LD78β, a non-allelic variant of human MIP-1α (LD78α), has enhanced receptor interactions and potent HIV suppressive activity

Abstract

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- α (LD78α), MIP-1β, 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-1α (LD78α), termed LD78β or MIP-1αP, has enhanced receptor binding affinities to CCR5 (~6-fold) and the promiscuous β-chemokine receptor, D6 (~15-20-fold). We demonstrate that a proline residue at position 2 of MIP-1αP is responsible for this enhanced activity. Moreover, MIP-1αP is by far the most potent natural CCR5 agonist described to date, and importantly, displays markedly higher HIV-1 suppressive activity than all other human MIP-1α isoforms examined. In addition, while RANTES has been described as the most potent inhibitor of CCR5-mediated HIV entry, MIP- 1αP was as potent as, if not more potent than, RANTES in HIV-1 suppressive assays. This property suggests that MIP-1αP may be of importance in controlling viral spread in HIV-infected individuals.