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*
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany;
Institute of Molecular Virology, GSF-Research Center for Environment and Health Neuherberg, Neuherberg; Germany,
Institute of Biomedical Sciences, University of Tampere, Tampere, Finland; and
Institute of Clinical Immunology, University Hospital Zürich, Zürich, Switzerland
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 171190 (but not of mAb 3E6, an anti-Nef Ab of
the same isotype, which maps the aa sequence 168175, 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-
, and IFN-
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.
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