LD78 beta, a non-allelic variant of human MIP-1 alpha (LD78 alpha), has enhanced receptor interactions and potent HIV suppressive activity

Chemokines play diverse roles in inflammatory and non-inflammatory situatio ns via activation of heptahelical G-protein-coupled receptors. Also, many c hemokine receptors can act as cofactors for cellular entry of human immunod eficiency virus (HIV) in vitro. CCR5, a receptor for chemokines MLP-1 alpha (LD78 alpha), MIP-1 beta, RAN-TES, and MCP2, is of particular importance i n vivo as polymorphisms in this gene affect HIV infection and rate of progr ession to APDS. Moreover, the CCR5 ligands can prevent HIV entry through th is receptor and likely contribute to the control of HIV infection. Here we show that a non-allelic isoform of human MIP-1 alpha (LD78 alpha), termed L D78 beta or MIP-1 alpha P, has enhanced receptor binding affinities to CCR5 (similar to 6-fold) and the promiscuous beta-chemokine receptor, D6 (simil ar to 15-20-fold). We demonstrate that a proline residue at position 2 of M IP-1 alpha P is responsible for this enhanced activity. Moreover, MIP-1 alp ha P is by far the most potent natural CCR5 agonist described to date, and importantly, displays markedly higher HIV1 suppressive activity than all ot her human MIP-1 alpha isoforms examined. In addition, while RANTES has been described as the most potent inhibitor of CCR5-mediated HIV entry, MIP-1 a lpha P was as potent as, if not more potent than, RANTES in HIV-1 suppressi ve assays. This property suggests that MLP-1 alpha P may be of importance i n controlling Viral spread in HN-infected individuals.