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

Townson, Jane R., Graham, Gerard J., Landau, Nathaniel R., Rasala, Beth, and Nibbs, Robert 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. ISSN 0021-9258 (doi:10.1074/jbc.M006768200)

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Publisher's URL: http://dx.doi.org/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:Article
Status:Published
Refereed:Yes
Glasgow Author(s):Nibbs, Prof Robert and Graham, Prof Gerard
Authors: Townson, Jane R., Graham, Gerard J., Landau, Nathaniel R., Rasala, Beth, and Nibbs, Robert J.B.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
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

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