Astrocyte Dysfunctions and HIV-1 Neurotoxicity

Abstract

Astrocytes play an important role in maintaining an optically suited milieu for neuronal functionality, and are involved in the progression and outcome of many neuropathological conditions. It becomes increasingly evident that astrocytes are significant contributors to HIV-1 associated neurological disorders by modulating the microenvironment in the central nervous system and releasing proinflammatory cytokines. Recent studies have revealed direct metabolic interactions between neurons and astrocytes observed particularly in HIV-1-associated neurological disorders by which astrocytic dysfunctions disregulate extracellular K+ homeostasis, intracellular calcium concentration, glutamate clearance, and blood brain barrier integrity and permeability. Such dysfunctions are amplified via gap junctions, directly or indirectly impacting surrounding neurons and significantly contributing to the pathogenesis of HIV-1-associated neuropathology. In this review, we tentatively address recent progresses on the roles astrocytes may play in HIV-1-associated neurotoxicity.

Keywords: Astrocytes; Blood brain barrier; Gap junctions; Glutamate uptake; HIV-1 associated neurotoxicity; K+ channels.

Figure 1

Schematic representation of astrocytic dysfunctions in HIV-1 neurotoxicity. (1) Astrocytes respond to HIV infection and viral proteins by rapid activation. (2) This response spreads and amplifies to surrounding astrocytes via gap junctions, which take part in modulating ATP release and glutamate and potassium homeostasis. (3) Reduced Kir4.1 expression and function impairs the ability of activated astrocytes to remove K⁺ in extracellular space and cause an increase in [K⁺]₀, which would induce the depolarization of neuronal membranes and the interruption of axonal conduction and synaptic transmission. (4) Down regulation of glutamate expression and function results in glutamate excitotoxicity, which eventually may lead to neuronal injury and death. (5) This detrimental process is induced by overactivation of glutamate receptors located in neuronal membranes and causes an increase in intracellular Ca²⁺ levels, resulting in further injury. (6) Elevation of intracellular Ca²⁺ in astrocytes can also lead to increase in neuronal Ca²⁺, which may trigger excessive glutamate receptor activation and consequent excitotoxicity. (7) In addition, HIV-1 induced activated astrocytes secrete proimflammatory cytokines and chemokines, which may cause neuronal dysfunction or injury. (8) Reduced glutamate uptake, impaired potassium channel activity and elevated intracellular Ca²⁺ affect the BBB integrity and permeability resulting in increased penetration of HIV into the CNS. These alterations are likely acting synergistically to contribute to the accumulation of neurotoxicity and potentially play a role in HIV-1 induced neuropathogenesis.