Aminooxypentane addition to the chemokine macrophage inflammatory Protein-1 alpha P increases receptor affinities and HIV inhibition

Townson, J. R., Graham, G. J. , Landau, N. R., Rasala, B. and Nibbs, R. J.B. (2000) Aminooxypentane addition to the chemokine macrophage inflammatory Protein-1 alpha P increases receptor affinities and HIV inhibition. Journal of Biological Chemistry, 275(50), pp. 39254-39261. (doi: 10.1074/jbc.M006768200)

Abstract

To enter its target cells, human immunodeficiency virus (HIV) must interact with CD4 and one of a family of chemokine receptors. CCR5 is widely used by the virus in this context, and its ligands can prevent HIV entry. Amino-terminal modified chemokine variants, in particular AOP-RANTES (aminooxypentane-linked regulated on activation normal T cell expressed and secreted), exhibit enhanced HIV entry inhibition. We have previously demonstrated that a non-allelic isoform of macrophage inflammatory protein (MIP)-1α, termed MIP-1αP, is the most active naturally occurring inhibitor of HIV entry known. Here we report the properties of a variant of MIP-1αP with an AOP group on the amino terminus. We show that, like RANTES, the addition of AOP to MIP-1αP enhances its interactions with CCR1 and CCR5, allows more effective internalization of CCR5, and increases the ligand's potency as an inhibitor of HIV entry through CCR5. Importantly, AOP-MIP-1αP is about 10-fold more active than AOP-RANTES at inhibiting HIV entry, making it the most effective chemokine-based inhibitor of HIV entry through CCR5 described to date. Surprisingly, the enhanced receptor interactions of AOP-MIP-1αP do not translate into increased chemotaxis or coupling to calcium ion fluxes, suggesting that this protein should be viewed as a partial, rather than a full, agonist for CCR1 and CCR5.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nibbs, Professor Rob and Graham, Professor Gerard
• Authors: Townson, J. R., Graham, G. J., Landau, N. R., Rasala, B., and Nibbs, R. J.B.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Biological Chemistry
• Journal Abbr.: J Biol Chem.
• Publisher: American Society for Biochemistry and Molecular Biology, Inc.
• ISSN: 0021-9258
• ISSN (Online): 1083-351X
• Published Online: 25 September 2000