When Human Immunodeficiency Virus Meets Chemokines and Microglia: Neuroprotection or Neurodegeneration?

Mocchetti, Italo; Campbell, Lee Ann; Harry, G. Jean; Avdoshina, Valeriya

doi:10.1007/s11481-012-9353-4

Cited by 24 publications

(31 citation statements)

References 170 publications

(186 reference statements)

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“…Chemokine receptors, in particular CXCR4 and CCR5, mediate HIV infection of immunocompetent cells as well as microglia [11]. The interplay of TNFα and HIV-1 leads to the enhanced expression of toxic chemokines [46].…”

Section: Discussionmentioning

confidence: 99%

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

Zheng

Huang

et al. 2014

Mol Pain

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zheng

Huang

et al. 2014

Mol Pain

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“…8 CXCR4 and its ligand SDF1a are important inflammatory factors in the neuropathogenesis of HIV/AIDS. 21 In this study, we tested if neuropathic pain induced by HIV gp120 affected TNFa, CXCR4 and SDF1a expression in the DRG and the spinal dorsal horn. To induce HIV neuropathic pain, rats received a recombinant gp120 application to the sciatic nerve 10,15 (for details, see Materials and methods section).…”

Section: Resultsmentioning

confidence: 99%

“…21 HIV gp120 binds to and activates CXCR4 expressed by the DRG neurons in a CD-4-independent manner 40,72 suggesting direct neurotoxic effects of gp120 on the neurons. 73 The effect of the drug is dependent on the route of administration, dosage and pain models and so on.…”

Section: Discussionmentioning

confidence: 99%

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HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

et al. 2014

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Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite extensive research, the detailed neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. In this study, we investigated the role of proinflammatory molecules, tumor necrosis factor-α (TNFα), CXCR4 and stromal-derived factor-1 α (SDF1α), in the L4/5 dorsal root ganglia (DRG) and the spinal dorsal horn in HIV gp120 protein-mediated neuropathic pain. Our results showed that the application of HIV gp120 to the sciatic nerve induced upregulation of TNFα, CXCR4 and SDF1α in both the DRG and the lumbar spinal dorsal horn. Non-replicating herpes simplex virus (HSV) vector encoding the p55TNFSR gene and producing a TNF-soluble receptor (TNFSR) to block bioactivity of TNFα reversed mechanical allodynia. Intrathecal AMD3100 (CXCR4 antagonist) increased mechanical threshold. The HSV vectors expressing p55TNFSR reversed upregulation of TNFα, CXCR4 and SDF1α induced by gp120 in the DRG and the spinal dorsal horn. These studies suggest that proinflammatory TNFα to the CXCR4/SDF1 pathway has an important role in the HIV-related neuropathic pain state and that blocking the proinflammatory cytokines or chemokines is able to reduce neuropathic pain. This work provides a novel gene therapy proof-of-concept for HIV-associated neuropathic pain.

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“…HIV can also infect Microglia, but it is important to note that microglia do not replicate in the brain, so that they do not represent the bulk of cells that occupy pathologic areas of disease wherein MDMs are prevalent. However, because of their role brain housekeeping processes, HIV infection or destruction of resident brain microglia likely contributes HAND pathogenesis (55, 75). Once activated, microglial cells essentially change morphology and become phenotypically and morphologically indistinguishable from MDMs (88).…”

Section: The Hiv Infected Brain and Cells Of The Cnsmentioning

confidence: 99%

HIV-associated neuropathogenesis: A systems biology perspective for modeling and therapy

Lamers¹,

Fogel

Nolan

et al. 2014

Biosystems

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Despite the development of powerful antiretroviral drugs, HIV-1 associated neurological disorders (HAND) will affect approximately half of those infected with HIV-1. Combined anti-retroviral therapy (cART) targets viral replication and increases T-cell counts, but it does not always control macrophage polarization, brain infection or inflammation. Moreover, it remains difficult to identify those at risk for HAND. New therapies that focus on modulating host immune response by making use of biological pathways could prove to be more effective than cART for the treatment of neuroAIDS. Additionally, while numerous HAND biomarkers have been suggested, they are of little use without methods for appropriate data integration and a systems-level interpretation. Machine learning, could be used to develop multifactorial computational models that provide clinicians and researchers with the ability to identify which factors (in what combination and relative importance) are considered important to outcome.

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When Human Immunodeficiency Virus Meets Chemokines and Microglia: Neuroprotection or Neurodegeneration?

Cited by 24 publications

References 170 publications

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

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

HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

HIV-associated neuropathogenesis: A systems biology perspective for modeling and therapy

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