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

Virology. 2004 Nov 24;329(2):302-18. doi: 10.1016/j.virol.2004.08.024.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • AIDS Dementia Complex / metabolism
  • AIDS Dementia Complex / physiopathology
  • Animals
  • Animals, Genetically Modified
  • Astrocytes / metabolism
  • Astrocytes / virology
  • Cell Death
  • Cells, Cultured
  • Chemokine CCL2 / biosynthesis
  • Chemokine CCL2 / genetics
  • Chemokine CXCL10
  • Chemokines, CXC / biosynthesis
  • Chemokines, CXC / pharmacology
  • Chemokines, CXC / physiology*
  • Gene Products, nef / biosynthesis
  • Gene Products, nef / genetics*
  • Genetic Vectors
  • HIV-1* / genetics
  • HIV-1* / pathogenicity
  • Humans
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / genetics
  • Interleukin-1beta
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Sequence Data
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neurotoxins / pharmacology
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics
  • RNA, Messenger / analysis
  • Recombinant Proteins / pharmacology
  • nef Gene Products, Human Immunodeficiency Virus


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CXCL10
  • Chemokines, CXC
  • Gene Products, nef
  • Interleukin-1
  • Interleukin-1beta
  • Neurotoxins
  • Peptide Fragments
  • RNA, Messenger
  • Recombinant Proteins
  • nef Gene Products, Human Immunodeficiency Virus
  • interleukin-1beta (163-171)

Associated data

  • GENBANK/AY701253