UC San Diego

Human immunodeficiency virus (HIV)-1 associated neurocognitive disorders (HAND) are characterized by cognitive impairment, motor dysfunction and progressive neurodegeneration. These neuropathological features are accompanied by infiltration of monocytic cells into the central nervous system (CNS); increases in inflammatory mediators in the cerebral spinal fluid (CSF); and activation of stress-activated signaling cascades such as the p38 Mitogen-Activated Protein Kinase (MAPK) pathway. Several neurotoxic substances have been implicated in the etiology of HAND, including HIV-1 encoded protein Tat and HIV-1 envelope glycoprotein 120 (gp120). Soluble gp120 can activate macrophages and microglia to produce neurotoxins. Therefore, the objectives of this dissertation were : 1) to investigate the cellular mechanisms of neuronal injury in in vitro models of HAND; 2) to examine the role of HIV- 1 gp120 in neurotoxicity within different brain cell populations; and 3) to analyze the activation of stress- activated kinase p38 MAPK and its downstream targets in the mechanisms of HIV-1 gp120-mediated neurotoxicity. To address these aims, in vitro studies using pharmacological compounds, heterologous expression and messenger RNA (mRNA) silencing were performed to inhibit p38 MAPK activity. These studies demonstrated that p38 MAPK signaling within both neurons and monocytic cells is critical for gp120-induced neurotoxicity. Using gene microarray and protein multiplex arrays, several genes were identified that are regulated by p38 MAPK and affect the neurotoxic phenotype of monocytes exposed to gp120. After pharmacological inhibition of p38 MAPK activity, neuroprotective beta chemokines and growth factors were found to be upregulated in addition to proinflammatory cytokines, while the arachidonate metabolism gene LTC4 synthase was down-regulated. These modulations possibly contribute to the reduction in gp120-induced macrophage- mediated neurotoxicity after inhibition of p38 MAPK activity. In fact, blocking the cysteinyl leukotriene receptor on microglia-depleted cerebrocortical cells increased neuronal survival after exposure to neurotoxic THP-1 supernatants. Taken together, the studies presented in this thesis establish that the p38 MAPK signaling cascade plays a vital role in HIV-1 neuropathogenesis by stimulating neuronal apoptosis and by possibly increasing the release of inflammatory mediators, such as cysteinyl leukotrienes, from monocytic cells. Future therapeutic approaches could target these molecular pathways to prevent or rescue neuronal populations from injury in patients with HAND