Aminooxypentane addition to the chemokine macrophage inflammatory protein-1alpha P increases receptor affinities and HIV inhibition.
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)-1alpha, termed MIP-1alphaP, is the most active naturally occurring inhibitor of HIV entry known. Here we report the properties of a variant of MIP-1alphaP with an AOP group on the amino terminus. We show that, like RANTES, the addition of AOP to MIP-1alphaP 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-1alphaP 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-1alphaP 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.
Townson
J R
JR
Beatson Institute for Cancer Research, CRC Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom.
Graham
G J
GJ
Landau
N R
NR
Rasala
B
B
Nibbs
R J
RJ
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000737:chemistry / Q000494:pharmacology; D018925:Chemokines; D002633:Chemotaxis; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry* / Q000494:pharmacology*; D010420:Pentanes / Q000737:chemistry*; D011485:Protein Binding; D020033:Protein Isoforms; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
C515429:CCL3 protein, human; C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D010420:Pentanes; D020033:Protein Isoforms; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; C033353:pentane; D002118:Calcium