Neuroscience. 2013 Nov 12;252:512-25.

Nerve growth factor acts through the TrkA receptor to protect sensory neurons from the damaging effects of the HIV-1 viral protein, Vpr.

Webber CA, Salame J, Luu GL, Acharjee S, Ruangkittisakul A, Martinez JA, Jalali H, Watts R, Ballanyi K, Guo GF, Zochodne DW, Power C.

Division of Anatomy, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Electronic address: webber2@ualberta.ca.

 

ABSTRACT

Distal sensory polyneuropathy (DSP) with associated neuropathic pain is the most common neurological disorder affecting patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Viral protein R (Vpr) is a neurotoxic protein encoded by HIV-1 and secreted by infected macrophages. Vpr reduces neuronal viability, increases cytosolic calcium and membrane excitability of cultured dorsal root ganglion (DRG) sensory neurons, and is associated with mechanical allodynia in vivo. A clinical trial with HIV/AIDS patients demonstrated that nerve growth factor (NGF) reduced the severity of DSP-associated neuropathic pain, a problem linked to damage to small diameter, potentially NGF-responsive fibers. Herein, the actions of NGF were investigated in our Vpr model of DSP and we demonstrated that NGF significantly protected sensory neurons from the effects of Vpr. Footpads of immunodeficient Vpr transgenic (vpr/RAG1(-/-)) mice displayed allodynia (p<0.05), diminished epidermalinnervation (p<0.01) and reduced NGF mRNA expression (p<0.001) compared to immunodeficient (wildtype/RAG1(-/-)) littermate control mice. Compartmented cultures confirmed recombinant Vpr exposure to the DRG neuronal perikarya decreased distal neurite extension (p<0.01), whereas NGF exposure at these distal axons protected the DRG neurons from the Vpr-induced effect on their cell bodies. NGF prevented Vpr-induced attenuation of the phosphorylated glycogen synthase-3 axon extension pathway and tropomyosin-related kinase A (TrkA) receptor expression in DRG neurons (p<0.05) and it directly counteracted the cytosolic calcium burst caused by Vpr exposure to DRG neurons (p<0.01). TrkA receptor agonist indicated that NGFacted through the TrkA receptor to block the Vpr-mediated decrease in axon outgrowth in neonatal and adult rat and fetal human DRG neurons (p<0.05). Similarly, inhibiting the lower affinity NGF receptor, p75, blocked Vpr’s effect on DRG neurons. Overall, NGF/TrkA signaling or p75 receptor inhibition protects somatic sensory neurons exposed to Vpr, thus laying the groundwork for potential therapeutic options for HIV/AIDS patients suffering from DSP. Copyright © 2013 IBRO. Published by Elsevier Ltd.

KEYWORDS: 1-β-d-arabinofuranosylcytosine, ACSF, AIDS, ANOVA, AraC, DMEM/F12, DRG, DSP, Dulbecco’s Modified Eagle’s Medium/Ham’s F-12, EDTA, GSK3β, HAART, HIV, NGF, PBS, TrkA, Vpr, acquired immunodeficiency syndrome, analysis of variance, artificial cerebral spinal fluid, distal sensory polyneuropathy, dorsal root ganglion, ethylenediaminetetraacetic acid, glycogen synthase kinase-3 beta, highly active antiretroviral therapy, human immunodeficiency virus, human immunodeficiency virus (HIV), nerve growth factor, nerve growth factor (NGF), neuropathic pain, pGSK3β, phosphate-buffered saline, phosphorylated GSK3β, qRT-PCR, quantitative real-time polymerase chain reaction, tropomyosin-related kinase A, tropomyosin-related kinase A (TrkA), viral protein R, viral protein R (Vpr)

PMID: 23912036

 

SUPPLEMENT:

Webber-2014-World-Biomed-Fron
Fig 1. Summary of our findings of Vpr’s effects on DRG neurons and epidermis

1) Vpr is expressed by macrophages in DRGN of HIV-infected patients (and our vpr/RAG1-/- mice). It is not known if Vpr is secreted by these macrophages, if Vpr binds to a receptor on DRGN or how Vpr induces its effects on DRGN (see the ‘?’). In vitro, recombinant Vpr acts on rat DRGN to provoke neuronal excitability (2), increase intracellular calcium levels (3) and decrease axon outgrowth (4). In our vpr/RAG1-/- mouse model, chronic Vpr expression causes mechanical allodynia (5), epidermal denervation (6), decreased TrkA receptor expression in DRGN (7) and decreased NGF expression at the skinpad (8). (9) We demonstrated that pre-treatment of DRGN with recombinant NGF blocked Vpr’s ability to promote neuronal excitability, increase intracellular calcium and hinder axonal outgrowth. 10) Pre-exposure of DRGN to a TrkA agonist or a p75ntr antagonist blocked Vpr’s effect on axon outgrowth.

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