Pathways to neuronal injury and apoptosis in HIV-associated dementia

Abstract

Human immunodeficiency virus-1 (HIV-1) can induce dementia with alarming occurrence worldwide. The mechanism remains poorly understood, but discovery in brain of HIV-1-binding sites (chemokine receptors) provides new insights. HIV-1 infects macrophages and microglia, but not neurons, although neurons are injured and die by apoptosis. The predominant pathway to neuronal injury is indirect through release of macrophage, microglial and astrocyte toxins, although direct injury by viral proteins might also contribute. These toxins overstimulate neurons, resulting in the formation of free radicals and excitotoxicity, similar to other neurodegenerative diseases. Recent advances in understanding the signalling pathways mediating these events offer hope for therapeutic intervention.

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

“…Chemokines mediate multiple inflammatory disorders in the CNS, including multiple sclerosis (Mahad and Ransohoff, 2003) and HIVE (Nath, 1999;Kaul et al, 2001). CC chemokine ligand 2 [CCL2, also known as monocyte chemoattractant protein-1 (MCP-1)], in particular, is a cofactor in HIV-1 pathogenesis and appears to initiate and sustain the neuroinflammatory process.…”

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

“…13,14 In any case, HIV-1/gp120 mediates infection or activation of macrophages and microglia. [1][2][3]7,15 This leads to toxin production by these monocytic cells, which seems essential for a pronounced neurodegenerative effect. 7,11,[16][17][18] Indeed, we and others have observed earlier that gp120 neurotoxicity was virtually absent if microglia were either removed from mixed cerebrocortical cultures or inactivated.…”

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

“…Transient exposure of otherwise healthy cells to viral particles can be sufficient to trigger cascades resulting in production of inflammatory factors that ultimately lead to neuronal damage (39). Various viral proteins such as gp120, Tat, Nef, Vpr, and gp41 induce neuronal injury as has been well-established in various culture systems and animal models, but to what extent and in what conditions the viral proteins induce toxicity in vivo is still unclear (40). Viral particles, however, are not the only mediators of CNS dysfunction and neuron toxicity.…”

“…This influx disrupts cell homeostasis via hypertonic-induced swelling, ATP depletion and ultimately membrane failure and necrotic cell death. The delayed mechanism is independent of cell swelling, and involves Ca 2+ influx that triggers multiple neurotoxic cascades including p38 and JNK MAP kinase activation, release of cytochrome c, caspase activation, lipid peroxidation, and chromatin condensation (40,(100)(101)(102). The massive influx of Ca 2+ triggers release of Ca 2+ from intracellular stores, further flooding the intracellular space with free Ca 2+ (Fig.…”

“…There is general agreement that HIV does not infect neurons (5,7), and while there is evidence for direct effects of viral proteins upon neuron viability, the indirect form of neurotoxicity seems to predominate (40,121,122). Supernatants from HIV-1 infected MP induce NMDA receptor dependent neurotoxicity (20,55).…”