Aminooxypentane Addition to the Chemokine Macrophage Inflammatory Protein-1αP Increases Receptor Affinities and HIV Inhibition

Jane R. Townson, Gerard J. Graham, Nathaniel R. Landau, Beth Rasala, Robert J. B. Nibbs
2000 Journal of Biological Chemistry  
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
more » ... phage inflammatory protein (MIP)-1␣, termed MIP-1␣P, is the most active naturally occurring inhibitor of HIV entry known. Here we report the properties of a variant of MIP-1␣P with an AOP group on the amino terminus. We show that, like RANTES, the addition of AOP to MIP-1␣P 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-1␣P is about 10-fold more active than AOP-RANTES at inhibiting HIV entry, making it the most effective chemokinebased inhibitor of HIV entry through CCR5 described to date. Surprisingly, the enhanced receptor interactions of AOP-MIP-1␣P 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.
doi:10.1074/jbc.m006768200 pmid:11005816 fatcat:bxmurqctkrbn7i3sjlpxfmu2ei