in highly active antiretroviral therapy (HAART). Specific drugs used for HAART are substrates for the efflux transport systems, such as P-glycoprotein (P-gp) and the multidrug resistance-associated proteins (MRPs), which are present on brain endothelial cells. Thus, drugs employed in HAART are actively removed from the CNS by P-gp and MRPs and cannot efficiently inhibit HIV replication in the brain. In addition, our preliminary data provide the first evidence that specific HIV proteins, such as Tat protein, can induce overexpression of transport efflux systems in brain endothelial cells. This may result in further impairment ofHAART efficacy in the CNS. Among antiinflammatory natural products, it was demonstrated that curcumin has anti-HIV activity and diosgenin can prevent Tat-induced toxicity. In addition, our data indicate that these natural products can protect against Tat-induced overexpression of efflux transport systems of brain endothelial cells. Therefore, we hypothesize that specific natural products can improve the efficacy of HAART by preventing overexpression of P_gp and/or MRPs in response to exposure to HIV proteins. Inclusion of natural products, such as curcumin and/or diosgenin in HIV treatment can be cost effective and provide significant therapeutic benefits. Data arising from this proposal will be critical for a better understanding of the development of drug resistance in HIV! AIDS, The long term goals oftrus proposal are to determine complementary therapeutic approaches in HIV/AIDS.