IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats.

Wenwen Zheng,Shue Liu,Wan Huang,David A Lubarsky,Keith A Candiotti,Roy C Levitt,Shuanglin Hao

doi:10.1186/1744-8069-10-49

Abstract

BackgroundHIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state.ResultsNeuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2′,3′-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks.ConclusionThe blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

Highlights

human immunodeficiency virus-1 (HIV)-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART)
The anti-allodynic effect of interleukin 10 (IL10) mediated by herpes simplex virus (HSV) vectors in the gp120 +ddC model Previous studies have demonstrated that the peripheral gp120 application into the sciatic nerve, systemic ddC, or combination of gp120 and ddC, results in neuropathic pain characterized by mechanical allodynia and upregulates tumor necrosis factor-α (TNFα) [4,28,29,30,31]
Recent studies show that animals inoculated with the HSV vectors expressing IL10 reduces mechanical allodynia induced by the spinal cord injury [27]

Summary

Introduction

HIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). Neuropathic pain (NP) related to human immunodeficiency virus-1 (HIV) infection is severe and unrelenting and represents an important unmet need in medicine [2]. This HIV neuropathy can be associated with viral infection alone, probably involving a role for the envelope glycoprotein gp120 and/or antiretroviral drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors as a component of highly active anti-retroviral therapy (HAART). Our studies and others show that stromal cell-derived factor-1α (SDF1α) and its receptor CXCR4 are involved in the NP induced by gp120 [14] or ddC [15,16,17]

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Conclusion