G protein-coupled receptors (GPCRs) are not only involved in many physiological processes and important drug targets but also critical cofactors for infection by human and simian immunodeficiency viruses (HIV and SIV, respectively). This project, utilizes SIV and HIV-2 as tools to characterize novel ligands of GPCRs playing roles in inflammation and cancer. It discovered that fragments of Cystatin C block GPR15-mediated virus infection without interfering with the physiological signaling function of this GPCR. Goals of the 2nd funding period are to determine the underlying mechanisms and to reveal whether proteolytic cleavage of abundant circulating proteins by immune-activated proteases frequently generates as-yet-unknown GPCR ligands.