Neural adaptations following exposure to HIV proteins

Abstract

HIV associated neurocognitive disorders (HAND) affect nearly half of the population infected with HIV. Symptoms range from subclinical cognitive deficits to severe dementia which can affect daily living. The neurotoxicity produced is likely indirect as the virus does not infect neurons but infects other cells in the brain such as microglia and astrocytes which can release viral proteins and inflammatory cytokines that then affect neurons and lead to synaptodendritic damage. Thus, understanding how these toxic viral factors affect neurons and the mechanisms underlying these changes will aid in the discovery of therapies for HAND. In this dissertation, I report viral proteins altering two types of receptors involved in regulating neuronal excitability and synaptic transmission, the excitatory NMDA receptor (NMDAR) and the inhibitory GABAAR. NMDARs initially become overactivated but then downregulate in hippocampal cultures exposed to the HIV protein transactivator of transcription (Tat). This downregulation was mediated by GluN2A-containing NMDARs signaling to the kinase Akt and the E3 ubiquitin ligase, Mdm2. This novel mechanism delineates a signaling pathway activated by viral proteins that regulates NMDAR-dependent loss of excitatory synapses. Second, I determined how the viral protein gp120 affects GABAergic inhibition. In hippocampal cultures, gp120 caused an increase in tonic GABAAR currents mediated by extrasynaptic GABAARs and an increase in the number of inhibitory synapses. Both increases in inhibition were dependent on microglial activation and release of interleukin-1β which activated interleukin-1 receptors. The increase in inhibitory synapses was dependent on IL-1R-mediated Src activation and subsequent potentiation of GluN2A-containing NMDARs and protein synthesis. On the other hand, the increase in tonic inhibition was dependent on IL-1R-mediated p38 MAPK activation and selective upregulation of α5-containing GABARs. The increases in inhibition likely dampen neuronal excitability and network function and may contribute to the cognitive deficits in HAND. These studies elucidate changes in two types of receptors affected by viral proteins and identify novel signaling pathways that may lead to therapeutic targets for HAND.