HIV-induced neurotoxicity: Determinants of developmental and regional neuronal susceptibility and potential neuroprotective strategies

My dissertation examines the neurodegenerative processes that occur during HIV infection of the brain. Infected and activated macrophages, astrocytes, and neurons in the brain contribute to a complex dysregulation of cellular function and, in the case of particular neuronal subtypes, to neuronal damage and death. HIV-1 infection of macrophages in the brain produces macrophage activation and release of excitotoxins that act via neuronal NMDA receptors. Notably, HIV-induced neurodegeneration does not affect all areas of the brain equally. Rather, neuronal death is most prominent in the basal ganglia, striatum, hippocampus, and cerebral cortex. HIV infection also differentially affects neurons in adult and pediatric brains, with pediatric brains presenting greater sensitivity to neuronal damage by HIV. However, the cause of differential neuronal susceptibility during HIV infection remains undefined, and protective strategies designed against HIV-induced neurodegeneration are lacking. In my dissertation, I examine the basis of regional and developmental susceptibility to HIV-induced neurodegeneration. We developed an in vitro model of HIV-induced neurotoxicity that incorporates both a relevant neuronal subtype and an HIV-isolate derived from the cerebrospinal fluid of an HIV patient. With this model, I defined how changes in NMDA receptor subunit expression in hippocampal neurons confer susceptibility to HIV-induced neurotoxicity as neurons mature. I also demonstrate how the particular NMDA receptor profile in hippocampal neurons, which is similar to other areas of the brain that are damaged during HIV infection, predicts vulnerability to HIV. Finally, I present a protective strategy for neurons in the central nervous system based upon activation of pro-survival signaling pathways in susceptible neurons. These findings define multiple targets for preventing HIV-induced neurodegeneration. In addition, I introduce preliminary data about the types of neurotoxins released from HIV-infected macrophages. In our in vitro model, HIV-infected macrophages released neurotoxic factors with features of excitotoxins. We confirm previous reports of glutamate as a major excitotoxin released by HIV-infected macrophages, but surprisingly found inconclusive evidence about the role of the kynurenine metabolic pathway in HIV-infected macrophages, which produces the HIV-associated neurotoxin quinolinic acid. Thus, we define a complete picture of HIV-induced neurotoxicity from the production of neurotoxins in HIV-infected macrophages to the balance of neuronal signaling pathways that determine the course of neuronal survival in HIV infection