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J Biol Chem, Vol. 274, Issue 25, 17478-17483, June 18, 1999

LD78, A Non-allelic Variant of Human MIP-1 (LD78), Has Enhanced Receptor Interactions and Potent HIV Suppressive Activity

Robert J. B. Nibbs, Jinying Yang^§, Nathaniel R. Landau^§, Jian-Hua Mao, and Gerard J. Graham

From the  Beatson Institute for Cancer Research,  Department of Medical Oncology, CRC Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD Scotland, United Kingdom and the ^§ Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York 10016

Chemokines play diverse roles in inflammatory and non-inflammatory situations via activation of heptahelical G-protein-coupled receptors. Also, many chemokine receptors can act as cofactors for cellular entry of human immunodeficiency virus (HIV) in vitro. CCR5, a receptor for chemokines MIP-1 (LD78), MIP-1, RANTES, and MCP2, is of particular importance in vivo as polymorphisms in this gene affect HIV infection and rate of progression to AIDS. Moreover, the CCR5 ligands can prevent HIV entry through this receptor and likely contribute to the control of HIV infection. Here we show that a non-allelic isoform of human MIP-1 (LD78), termed LD78 or MIP-1P, has enhanced receptor binding affinities to CCR5 (~6-fold) and the promiscuous -chemokine receptor, D6 (~15-20-fold). We demonstrate that a proline residue at position 2 of MIP-1P is responsible for this enhanced activity. Moreover, MIP-1P is by far the most potent natural CCR5 agonist described to date, and importantly, displays markedly higher HIV1 suppressive activity than all other human MIP-1 isoforms examined. In addition, while RANTES has been described as the most potent inhibitor of CCR5-mediated HIV entry, MIP-1P was as potent as, if not more potent than, RANTES in HIV-1 suppressive assays. This property suggests that MIP-1P may be of importance in controlling viral spread in HIV-infected individuals.

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