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Significance G protein-coupled receptors (GPCRs) are involved in many physiological processes and important drug targets. However, most therapeutic agents targeting GPCRs, such as the coreceptors of HIV-1 CCR5 and CXCR4, also interfere with their signaling function. Here, we used primate lentiviruses as tools to discover novel endogenous ligands of GPR15, a coreceptor for HIV-2 and SIV proposed to play a role in mucosal immunity. We found that C-terminal fragments of cystatin C generated by immune-activated proteases inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L chemokine signaling. Thus, we identified an endogenous bioactive peptide that specifically prevents the detrimental activity of a GPCR (i.e. virus infection) without compromising its physiological signaling function.

Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling