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HIV Type 1 Nef Protein Is a Viral Factor for Leukocyte Recruitment into the Central Nervous System¹

Uwe Koedel^*, Birgit Kohleisen, Bernd Sporer^*, Fritz Lahrtz, Vladimir Ovod, Adriano Fontana, Volker Erfle and Hans-Walter Pfister^2,*

^* 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 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-, 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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