VIP and D-ala-peptide T-amide release chemokines which prevent HIV-1 GP120-induced neuronal death

Vasoactive intestinal peptide (VIP) and DAPTA (D-ala(1)-peptide T-amide, a gp120-derived octapeptide homologous to VIP) prevent neuronal cell death pr oduced by five variants of HIV-1 (human immunodeficiency virus) envelope pr otein (gp120). VIP or DAPTA treatment of astrocyte cultures resulted in the release of macrophage inflammatory protein-1 alpha (MIP-1 alpha) and RANTE S, beta chemokines known to block gp120 interactions with microglial chemok ine receptors. In rat cerebral cortical cultures, gp120-induced neuronal ki lling was partially or completely prevented by chemokines that stimulate th e CXCR4, CCR3 or CCR5 chemokine receptors. Chemokines exhibited marked diff erences in potency and efficacy in preventing toxicity associated with five gp120 variants (LAV/BRU, CM243, RF, SF2, and MN). RANTES had the broadest and most potent inhibition (IC50 <3 pM for RF isolate). An octapeptide deri ved from RANTES also exhibited neuroprotection from gp120 (RF isolate) toxi city (IC50 = 0.3 mu M). Treatment with chemokines alone had no delectable e ffect on neuronal cell number. However, antiserum to MTP-la produced neuron al cell death that was prevented by co-treatment with MIP-1 alpha, suggesti ng that this endogenous chemokine exerts a tonic regulation important to ne uronal survival. The neuroprotective action of VIP on gp120 was attenuated by co-treatment with anti-MIP-1 alpha. These studies suggest that the neuro protective action of VIP is linked in part to its release of MIP-1 alpha. F urthermore, neuroprotection produced by chemokines is dependent on both the type of chemokine and the variant structure of gp120 and may be relevant t o drug strategies for the treatment of AIDS dementia. (C) 1999 Published by Elsevier Science B.V. All rights reserved.