期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 50, 页码 39254-39261出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M006768200
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资金
- NCI NIH HHS [CA7214] Funding Source: Medline
- NIAID NIH HHS [AI43252] Funding Source: Medline
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)-l alpha termed MIP-1 alphaP, is the most active naturally occurring inhibitor of HIV entry known. Here we report the properties of a variant of MIP-l alphaP with an AOP group on the amino terminus. We show that, like RANTES, the addition of AOP to MIP-1 alphaP 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-l alphaP is about 10-fold more active than AOP-RANTES at inhibiting HIV entry, malting it the most effective chemokine-based inhibitor of HIV entry through CCR5 described to date. Surprisingly, the enhanced receptor interactions of AOP-MIP-1 alphaP 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.
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