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.