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

Abstract

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.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice

“…1). Previous studies indicated that ddC administration also induce pain in young adult rats (Zheng et al, 2014; Iida et al, 2016). These results collectively indicate that pathogenesis of pain is a general side effect of the NRTI components in HAART.…”

“…2). Recent studies revealed NRTI-induced neuroinflammation in the spinal cord of young adult rodents (Zheng et al, 2014; Wu et al, 2017). It is likely that neuroinflammation is a common pathogenic consequence in the pain neural pathway in different ages of animals.…”

Ameliorative potential of ferulic acid in vincristine-induced painful neuropathy in rats: An evidence of behavioral and biochemical examination

“…45,46 Moreover, the IL-10 expression through herpes simplex virus vectors also reversed the up-regulation of p-p38, TNF-alpha, stromal cell-derived factor 1-alpha (SDF1-alpha), and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the dorsal root ganglion (DRG) at second and/or fourth weeks of the therapy. 47 It recommended the anti-inflammatory role of IL-10. In addition, study of various spinal cord injury models exhibited that IL-10 down regulates pro-inflammatory species, for example, IL-1 beta, IL-2, IL-6, TNF-alpha, interferon-gamma, matrix metalloproteinase-9, NO synthase, MPO, and 48 On the other hand, various pro-apoptotic factors such as cytochrome-c, caspase-3, and Bax were down-regulated by IL-10, while anti-apoptotic factors B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X, B-cell lymphoma-extra large (Bcl-xl) were amplified by IL-10.…”

Regular physical activity prevents chronic pain by altering resident muscle macrophage phenotype and increasing interleukin-10 in mice

“…In fact, IL-10 reduces inflammatory cytokines in the spinal cord after intrathecal IL-10 injection, and in inflamed skin after systemic IL-10 injection. Similarly, over-expression of IL-10 peripherally (HSV viral vector expressing IL-10) [73;74] reduces HIV-induced hyperalgesia and inflammatory cytokines in the spinal cord, and formalin-induced nociceptive behaviors [75]. Studies in IL-10−/− mice are mixed.…”