Dissertation Defense: Lorenzo Bozzelli
Candidate Name: Lorenzo Bozzelli
Advisor: Katherine E. Conant, M.D.
Title: HIV-induced Matrix Metalloproteinases Alter Glial and Neuronal Function
Approximately 37 million individuals are currently infected with human immunodeficiency virus (HIV). The advent of combination antiretroviral therapy (cART) has revolutionized the treatment of HIV by dramatically increasing life-expectancy. Despite these life-saving drugs, however, up to 50% of those infected will go on to experience HIV-associated neurocognitive disorders (HAND). Although the underlying mechanisms of HAND are largely unknown, previous work has identified a class of enzymes called matrix metalloproteinases (MMPs) as correlates of cognitive impairment in HIV. I therefore sought to examine HIV-induced MMPs alterations in both glial and neuronal function.
In terms of glial function, I found that the HIV soluble protein Tat, which is released by infected cells, increased astrocytic expression of a unique subset of MMPs that target a non-matrix substrate called protease-activated receptor 1 (PAR-1). Activation of PAR-1 was found to be involved in the release of a potent chemokine, CCL2, and this effect was significantly attenuated by both genetic knock-out and pharmacological blockade of PAR-1.
Furthermore, I explored the role of MMPs in terms of neuronal activity by examining the MMP substrate called perineuronal net (PNN). The PNN is a lattice-like structure that is particularly enriched surrounding parvalbumin-positive (PV+) inhibitory interneurons. PNNs modulate neuronal excitability of PV+ neurons, which are critical in the generation of gamma oscillations—a form of activity important in cognitive processes that are affected in HAND.
Cortical gamma oscillations are altered in HIV+ patients; however, the underlying mechanisms remain unknown. Post-mortem human brain tissue revealed that HIV infection increased MMP expression and proteolysis of PNN proteins. Using ex vivo acute mouse brain slices, local field potential recordings revealed that removal of PNNs increased gamma oscillations. These data demonstrate that elevated MMPs are correlated with PNN proteolysis, and that removal of PNNs is causal to altered gamma oscillations.
Together, this work has identified both glial and neuronal disruptions that result from HIV-induced MMP activity. Therefore, MMPs and their substrates may be indicated as potential new therapeutic targets in the treatment of HAND.
Friday, June 14 at 12:00pm to 2:00pm
Medical and Dental Building, NE 401
3900 Reservoir Road, N.W., Washington