HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

Huang, Wenlong; Zheng, Wenwen; Liu, S.; Zeng, Weian; Levitt, Roy C.; Candiotti, Keith A.; Lubarsky, David A.; Hao, Shuanglin

doi:10.1038/gt.2013.90

Cited by 24 publications

(31 citation statements)

References 74 publications

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“…The latter has been strongly implied from prior studies using similar pain-relieving vectors, in which blockade of the effects of enkephalin were obtained following intrathecal administration of antagonists. 32,39–42 We conclude from this data that it is unlikely that VZV-induced pain and its relief induced by vHPPE vector were a consequence of effects mediated at the periphery.…”

Section: Resultsmentioning

confidence: 76%

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

et al. 2014

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Acute and chronic pain (post-herpetic neuralgia or PHN) are encountered in patients with herpes zoster that is caused by reactivation of varicella-zoster virus (VZV) from a state of neuronal latency. PHN is often refractory to current treatments, and additional strategies for pain relief are needed. Here we exploited a rat footpad model of PHN to show that herpes simplex virus (HSV) vector-mediated gene delivery of human preproenkephalin (vHPPE) effectively reduced chronic VZV-induced nocifensive indicators of pain. VZV inoculated at the footpad induced prolonged mechanical allodynia and thermal hyperalgesia that did not develop in controls or with ultraviolet light-inactivated VZV. Subsequent footpad administration of vHPPE relieved VZV-induced pain behaviors in a dose-dependent manner for extended periods, and prophylactic vector administration prevented VZV-induced pain from developing. Short-term pain relief following low-dose vHPPE administration could be effectively prolonged by vector re-administration. HPPE transcripts were increased three- to fivefold in ipsilateral ganglia, but not in the contralateral dorsal root ganglia. VZV hypersensitivity and its relief by vHPPE were not affected by peripheral delivery of opioid receptor agonist or antagonist, suggesting that the efficacy was mediated at the ganglion and/or spinal cord level. These results support further development of ganglionic expression of enkephalin as a novel treatment for the pain associated with Zoster.

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Section: Resultsmentioning

confidence: 76%

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

et al. 2014

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“…Evidence shows that HIV gp120 or ddC mediated-neuropathic pain increases TNFα in the spinal cord and the DRG [4,14,30]. In the current study, we examined whether overexpression of IL10 mediated by the HSV vectors reduced TNFα in neuropathic pain induced by gp120 + ddC.…”

Section: Resultsmentioning

confidence: 98%

“…Furthermore, CXCR4 is required for gp120-induced cell death [13]. Importantly, 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 [15-17]. …”

Section: Introductionmentioning

confidence: 81%

“…Furthermore, intrathecal TNFα siRNA or TNF soluble receptor (TNFSR) reduces the gp120 application-induced mechanical allodynia, indicating that TNFα in the spinal cord and/or the DRG are involved in neuropathic pain induced by HIV gp120 [4]. TNF soluble receptor mediated by the HSV vectors suppresses gp120-induced neuropathic pain and reduces TNFα [14]. Taken together, these data highlight the importance of TNFα in the development of the exaggerated pain state related to HIV gp120.…”

Section: Discussionmentioning

confidence: 99%

“…HIV gp120 may bind to and activate CXCR4 expressed in the DRG neurons in a CD-4-independent manner [47,48], suggesting the direct neurotoxic effects of gp120 on the neurons [49]. Our recent studies have shown that HIV gp120 induces the upregulation of SDF1 and CXCR4 in the spinal cord and the DRG [14]. White and colleagues reported that systemic ddC induces the expression of CXCR4 mRNA in glia and neurons, and SDF1 mRNA in glia [15].…”

Section: Discussionmentioning

confidence: 99%

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IL-10 Mediated by Herpes Simplex Virus Vector Reduces Neuropathic Pain Induced by HIV gp120 Combined with ddC in Rats

Zheng

Huang

et al. 2014

Mol Pain

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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.

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Translating Gene Therapy for Pain from Animal Studies to the Clinic

Wolfe

Krisky

Goss

et al. 2016

Translational Neuroscience

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HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

Cited by 24 publications

References 74 publications

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

IL-10 Mediated by Herpes Simplex Virus Vector Reduces Neuropathic Pain Induced by HIV gp120 Combined with ddC in Rats

Translating Gene Therapy for Pain from Animal Studies to the Clinic

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