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 produced by five variants of HIV-1 (human immunodeficiency virus) envelope protein (gp120). VIP or DAPTA treatment of astrocyte cultures resulted in the release of macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES, beta chemokines known to block gp120 interactions with microglial chemokine receptors. In rat cerebral cortical cultures, gp120-induced neuronal killing was partially or completely prevented by chemokines that stimulate the CXCR4, CCR3 or CCR5 chemokine receptors. Chemokines exhibited marked differences 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 (IC(50)<3 pM for RF isolate). An octapeptide derived from RANTES also exhibited neuroprotection from gp120 (RF isolate) toxicity (IC(50)=0.3 microM). Treatment with chemokines alone had no detectable effect on neuronal cell number. However, antiserum to MIP-1alpha produced neuronal cell death that was prevented by co-treatment with MIP-1alpha, suggesting that this endogenous chemokine exerts a tonic regulation important to neuronal survival. The neuroprotective action of VIP on gp120 was attenuated by co-treatment with anti-MIP-1alpha. These studies suggest that the neuroprotective action of VIP is linked in part to its release of MIP-1alpha. Furthermore, neuroprotection produced by chemokines is dependent on both the type of chemokine and the variant structure of gp120 and may be relevant to drug strategies for the treatment of AIDS dementia.
Brenneman
D E
DE
Section on Developmental and Molecular Pharmacology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. dbrenn@codon.nih.gov
Hauser
J
J
Spong
C Y
CY
Phillips
T M
TM
Pert
C B
CB
Ruff
M
M
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000032:analysis; D018925:Chemokines / Q000378:metabolism*; D014644:Genetic Variation; D006678:HIV; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000235:genetics; D015717:Peptide T / Q000494:pharmacology*; D051381:Rats; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D018946:Chemokine CCL5; D018925:Chemokines; D015699:HIV Envelope Protein gp120; D009498:Neurotoxins; D015717:Peptide T; C055175:peptide T amide; D014660:Vasoactive Intestinal Peptide