Human immunodeficiency virus type-1 Nef protein induces blood-brain barrier disruption in the rat: role of matrix metalloproteinase-9.

We recently showed that MMP-9 activity was detectable in the cerebrospinal fluid (CSF) of about half of neurologically symptomatic HIV-infected patients. Using an experimental animal model, we detected MMP-9 activity in CSF samples from rats that had been injected intracisternally with recombinant HIV-1 Nef protein, but not after injection of heat-treated Nef, gp120, gp160 or PBS. Nef also induced a breaching of the blood-brain barrier (BBB), which could be inhibited by pretreatment with the matrix metalloproteinase (MMP) inhibitor batimastat. In vitro Nef only slightly induced MMP-9 activity in freshly isolated human peripheral blood mononuclear cells and in the murine macrophage cell line RAW 264.7, but not in endothelial, neuronal or astroglial cell lines. Taken together, our findings indicate that HIV-1 Nef protein can induce BBB disruption in the rat - presumably via MMP induction.