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IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats.

Zheng W, Huang W, Liu S, Levitt RC, Candiotti KA, Lubarsky DA, Hao S - Mol Pain (2014)

Bottom Line: IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold.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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

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.

Conclusion: 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.

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The anti-allodynic effect of IL-10 mediated by the HSV vectors on neuropathic pain induced by HIV gp120 combined with ddC. (A) Mechanical allodynia in rats was shown 1 week post the gp120 application with ddC. The times of gp120 + ddC and HSV vector inoculation were indicated by arrows. QHIL10 resulted in a statistically significant elevation of the mechanical threshold (g) compared with the control vectors (F(1,12) = 11.996, P < 0.01, repeated measures ANOVA, n = 7). The comparison of differences at individual time points between two groups was shown, *P < 0.05, **P < 0.01 vs. Q0ZHG, two-tailed t test. (B) The AUC in QHIL10 group was significantly higher than that in Q0ZHG, ***P < 0.001, t test, n = 7 rats).
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Figure 1: The anti-allodynic effect of IL-10 mediated by the HSV vectors on neuropathic pain induced by HIV gp120 combined with ddC. (A) Mechanical allodynia in rats was shown 1 week post the gp120 application with ddC. The times of gp120 + ddC and HSV vector inoculation were indicated by arrows. QHIL10 resulted in a statistically significant elevation of the mechanical threshold (g) compared with the control vectors (F(1,12) = 11.996, P < 0.01, repeated measures ANOVA, n = 7). The comparison of differences at individual time points between two groups was shown, *P < 0.05, **P < 0.01 vs. Q0ZHG, two-tailed t test. (B) The AUC in QHIL10 group was significantly higher than that in Q0ZHG, ***P < 0.001, t test, n = 7 rats).

Mentions: Previous studies have demonstrated that the peripheral gp120 application into the sciatic nerve, systemic ddC, or combination of gp120 and ddC (gp120+ddC), results in neuropathic pain characterized by mechanical allodynia and upregulates TNFα [4,28-31]. The principal anti-inflammatory activity of IL-10 is to inhibit the production of proinflammatory cytokines [21]. We have demonstrated that IL-10 mediated by the HSV vectors reversed formalin-induced inflammatory pain [8]. Recent studies show that animals inoculated with the HSV vectors expressing IL10 reduces mechanical allodynia induced by the spinal cord injury [27]. In this study, we further examined whether overexpression of IL-10 mediated by the HSV vectors, reduced neuropathic pain induced by HIV gp120 + ddC. HIV gp120 combined with ddC induced a rapid decrease in mechanical threshold at 1 week. Subcutaneous inoculation with QHIL10 (30 μl containing 1 × 109 plaque-forming units/ml) or control vector Q0ZHG was carried out in the plantar surface of the hind foot of rats with neuropathic pain 1 week post application of gp120 + ddC. QHIL10 resulted in a statistically significant elevation of mechanical threshold that was apparent on day 7 post vector inoculation compared with the control vectors (F(1,12) = 11.996, P < 0.01, repeated measures ANOVA, n = 7) (Figure 1A). The anti-allodynic effect of the HSV vectors lasted for more than 3 weeks. For the comparison of the differences at individual time points between two groups, we used a two-tailed t test; there was a significant difference at week 1, 2, and 3 between the 2 groups. The area under the effect-time curves (AUC) after HSV in the QHIL10 group was significantly higher than that in the Q0ZHG group (P < 0.001, t test, n = 7, Figure 1B).


IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats.

Zheng W, Huang W, Liu S, Levitt RC, Candiotti KA, Lubarsky DA, Hao S - Mol Pain (2014)

The anti-allodynic effect of IL-10 mediated by the HSV vectors on neuropathic pain induced by HIV gp120 combined with ddC. (A) Mechanical allodynia in rats was shown 1 week post the gp120 application with ddC. The times of gp120 + ddC and HSV vector inoculation were indicated by arrows. QHIL10 resulted in a statistically significant elevation of the mechanical threshold (g) compared with the control vectors (F(1,12) = 11.996, P < 0.01, repeated measures ANOVA, n = 7). The comparison of differences at individual time points between two groups was shown, *P < 0.05, **P < 0.01 vs. Q0ZHG, two-tailed t test. (B) The AUC in QHIL10 group was significantly higher than that in Q0ZHG, ***P < 0.001, t test, n = 7 rats).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: The anti-allodynic effect of IL-10 mediated by the HSV vectors on neuropathic pain induced by HIV gp120 combined with ddC. (A) Mechanical allodynia in rats was shown 1 week post the gp120 application with ddC. The times of gp120 + ddC and HSV vector inoculation were indicated by arrows. QHIL10 resulted in a statistically significant elevation of the mechanical threshold (g) compared with the control vectors (F(1,12) = 11.996, P < 0.01, repeated measures ANOVA, n = 7). The comparison of differences at individual time points between two groups was shown, *P < 0.05, **P < 0.01 vs. Q0ZHG, two-tailed t test. (B) The AUC in QHIL10 group was significantly higher than that in Q0ZHG, ***P < 0.001, t test, n = 7 rats).
Mentions: Previous studies have demonstrated that the peripheral gp120 application into the sciatic nerve, systemic ddC, or combination of gp120 and ddC (gp120+ddC), results in neuropathic pain characterized by mechanical allodynia and upregulates TNFα [4,28-31]. The principal anti-inflammatory activity of IL-10 is to inhibit the production of proinflammatory cytokines [21]. We have demonstrated that IL-10 mediated by the HSV vectors reversed formalin-induced inflammatory pain [8]. Recent studies show that animals inoculated with the HSV vectors expressing IL10 reduces mechanical allodynia induced by the spinal cord injury [27]. In this study, we further examined whether overexpression of IL-10 mediated by the HSV vectors, reduced neuropathic pain induced by HIV gp120 + ddC. HIV gp120 combined with ddC induced a rapid decrease in mechanical threshold at 1 week. Subcutaneous inoculation with QHIL10 (30 μl containing 1 × 109 plaque-forming units/ml) or control vector Q0ZHG was carried out in the plantar surface of the hind foot of rats with neuropathic pain 1 week post application of gp120 + ddC. QHIL10 resulted in a statistically significant elevation of mechanical threshold that was apparent on day 7 post vector inoculation compared with the control vectors (F(1,12) = 11.996, P < 0.01, repeated measures ANOVA, n = 7) (Figure 1A). The anti-allodynic effect of the HSV vectors lasted for more than 3 weeks. For the comparison of the differences at individual time points between two groups, we used a two-tailed t test; there was a significant difference at week 1, 2, and 3 between the 2 groups. The area under the effect-time curves (AUC) after HSV in the QHIL10 group was significantly higher than that in the Q0ZHG group (P < 0.001, t test, n = 7, Figure 1B).

Bottom Line: IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold.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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus