Direct Effects of HIV-1 Tat on Excitability and Survival of Primary Dorsal Root Ganglion Neurons: Possible Contribution to HIV-1-Associated Pain

Abstract

The vast majority of people living with human immunodeficiency virus type 1 (HIV-1) have pain syndrome, which has a significant impact on their quality of life. The underlying causes of HIV-1-associated pain are not likely attributable to direct viral infection of the nervous system due to the lack of evidence of neuronal infection by HIV-1. However, HIV-1 proteins are possibly involved as they have been implicated in neuronal damage and death. The current study assesses the direct effects of HIV-1 Tat, one of potent neurotoxic viral proteins released from HIV-1-infected cells, on the excitability and survival of rat primary dorsal root ganglion (DRG) neurons. We demonstrated that HIV-1 Tat triggered rapid and sustained enhancement of the excitability of small-diameter rat primary DRG neurons, which was accompanied by marked reductions in the rheobase and resting membrane potential (RMP), and an increase in the resistance at threshold (RTh). Such Tat-induced DRG hyperexcitability may be a consequence of the inhibition of cyclin-dependent kinase 5 (Cdk5) activity. Tat rapidly inhibited Cdk5 kinase activity and mRNA production, and roscovitine, a well-known Cdk5 inhibitor, induced a very similar pattern of DRG hyperexcitability. Indeed, pre-application of Tat prevented roscovitine from having additional effects on the RMP and action potentials (APs) of DRGs. However, Tat-mediated actions on the rheobase and RTh were accelerated by roscovitine. These results suggest that Tat-mediated changes in DRG excitability are partly facilitated by Cdk5 inhibition. In addition, Cdk5 is most abundant in DRG neurons and participates in the regulation of pain signaling. We also demonstrated that HIV-1 Tat markedly induced apoptosis of primary DRG neurons after exposure for longer than 48 h. Together, this work indicates that HIV-1 proteins are capable of producing pain signaling through direct actions on excitability and survival of sensory neurons.

Effects of HIV-1 Tat on Enteric Neuropathogenesis

“…To our knowledge, this is the first study that evaluates the effects of Tat on enteric neuronal excitability and the first study to highlight the role of sodium channel expression and kinetics in Tatmediated effects. The direct effects of Tat on neuronal excitability have been previously examined in human fetal brain cells, cultured rat cerebral cortical neurons, and in DRG neurons (Nath et al, 1996;Brailoiu et al, 2008;Chi et al, 2011). In fetal brain cells, Tat induced a depolarization in membrane potentials that were likely due to activation of a nonselective cation channel.…”

“…The increase in sodium current density resulted in significant loss of voltage control. This might be due to enhanced expression of Na v 1.8, which appears to be localized on neuronal projections and thus contributes to the inability to adequately control the voltage (Cummins et al, 2009).…”

HIV-1 Tat protein inhibits neurosecretion by binding to phosphatidylinositol 4,5-bisphosphate

“…Tat also appears to have an impact on dopamine (Ferris et al, 2009), norepinephrine (Longordo et al, 2006), glutamate and GABA release (Musante et al, 2010). Moreover, it was recently shown that Tat application increased dorsal root ganglion neuron excitability (Chi et al, 2011). Although these findings suggest that Tat is able to affect neurotransmission, direct evidence of a Tat effect on the molecular process of exocytosis has been missing.…”

Neuronal Apoptosis in HIV-1-Associated Central Nervous Diseases and Neuropathic Pain

“…Nef expression in these mice also indirectly contributes to HIV-1-associated neuropathy by enhancing protein expression of other HIV-1 genes and altering cellular maturation in vivo 57 . In vitro exposure to HIV-1 proteins including gp160, gp120, gp41, Tat, Nef, Rev, and Vpr has been reported to initiate neuronal damage [58][59][60][61][62] . Dorsal root ganglion (DRG) neurons have central terminals in the spinal cord dorsal horn and peripheral terminals in skin, muscle and other peripheral tissues.…”

“…This increased firing is believed to be critical in the enhanced perception of pain sensation for both inflammatory and neuropathic conditions 64,65 . Our group has recently explored the direct effects of HIV-1 Tat protein on excitability of rat primary DRG neurons 62 . We demonstrated that HIV-1 Tat triggered a rapid and sustained enhancement of the excitability of smalldiameter rat primary DRG neurons, which was accompanied by marked reductions in the rheobase and resting membrane potential (RMP), and an increase in the resistance at threshold (RTh).…”