HIV-Associated Neurocognitive Disorders (HAND) continue to affect more than 50% of persons living with HIV, despite the widespread use of effective antiviral drugs. This suggests that chronic, virally-initiated, neuroinflammation may persist over time – leading to neuronal disfunction and damage. In collaboration with Handy Gelbard, we are working to develop new therapies for HAND, by targeting mixed lineage kinase (MLK)-3, an upstream kinase involved in the regulation of neuroinflammation and cell fate. Current studies focus on how novel, drug-like, small molecule inhibitors of MLK-3 regulate the inflammatory activation of macrophages by HIV-1; the long-term goal is to progress our lead inhibitor (URMC-099) into a first-in-human trial for the treatment of HAND.
A new collaborative project with the Gelbard lab and the Gendelman lab (University of Nebraska) seeks to understand the molecular basis for an unexpected and serendipitous finding: that the efficacy of nanoformulated antiretroviral drugs may be potentiated by our novel MLK-3 inhibitor, URMC-099. This has the potential to greatly improve clearance of virus reservoirs within the CNS.
Finally, we are also investigating the role of vascular dysfunction in the development of HAND. We recently found that exposure of the central nervous system to the HIV-1 protein Tat leads to rarefaction of cerebral capillaries, which may partially explain the prominence of cognitive defects in an aging HIV-positive population. Further studies of HIV-induced cerebrovascular dysfunction and its association with aging are important as the number of individuals living with HAND is on the rise.