Neuroinflammation and Excitotoxicity in Neurobiology of HIV-1 Infection and AIDS: Targets for Neuroprotection

Abstract

Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) pose a persistent health problem worldwide. Infected peripheral immune-competent cells, in particular macrophages, appear to infiltrate the central nervous system (CNS) and provoke a neuropathological and inflammatory response involving all cell types in the brain. In fact, HIV-1 seems to enter the brain very soon after infection and can subsequently induce severe and debilitating neurological problems that range from mild behavioral abnormalities and motor dysfunction to frank dementia. The course of HIV-1 disease is strongly influenced by viral and host factors, such as the viral strain and the response of the host’s immune system. In addition, HIV-1-dependent disease processes in the periphery, such as inflammation, have a substantial effect on the pathological changes in the CNS, despite the fact that the brain seems to harbor a distinctive viral population of its own. In the CNS, HIV-1 incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes, and glutamate receptor-mediated excitotoxicity, all of which can initiate numerous downstream signaling pathways and perturb neuronal and glial function. Despite many major improvements in the control of viral infection in the periphery, an effective therapy for HIV-1 associated dementia remains to be developed. This chapter will address recently uncovered pathologic and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and discuss experimental and potential future therapeutic approaches.