Apelin, the natural ligand of the orphan seven-transmembrane receptor APJ,inhibits human immunodeficiency virus type 1 entry

In addition to the CCR5 and CXCR4 chemokine receptors, a subset of primary human immunodeficiency virus type I (HIV-1) isolates can also use the seven -transmembrane-domain receptor APJ as a coreceptor. A previously identified ligand of APJ, apelin, specifically inhibited the entry of primary T-tropi c and dualtropic HIV-1 isolates from different clades into cells expressing CD4 and APJ. Analysis of apelin analogues demonstrated that potent and spe cific antiviral activity was retained by a 13-residue, arginine-rich peptid e. Antiviral potency was influenced by the integrity of methionine 75, whic h contributes to APJ-binding affinity, and by the retention of apelin resid ues 63 to 65. These studies demonstrate the ability of a small peptide liga nd to block the function of APJ as an HIV-1 coreceptor, identify apelin seq uences important for the inhibition, and provide new reagents for the inves tigation of the significance of APJ to HIV-1 infection and pathogenesis.