Figure 1. Mechanisms of neurodegeneration and neuroprotection in AIDS [6].

a) Infected perivascular macrophages and microglia are responsible for producing HIV but might also release viral proteins that can be deleterious to the central nervous system. The HIV-envelope protein gp120 (glycoprotein 120), Tat (transcriptional transactivator) and Vpr (viral protein R) have all been shown to be toxic in vitro to neurons and/or astrocytes, although their relevance in vivo is unknown. Infected and activated cells also produce other factors — such as cytokines (including tumour-necrosis factor, TNF), quinolinic and arachidonic acid, platelet-activating factor (PAF) and nitric oxide-which are known to have neurotoxic effects; b)Importantly, they promote the further activation (and to some extent, proliferation) of macrophages and/or microglia, as well as the proliferation and activation of astrocytes; c) Activated astrocytes modify the permeability of the blood–brain barrier and promote the migration of more monocytes into the brain; d) In addition, through increases in release of intracellular Ca2+ and glutamate and through decreases in glutamate uptake, the brain concentration of glutamate and other neurotoxins increases and results in excitotoxic death of neurons; e) Activation of macrophages and/or microglia, and TNF-mediated activation of astrocytes, also results in the release of beta-chemokines, CX3C-chemokine ligand 1 (CX3CL1) and growth factors, all of which are known to regulate Ca2+ homeostasis in neurons, to promote anti-apoptotic signaling pathways and to decrease gp120-mediated and excitotoxic neuronal cell death, thereby promoting neuronal survival. Grey arrows indicate neuroprotective pathways. (Reproduce with permission from authors- González-Scarano and Martín-García - Nature Reviews Immunology, 2005).