title: IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats.
abstract: BACKGROUND
  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). 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.
  
  
  RESULTS
  Neuropathic 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.
  
  
  CONCLUSIONS
  The 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.
authors: Wenwen
authors: W
authors: Zheng
authors: Wan
authors: W
authors: Huang
authors: Shue
authors: S
authors: Liu
authors: Roy C
authors: RC
authors: Levitt
authors: Keith A
authors: KA
authors: Candiotti
authors: David A
authors: DA
authors: Lubarsky
authors: Department of Anesthesiology, University of Miami Miller School of Medicine, 1550 NW 10th Ave, Fox BLDG, Rm 304C, Miami, FL 33136, USA. shao@med.miami.edu.
authors: Shuanglin
authors: S
authors: Hao
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D005822:Genetic Vectors / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000473:pathology / Q000628:therapy*; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016047:Zalcitabine / Q000633:toxicity*
chemical_list: D000998:Antiviral Agents; D054377:Chemokine CXCL12; D015699:HIV Envelope Protein gp120; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016047:Zalcitabine