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

Abstract

GPR15 is a G protein-coupled receptor proposed to play a role in mucosal immunity that also serves as entry cofactor for HIV and SIV. To discover novel endogenous GPR15 ligands, we screened a hemofiltrate-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of Cystatin C(CysC95-146) that specifically inhibits GPR15-dependent HIV-1, HIV-2 and SIV infection. In contrast, GPR15L, the chemokine ligand of GPR15, failed to inhibit virus infection. We found that Cystatin C fragments preventing GPR15-mediated viral entry do not interfere with GPR15L signaling and are generated by proteases activated at sites of inflammation. The antiretroviral activity of CysC95-146 was confirmed in primary CD4+ T cells and is conserved in simian hosts of SIV infection. Thus, we identified a potent endogenous inhibitor of GPR15-mediated HIV and SIV infection that does not interfere with the physiological function of this G protein-coupled receptor.

GPR15 in colon cancer development and anti-tumor immune responses

“…This could be due to downregulation of surface GPR15 upon GPR15L binding. Indeed, a recent report shows that GPR15L facilitates GPR15 endocytosis using GPR15-expressing cell lines 38 . Additional studies are required to understand GPR15L-dependent regulation of surface GPR15 levels on immune cells and its role in GPR15-mediated immune mechanisms in health and inflammatory diseases such as colitis and colon cancer to realize the therapeutic potential of GPR15-GPR15L axis in these indications.…”