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.

中文翻译：

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天然胱抑素C片段可抑制GPR15介导的HIV和SIV感染，而不会干扰GPR15L信号传导

GPR15是一种G蛋白偶联受体，被提议在粘膜免疫中发挥作用，也可作为HIV和SIV的进入辅助因子。为了发现新的内源性GPR15配体，我们筛选了血滤液衍生的肽库来检测GPR15介导的SIV感染的抑制剂。我们的方法确定了胱抑素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介导的病毒进入的胱抑素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。CysC95-146的抗逆转录病毒活性在原代CD4 + T细胞中得到证实，在SIV感染的猿猴宿主中得以保留。从而，