1. Natural Cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling
- Author
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Stefan Pöhlmann, Beatrice H. Hahn, Jan Münch, Konstantin M. J. Sparrer, Christina M. Stürzel, Klaus Seuwen, Rüdiger Gross, Ludger Ständker, Manuel Hayn, Timo Jacob, Andrea Blötz, Frank Kirchhoff, Wolf-Georg Forssmann, Solange Vidal, Mirja Harms, Armando Rodríguez, Sebastian Wiese, Christoph Jung, Nico Preising, and Miriam Kiene
- Subjects
Kidney function tests ,Chemokine ,viruses ,T-Lymphocytes ,Simian Acquired Immunodeficiency Syndrome ,chemokines ,HIV Infections ,medicine.disease_cause ,Receptors, G-Protein-Coupled ,Chemokine receptor ,DDC 570 / Life sciences ,Immunology and Inflammation ,G protein-coupled receptors ,cystatin C ,immunodeficiency viruses ,Kathepsine ,Receptor ,SMALL-MOLECULE INHIBITOR ,Multidisciplinary ,biology ,virus diseases ,Biological Sciences ,CHEMOKINE RECEPTOR ,CORECEPTOR ,ENTRY ,Receptors, Virus ,Simian Immunodeficiency Virus ,Chemokines ,medicine.symptom ,G proteins ,Signal Transduction ,Proteases ,Receptors, Peptide ,Inflammation ,Virus ,PROTEIN-COUPLED RECEPTORS ,Viral entry ,ddc:570 ,DIVERSE ROLES ,medicine ,Animals ,Humans ,ddc:610 ,Peptide library ,HIV (Viruses) ,CCR5-Rezeptor ,Simian immunodeficiency virus ,Virus Internalization ,Cystatins ,Virology ,Cystatin C ,HIV-1 ,biology.protein ,GPR15 ,DDC 610 / Medicine & health - Abstract
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., publishedVersion
- Published
- 2020
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