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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2004-11-2
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pubmed:databankReference |
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Ccl2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokine CCL2,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokine CXCL10,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokines, CXC,
http://linkedlifedata.com/resource/pubmed/chemical/Gene Products, nef,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1beta,
http://linkedlifedata.com/resource/pubmed/chemical/Neurotoxins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/interleukin-1beta (163-171),
http://linkedlifedata.com/resource/pubmed/chemical/nef Gene Products, Human...
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0042-6822
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
24
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pubmed:volume |
329
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
302-18
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:15518810-AIDS Dementia Complex,
pubmed-meshheading:15518810-Animals,
pubmed-meshheading:15518810-Animals, Genetically Modified,
pubmed-meshheading:15518810-Astrocytes,
pubmed-meshheading:15518810-Cell Death,
pubmed-meshheading:15518810-Cells, Cultured,
pubmed-meshheading:15518810-Chemokine CCL2,
pubmed-meshheading:15518810-Chemokine CXCL10,
pubmed-meshheading:15518810-Chemokines, CXC,
pubmed-meshheading:15518810-Gene Products, nef,
pubmed-meshheading:15518810-Genetic Vectors,
pubmed-meshheading:15518810-HIV-1,
pubmed-meshheading:15518810-Humans,
pubmed-meshheading:15518810-Interleukin-1,
pubmed-meshheading:15518810-Interleukin-1beta,
pubmed-meshheading:15518810-Male,
pubmed-meshheading:15518810-Mice,
pubmed-meshheading:15518810-Mice, Inbred NOD,
pubmed-meshheading:15518810-Mice, SCID,
pubmed-meshheading:15518810-Molecular Sequence Data,
pubmed-meshheading:15518810-Neurons,
pubmed-meshheading:15518810-Neurotoxins,
pubmed-meshheading:15518810-Peptide Fragments,
pubmed-meshheading:15518810-RNA, Messenger,
pubmed-meshheading:15518810-Recombinant Proteins,
pubmed-meshheading:15518810-nef Gene Products, Human Immunodeficiency Virus
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pubmed:year |
2004
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pubmed:articleTitle |
Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10.
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pubmed:affiliation |
Department of Clinical Neurosciences, University of Calgary, Calgary AB, Canada.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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