Grant: Project Grant

Over 37 million people are infected by HIV-1 worldwide and up to 50% of these patients can develop HIV-associated neurocognitive disorders that highly impair their quality of life. It is well established that antiretroviral drugs are not as effective in the treatment of HIV-1 brain infection and equally well established that the brain concentrations of several antiretroviral drugs are much less than those seen in the peripheral blood. Ample evidence suggests that HIV-1 can induce an inflammatory response in brain cellular compartments that in turn can promote neuronal loss and contribute to the development of neurocognitive disorders. Peroxisome Proliferator-Activated Receptors (PPARs) are cellular receptors known to play a major role in fat and sugar metabolism. We have recently demonstrated that once activated by specific compounds, these receptors can reverse HIV-associated inflammation both in isolated brain cells, known to be a target or HIV-1, and in animal models of HIV-brain infection and inflammation. Furthermore, PPAR activation has also been shown to inhibit HIV-1 replication. Using various human and animal cell culture systems of the brain or brain tissues isolated from humans and macaques (healthy or HIV-1 infected or SIV infected) as well as animal models of HIV-1 brain inflammation, we plan to investigate the protective role of these receptors in reversing HIV-associated brain inflammation, once activated by specific novel compounds. This work is clinically important since identifying novel compounds that can effectively permeate into the brain and exhibit anti-inflammatory properties may provide a treatment option in preventing/treating HIV-1 brain inflammation and associated neurocognitive deficits which ultimately will improve the health of HIV-1 infected populations in Canada and worldwide.