Human immunodeficiency virus type 1 Nef protein mediates neural cell death: A neurotoxic role for IP-10

Guido Van Marle, Scot Henry, Tiona Todoruk, Andrea Sullivan, Claudia Silva, Sean B. Rourke, Janet Holden, Justin C. McArthur, M. John Gill, Christopher Power

Research output: Contribution to journalArticlepeer-review

Abstract

HIV-1 Nef is expressed in astrocytes, but a contribution to neuropathogenesis and the development of HIV-associated dementia (HAD) remains uncertain. To determine the neuropathogenic actions of the HIV-1 Nef protein, the brain-derived (YU-2) and blood-derived (NL4-3) Nef proteins were expressed in neural cells using an alphavirus vector, which resulted in astrocyte death (P < 0.001). Supernatants from Nef-expressing astrocytes also caused neuronal death, suggesting the release of neurotoxic molecules by astrocytes. Analysis of pro-inflammatory gene induction in astrocytes expressing Nef revealed increased IP-10 mRNA expression (4000-fold) that was Nef sequence dependent. Recombinant IP-10 caused selective cell death in neurons (P < 0.001) but not astrocytes, and the cytotoxicity of supernatant from astrocytes expressing Nef YU-2 was blocked by an antibody directed against the chemokine receptor CXCR3 (P < 0.001). SCID/NOD mice implanted with a Nef YU-2-expressing vector displayed abnormal motor behavior (P < 0.05), neuroinflammation, and neuronal loss relative to controls. Analysis of mRNA levels in brains from patients with HAD also revealed increased expression of IP-10 (P < 0.05), which was confirmed by immunoreactivity detected principally in astrocytes. Phylogenetic and protein structure analyses of Nef sequences derived from HIV/AIDS patients with and without HAD suggested viral evolution toward a neurotropic Nef protein. These results indicate that HIV-1 Nef contributes to neuropathogenesis by directly causing astrocyte death together with indirect neuronal death through the cytotoxic actions of IP-10 on neurons. Furthermore, Nef molecular diversity was evident in brain tissue among patients with neurological disease and which may influence IP-10 production by astrocytes.

Original languageEnglish (US)
Pages (from-to)302-318
Number of pages17
JournalVirology
Volume329
Issue number2
DOIs
StatePublished - Nov 24 2004

Keywords

  • Astrocytes
  • Cell death
  • HIV-1
  • HIV-1-associated dementia
  • Nef
  • Neuron
  • Sindbis virus

ASJC Scopus subject areas

  • Virology

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