Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Core Facility Functional Peptidomics, Ulm University Medical Center, 89081 Ulm, Germany.
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). doi: 10.1073/pnas.2023776118.
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），据推测它在黏膜免疫中发挥作用，同时也是 HIV-2 和猴免疫缺陷病毒（SIV）的主要进入辅助因子。为了发现新型内源性 GPR15 配体，我们筛选了一种血滤液（HF）衍生的肽文库，以寻找抑制 GPR15 介导的 SIV 感染的抑制剂。我们的方法鉴定出半胱氨酸蛋白酶抑制剂 C（CysC）的 C 端片段（CysC95-146）可特异性抑制 GPR15 依赖性 HIV-1、HIV-2 和 SIV 感染。相比之下，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 信号转导，而是由炎症部位激活的蛋白酶产生的。CysC95-146 在原代 CD4 T 细胞中的抗逆转录病毒活性得到了证实，并且在 SIV 感染的灵长类动物宿主中保守。因此，我们鉴定出一种有效的内源性 GPR15 介导的 HIV 和 SIV 感染抑制剂，它不会干扰该 GPCR 的生理功能。
