L D78α and LD78β are 2 highly related nonallelic genes that code for different isoforms of the human CC chemokine macrophage inflammatory protein-1α (MIP-1α). Two molecular forms of natural LD78β (7.778 and 7.793 kDa) were identified from conditioned media of stimulated peripheral blood mononuclear cells. Although LD78α and LD78β only differ in 3 amino acids, both LD78β variants were 100-fold more potent chemoattractants for mouse lymphocytes than was LD78α. On the contrary, LD78β was only 2-fold more efficient than LD78α in chemoattracting human lymphocytes and monocytes. Using CC chemokine receptor–transfected cells, both molecular forms of LD78β proved to be much more potent than LD78α in inducing an intracellular calcium rise through CCR5. Compared with LD78α and RANTES, this preferential binding of LD78β to CCR5 resulted in a 10- to 50-fold higher potency in inhibiting infection of peripheral blood mononuclear cells by CCR5-using (R5) HIV-1 strains. To date, LD78β is the most potent chemokine for inhibiting HIV-1 infection, and can be considered as a potentially important drug candidate for the treatment of infection with R5 HIV-1 strains.J. Clin. Invest. 104: R1-R5 (1999)