HIV-1gp120 Induces Neuronal Apoptosis through Enhancement of 4-Aminopyridine-Senstive Outward K+ Currents

Abstract

Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) usually occurs late in the course of HIV-1 infection and the mechanisms underlying HAD pathogenesis are not well understood. Accumulating evidence indicates that neuronal voltage-gated potassium (Kv) channels play an important role in memory processes and acquired neuronal channelopathies in HAD. To examine whether Kv channels are involved in HIV-1-associated neuronal injury, we studied the effects of HIV-1 glycoprotein 120 (gp120) on outward K+ currents in rat cortical neuronal cultures using whole-cell patch techniques. Exposure of cortical neurons to gp120 produced a dose-dependent enhancement of A-type transient outward K+ currents (IA). The gp120-induced increase of IA was attenuated by T140, a specific antagonist for chemokine receptor CXCR4, suggesting gp120 enhancement of neuronal IA via CXCR4. Pretreatment of neuronal cultures with a protein kinase C (PKC) inhibitor, GF109203X, inhibited the gp120-induced increase of IA. Biological significance of gp120 enhancement of IA was demonstrated by experimental results showing that gp120-induced neuronal apoptosis, as detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspase-3 staining, was attenuated by either an IA blocker 4-aminopyridine or a specific CXCR4 antagonist T140. Taken together, these results suggest that gp120 may induce caspase-3 dependent neuronal apoptosis by enhancing IA via CXCR4-PKC signaling.

Oxidative Stress during HIV Infection: Mechanisms and Consequences

“…Gp120 and Vpr induce TNF- α , IL-6, IL-8, and MCP-1 in the ROS-dependent fashion (Figure 2) [80, 87, 167, 168]. In addition, Gp120 stimulates A-type transient outward K + currents that contribute to the cell death [169]. Notably, this effect is also ROS-dependent [80].…”

P2X₇ receptor in the hippocampus is involved in gp120-induced cognitive dysfunction

“…HIV infection can lead to ADC/HAD, a serious complication of the nervous system (Chen et al, 2011;Yilmaz et al, 2012;Thomas et al, 2013). HAD contributes to functional deficits such as learning and memory decline, cognitive and reasoning dysfunction, inattention, impaired motor skills, and abulia, among others (Singer et al, 2010;Rosca et al, 2012;Peluso and Spudich 2014).…”

Viruses, apoptosis, and neuroinflammation—a double-edged sword

“…However, in the context of this discussion, it should be appreciated that there is in vitro evidence for HIVinduced neuronal apoptosis. For example, HIV-1 gp120 induces neuronal apoptosis in rat cortical neuronal cultures (Chen et al 2011;Guo et al 2013) and HIV-1 Tat markedly induced apoptosis of primary DRG neurons after exposures longer than 48 h (Chi et al 2011). It is evident from the above examples that the mechanisms of virally induced damage to the CNS caused by apoptosis are different in rabies, HIV, and other viral infections.…”