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