GPR15 is a G protein-coupled receptor (GPCR) proposed to play a role in mucosal immunity that also serves as a major entry cofactor for HIV-2 and simian immunodeficiency virus (SIV). To discover novel endogenous GPR15 ligands, we screened a hemofiltrate (HF)-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 GPCR.

GPR15是一种G蛋白偶联受体（GPCR），被提议在粘膜免疫中发挥作用，它也是HIV-2和猿猴免疫缺陷病毒（SIV）的主要进入辅助因子。为了发现新的内源性GPR15配体，我们筛选了血滤液（HF）衍生的肽库，以寻找GPR15介导的SIV感染的抑制剂。我们的方法确定了半胱氨酸蛋白酶抑制剂C（CysC95-146）的C末端片段，该片段特异性抑制GPR15依赖性HIV-1，HIV-2和SIV感染。相反，GPR15的趋化因子配体GPR15L不能抑制病毒感染。我们发现，阻止GPR15介导的病毒进入的半胱氨酸蛋白酶抑制剂C片段不会干扰GPR15L信号传导，而是由在炎症部位激活的蛋白酶产生的。在原发性CD4 ^+中证实了CysC95-146的抗逆转录病毒活性T细胞在SIV感染的猿猴宿主中是保守的。因此，我们确定了一种有效的内源性GPR15介导的HIV和SIV感染抑制剂，该抑制剂不会干扰此GPCR的生理功能。