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-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 antiinflammatory 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 (AUC). The expression of phosphorylated p38 mitogen-activated kinase, as tumor necrosis factor alpha, stromal cell-derived factor-1α (SDF-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<0.0001). The antiallodynic effect of the single HSV vector inoculation expressing IL-10 lasted more than 28 days. The AUC 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, as tumor necrosis factor alpha, stromal cell-derived factor-1α (SDF-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.

Anti-allodynic effect of interleukin 10 in a mouse model of complex regional pain syndrome through reduction of NK1 receptor expression of microglia in the spinal cord

“… 20 By inhibiting the release of the pro-inflammatory cytokines TNF-α and IL-1β by activated microglia, it has already been reported that IL-10 possesses anti-allodynic or anti-hyperalgesic effects. 11 , 12 , 14 The anti-allodynic effect of IL-10 is consistent with the results of our study, which showed a decrease in microglial activation (decrease of microglial marker, Iba 1) in immunohistochemistry and a significant decrease in mRNA expression of TNF-α and IL-1β in the spinal cord of the IL-10-injected group. In addition, the results of this study also showed that mRNA expression of TACR1 (neurokinin 1 receptor [NK1R]) was significantly decreased in the spinal cord of the IL-10-injected group, unlike substance P, which did not show a significant difference from the BSA-injected group in the IL-10-injected group.…”

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.…”

CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain

“…These results are the first to report the involvement of CXCL12/CXCR4 axis in DRG processing of NRTIinduced neuropathy. Perineural administration of gp120 caused sciatic nerve injury and persistent pain in rat hind paw (Zheng et al, 2014). Herpes simplex virus vectors expressing anti-inflammatory cytokine, interleukin 10 (IL-10), was constructed and injected into ipsilateral hind paw of gp120-treated rats, which reversed the established mechanical allodynia.…”