title: Interleukin 10 mediated by herpes simplex virus vectors suppresses neuropathic pain induced by human immunodeficiency virus gp120 in rats.
abstract: BACKGROUND
  Human immunodeficiency virus (HIV)-associated sensory neuropathy is a common neurological complication of HIV infection affecting up to 30% of HIV-positive individuals. However, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments for HIV-related neuropathic pain (NP). In this study, we tested the hypothesis that inhibition of proinflammatory factors with overexpression of interleukin (IL)-10 reduces HIV-related NP in a rat model.
  
  
  METHODS
  NP was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. The hindpaws of rats were inoculated with nonreplicating herpes simplex virus (HSV) vectors expressing anti-inflammatory cytokine IL-10 or control vector. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The mechanical threshold response was assessed over time using the area under curves. The expression of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 in both the lumbar spinal cord and the L4/5 dorsal root ganglia (DRG), was examined at 14 and 28 days after vector inoculation using Western blots.
  
  
  RESULTS
  We found that in the gp120-induced NP model, IL-10 overexpression mediated by the HSV vector resulted in a significant elevation of the mechanical threshold that was apparent on day 3 after vector inoculation compared with the control vector (P < 0.001). The antiallodynic effect of the single HSV vector inoculation expressing IL-10 lasted >28 days. The area under curve in the HSV vector expressing IL-10 was increased compared with that in the control vector (P < 0.0001). HSV vectors expressing IL-10 reversed the upregulation of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 expression at 14 and/or 28 days in the DRG and/or the spinal dorsal horn.
  
  
  CONCLUSIONS
  Our studies demonstrate that blocking the signaling of these proinflammatory molecules in the DRG and/or the spinal cord using the HSV vector expressing IL-10 is able to reduce HIV-related NP. These results provide new insights on the potential mechanisms of HIV-associated NP and a proof of concept for treating painful HIV sensory neuropathy with this type of gene therapy.
authors.affiliation: From the Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida; Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; Hussman Institute of Human Genomics, University of Miami Miller School of Medicine; and Veterans Affairs Medical Center, Miami, Florida.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zheng
authors.forename: Wan
authors.initials: W
authors.lastname: Huang
authors.forename: Shue
authors.initials: S
authors.lastname: Liu
authors.forename: Roy C
authors.initials: RC
authors.lastname: Levitt
authors.forename: Keith A
authors.initials: KA
authors.lastname: Candiotti
authors.forename: David A
authors.initials: DA
authors.lastname: Lubarsky
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Hao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005727:Ganglia, Spinal / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015699:HIV Envelope Protein gp120; D006801:Humans; D006930:Hyperalgesia / Q000517:prevention & control; D016753:Interleukin-10 / Q000235:genetics* / Q000502:physiology*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000517:prevention & control*; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics; D012584:Sciatic Nerve / Q000502:physiology; D018139:Simplexvirus / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases