HIV type 1 Nef protein is a viral factor for leukocyte recruitment into the central nervous system.
Recombinant HIV-1 Nef protein, but not Tat, gp120, and gp160, provoked leukocyte recruitment into the CNS in a rat model. The strong reduction of bioactivity by heat treatment of Nef, and the blocking effect of the mAb 2H12, which recognizes the carboxy-terminal amino acid (aa) residues 171-190 (but not of mAb 3E6, an anti-Nef Ab of the same isotype, which maps the aa sequence 168-175, as well as a mixture of mAbs to CD4) provided evidence for the specificity of the observed Nef effects. Using a modified Boyden chamber technique, Nef exhibited chemotactic activity on mononuclear cells in vitro. Coadministration of the anti-Nef mAb 2H12, as well as treatment of Nef by heat inhibited Nef-induced chemotaxis. Besides soluble Nef, chemotaxis was also induced by a Nef-expressing human astrocytoma cell line, but not by control cells. These data suggest a direct chemotactic activity of soluble Nef. The detection of elevated levels of IL-6, TNF-alpha, and IFN-gamma in rat cerebrospinal fluid 6 h after intracisternal Nef injection hint at the additional involvement of indirect mechanisms in Nef-induced leukocyte migration into rat CNS. These data propose a mechanism by which HIV-1 Nef protein may be essential for AIDS neuropathogenesis, as a mediator of the recruitment of leukocytes that may serve as vehicles of the virus and perpetrators for disease through their production of neurotoxins.
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Germany.
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Koedel
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Kohleisen
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Sporer
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Lahrtz
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Ovod
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Fontana
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Erfle
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Pfister
D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology* / Q000821:virology; D002555:Cerebrospinal Fluid / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D002946:Cisterna Magna; D015194:Diffusion Chambers, Culture; D004306:Dose-Response Relationship, Immunologic; D015693:Gene Products, nef / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007267:Injections; D007371:Interferon-gamma / Q000134:cerebrospinal fluid; D015850:Interleukin-6 / Q000134:cerebrospinal fluid; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology*; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000821:virology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid; D054311:nef Gene Products, Human Immunodeficiency Virus
D018932:Chemokine CCL2; D015693:Gene Products, nef; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D054311:nef Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma