HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity.
Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite extensive research, the detailed neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. In this study, we investigated the role of proinflammatory molecules, tumor necrosis factor-α (TNFα), CXCR4 and stromal-derived factor-1 α (SDF1α), in the L4/5 dorsal root ganglia (DRG) and the spinal dorsal horn in HIV gp120 protein-mediated neuropathic pain. Our results showed that the application of HIV gp120 to the sciatic nerve induced upregulation of TNFα, CXCR4 and SDF1α in both the DRG and the lumbar spinal dorsal horn. Non-replicating herpes simplex virus (HSV) vector encoding the p55TNFSR gene and producing a TNF-soluble receptor (TNFSR) to block bioactivity of TNFα reversed mechanical allodynia. Intrathecal AMD3100 (CXCR4 antagonist) increased mechanical threshold. The HSV vectors expressing p55TNFSR reversed upregulation of TNFα, CXCR4 and SDF1α induced by gp120 in the DRG and the spinal dorsal horn. These studies suggest that proinflammatory TNFα to the CXCR4/SDF1 pathway has an important role in the HIV-related neuropathic pain state and that blocking the proinflammatory cytokines or chemokines is able to reduce neuropathic pain. This work provides a novel gene therapy proof-of-concept for HIV-associated neuropathic pain.
1] Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA [2] Department of Anesthesiology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Huang
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
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Zheng
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
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Liu
Department of Anesthesiology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Zeng
1] Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA [2] Hussman Institute of Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA [3] Veterans Affairs Medical Center, Miami, FL, USA.
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Levitt
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
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Candiotti
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
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Lubarsky
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
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Hao
D000818:Animals; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D000080027:Cyclams; D005727:Ganglia, Spinal / Q000378:metabolism; D015316:Genetic Therapy; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics / Q000378:metabolism; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D015699:HIV Envelope Protein gp120; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; C088327:plerixafor