The LD78β Isoform of MIP-1α Is the Most Potent CC-Chemokine in Inhibiting CCR5-Dependent Human Immunodeficiency Virus Type 1 Replication in Human Macrophages

Abstract

ABSTRACT The CC-chemokines RANTES, macrophage inflammatory protein 1α (MIP-1α), and MIP-1β are natural ligands for the CC-chemokine receptor CCR5. MIP-1α, also known as LD78α, has an isoform, LD78β, which was identified as the product of a nonallelic gene. The two isoforms differ in only 3 amino acids. LD78β was recently reported to be a much more potent CCR5 agonist than LD78α and RANTES in inducing intracellular Ca 2+ signaling and chemotaxis. CCR5 is expressed by human monocytes/macrophages (M/M) and represents an important coreceptor for macrophage-tropic, CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) strains to infect the cells. We compared the antiviral activities of LD78β and the other CC-chemokines in M/M. LD78β at 100 ng/ml almost completely blocked HIV-1 replication, while at the same concentration LD78α had only weak antiviral activity. Moreover, when HIV-1 infection in M/M was monitored by a flow cytometric analysis using p24 antigen intracellular staining, LD78β proved to be the most antivirally active of the chemokines. RANTES, once described as the most potent chemokine in inhibiting R5 HIV-1 infection, was found to be considerably less active than LD78β. LD78β strongly downregulated CCR5 expression in M/M, thereby explaining its potent antiviral activity.