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BACKGROUND: Human immunodeficiency virus (HIV)-associated sensory neuropathy (SN) is the most frequent neurological complication of HIV disease. Among the probable mechanisms underlying HIV-SN are neurotoxicity induced by the HIV glycoprotein gp120 and antiretroviral therapies (ART). Since HIV-SN prevalence remains high in patients who have not been exposed to toxic ART drugs, here we focused on gp120-mediated mechanisms underlying HIV-SN. METHODS: We hypothesized that a direct gp120-sensory neurone interaction is not the cause of neurite degeneration; rather, an indirect interaction of gp120 with sensory neurones involving macrophages underlies axonal degeneration. Rat dorsal root ganglion (DRG) cultures were used to assess gp120 neurotoxicity. Rat bone marrow-derived macrophage (BMDM) cultures and qPCR array were used to assess gp120-associated gene expression changes. RESULTS: gp120 induced significant, but latent onset, neurite degeneration until 24 h after application. gp120-neurone interaction occurred within 1 h of application in <10% of DRG neurones, despite neurite degeneration having a global effect. Application of culture media from gp120-exposed BMDMs induced a significant reduction in DRG neurite outgrowth. Furthermore, gp120 significantly increased the expression of 25 cytokine-related genes in primary BMDMs, some of which have been implicated in other painful polyneuropathies. The C-C chemokine receptor type 5 (CCR5) antagonist, maraviroc, concentration-dependently inhibited gp120-induced tumour necrosis factor-α gene expression, indicating that these effects occurred via gp120 activation of CCR5. CONCLUSIONS: Our findings highlight macrophages in the pathogenesis of HIV-SN and upstream modulation of macrophage response as a promising therapeutic strategy.

Original publication

DOI

10.1093/bja/aeu311

Type

Journal article

Journal

Br J Anaesth

Publication Date

03/2015

Volume

114

Pages

499 - 508

Keywords

cytokines; HIV envelope protein; macrophages; maraviroc; peripheral nervous system diseases, peripheral neuropathies, Animals, Cell Culture Techniques, Cells, Cultured, Disease Models, Animal, Female, Gene Expression, HIV Envelope Protein gp120, HIV-1, Macrophages, Nerve Degeneration, Neurotoxicity Syndromes, Peripheral Nervous System Diseases, Polymerase Chain Reaction, Rats, Rats, Wistar, Sensory Receptor Cells