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.
Highlights
The human immunodeficiency virus type 1 (HIV-1) pandemic has claimed over 25 million lives with 33.4 million people currently infected (2009 AIDS Epidemic Update by UNAIDS/ WHO, www.unaids.org)
We demonstrated that HIV-1 Tat triggered rapid and sustained enhancement of the excitability of small-diameter rat primary dorsal root ganglion (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)
We demonstrated that Tat directly triggered rapid and sustained enhancement of the excitability of the small-diameter DRG neurons, probably by inhibiting kinase activity and messenger RNA (mRNA) production of cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase that has recently emerged as a key kinase in regulation of pain signaling in sensory neurons [38,39,40]
Summary
The HIV-1 (the causative agent of AIDS) pandemic has claimed over 25 million lives with 33.4 million people currently infected (2009 AIDS Epidemic Update by UNAIDS/ WHO, www.unaids.org). The vast majority (up to 90%) of these individuals living with HIV-1/AIDS have pain syndrome that has a significant impact on their psychological wellbeing and quality of life [1,2,3,4,5,6,7,8,9,10,11,12]. The most common pain syndromes in HIV-1/AIDS patients include painful peripheral neuropathies, headache, oral and pharyngeal pain, abdominal pain, chest pain, arthralgias and myalgias, painful dermatological conditions, and pain caused by HIV-1/AIDS-related malignancies such as Kaposi’s sarcoma [15,16]. Pain is often under-assessed and undertreated in people with HIV-1/AIDS illness, and little progress has been made to address the issues of pain etiologies that are the key for pain management and improvement of the quality of life
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