Diverging binding capacities of natural LD78β isoforms of macrophage inflammatory protein-1α to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils

Recently, the LD78 beta isoform of the CC chemokine macrophage inflammatory protein (MIP)1 alpha was shown to efficiently chemoattract lymphocytes and monocytes and to inhibit infection of mononuclear cells by R5 HIV-1 strains. We have now demonstrated that after cleavage of the NH2-terminal Ala-Pro dipeptide by CD26, LD78 beta (3-70) became the most potent chemokine blocking HIV-1. LD78 beta (3-70) competed tenfold more efficiently than LD78 beta (1-70) with [I-125]RANTES for binding to the CC chemokine receptors CCR5 and CCR1, Contrary to LD78 alpha, LD78 beta (1-70) at 30 ng/ml efficiently competed with [I-125] RANTES for binding to CCR3 and mobilized calcium in CCR3 transfectants, whereas LD78 beta (3-70) showed a 30-fold decrease in CCR3 affinity compared to LD78 beta (1-70). This demonstrates the importance of the penultimate proline in LD78 beta (1-70) for CCR3 recognition. Both LD78 beta isoforms efficiently chemoattracted eosinophils from responsive donors. in contrast, only the CCR3 agonist LD78 beta (1-70) and: not LD78 beta (3-70), induced calcium increases in eosinophils with low levels of CCR1. In responder neurophils, LD78 beta (3-70) elicited calcium fluxes at a 30-fold lower dose (10 ng/ml) compared to intact LD78 beta and LD78 alpha, whereas the three MIP-1 alpha isoforms were equipotent. neutrophil chemoattractants. Taken together, both LD78 beta isoforms are potent HIV-1 inhibitors (CCR5) and activators for neutrophils (CCR1) and eosinophils (CCR1, CCR3), affecting infection and inflammation.