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

Gene Therapy volume 21, pages 328–336 (2014)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the NIH DA026734 (SH), DA025527 (SH) and NS066792 (SH). WH was supported by Sun Yat-Sen University, China. RCL was supported by NIH DE022903. We greatly acknowledge Dr David Fink and Dr Marina Mata (Department of Neurology, University of Michigan, Ann Arbor, MI, USA) providing the high-quality HSV vectors and the excellent technical assistance of Vikram Thakur.

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  1. W Huang and W Zheng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA

    W Huang, W Zheng, S Liu, R C Levitt, K A Candiotti, D A Lubarsky & S Hao

  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

    W Huang & W Zeng

  3. Hussman Institute of Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA

    R C Levitt

  4. Veterans Affairs Medical Center, Miami, FL, USA

    R C Levitt

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Correspondence to S Hao.

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Huang, W., Zheng, W., Liu, S. et al. HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity. Gene Ther 21, 328–336 (2014). https://doi.org/10.1038/gt.2013.90

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