title: Macrophage-sensory neuronal interaction in HIV-1 gp120-induced neurotoxicity‡.
abstract: 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.
authors.affiliation: Pain Research Group, Department of Surgery and Cancer, Faculty of Medicine and.
authors.forename: P J
authors.initials: PJ
authors.lastname: Moss
authors.affiliation: Pain Research Group, Department of Surgery and Cancer, Faculty of Medicine and Current address: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK w.huang@abdn.ac.uk.
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.affiliation: Wolfson Centre for Age Related Disease, King's College London, London, UK Current address: The Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Dawes
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Okuse
authors.affiliation: Wolfson Centre for Age Related Disease, King's College London, London, UK.
authors.forename: S B
authors.initials: SB
authors.lastname: McMahon
authors.affiliation: Pain Research Group, Department of Surgery and Cancer, Faculty of Medicine and Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: A S C
authors.initials: AS
authors.lastname: Rice
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D010523:Peripheral Nervous System Diseases; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000473:pathology*
chemical_list: D015699:HIV Envelope Protein gp120
keywords: cytokines; HIV envelope protein; macrophages; maraviroc; peripheral nervous system diseases; peripheral neuropathies