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Title: Investigations into the mechanisms underlying HIV-1 gp120-associated neurotoxicity
Author: Moss, Philippa
ISNI:       0000 0004 2714 8638
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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HIV-associated distal sensory polyneuropathy is a frequent (~40% prevalence) complication of HIV infection and treatment. It is characterised by a dying back pattern of axonal degeneration, predominantly of nociceptors usually accompanied by neuropathic pain. The HIV envelope glycoprotein, gp120, has recently been identified as a key mediator of axonal degeneration both in vitro and in vivo. We hypothesised that gp120 interacts, in a chemokine receptor-dependant manner, with primary sensory neurons either directly or indirectly via macrophages and/or Schwann cells. Neurite outgrowth of cultured adult rat dorsal root ganglia (DRG) cells was used to assess direct or indirect neurotoxicity. Gp120 induced concentration-dependent neurite degeneration 24h after exposure, which was not restricted to phenotypic subsets of DRG cells. However, gp120 localisation studies indicated that only a minority (approx. 10%) of neurons internalised gp120 before the onset of neurite degeneration suggesting that the direct toxicity was not a predominant mechanism. Therefore, indirect mechanisms of neurotoxicity were investigated. Application of gp120-conditioned macrophage or Schwann cell media to DRG neuronal cultures revealed that gp120-conditioned media also had the capacity to induce neurite degeneration. Using qPCR it was shown that 4hr exposure to gp120 increased transcription of cytokine–related genes, in cultured Schwann cells and macrophages. These gp120-mediated effects were then explored in vivo. The cytokine expression profiles 4hrs following intradermal gp120 injection in rats were similar to the gene upregulation observed in vitro. These findings highlight the complexity of gp120-mediated mechanisms and indicate that macrophages and Schwann cells may play a key indirect role in the pathogenesis of HIV-associated peripheral neuropathy.
Supervisor: Rice, Andrew ; Okuse, Kenji Sponsor: London Pain Consortium (LPC) ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral