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Research Article

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

View ORCID ProfileManuel Hayn, Andrea Blötz, View ORCID ProfileArmando Rodríguez, View ORCID ProfileSolange Vidal, Nico Preising, View ORCID ProfileLudger Ständker, View ORCID ProfileSebastian Wiese, Christina M. Stürzel, Mirja Harms, View ORCID ProfileRüdiger Gross, View ORCID ProfileChristoph Jung, Miriam Kiene, View ORCID ProfileTimo Jacob, View ORCID ProfileStefan Pöhlmann, Wolf-Georg Forssmann, View ORCID ProfileJan Münch, View ORCID ProfileKonstantin M. J. Sparrer, View ORCID ProfileKlaus Seuwen, View ORCID ProfileBeatrice H. Hahn, and View ORCID ProfileFrank Kirchhoff
  1. aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
  2. bCore Facility Functional Peptidomics, Ulm University Medical Center, 89081 Ulm, Germany;
  3. cCore Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany;
  4. dPHARIS Biotec GmbH, 30625 Hannover, Germany;
  5. eNovartis Institutes for Biomedical Research, 4056 Basel, Switzerland;
  6. fInstitute of Electrochemistry, Ulm University, 89081 Ulm, Germany;
  7. gInfection Biology Unit, German Primate Center–Leibniz Institute for Primate Research, 37077 Göttingen, Germany;
  8. hFaculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany;
  9. iDepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076;
  10. jDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076

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PNAS January 19, 2021 118 (3) e2023776118; https://doi.org/10.1073/pnas.2023776118
Manuel Hayn
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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  • ORCID record for Manuel Hayn
Andrea Blötz
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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Armando Rodríguez
bCore Facility Functional Peptidomics, Ulm University Medical Center, 89081 Ulm, Germany;
cCore Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany;
dPHARIS Biotec GmbH, 30625 Hannover, Germany;
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  • ORCID record for Armando Rodríguez
Solange Vidal
eNovartis Institutes for Biomedical Research, 4056 Basel, Switzerland;
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  • ORCID record for Solange Vidal
Nico Preising
bCore Facility Functional Peptidomics, Ulm University Medical Center, 89081 Ulm, Germany;
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Ludger Ständker
bCore Facility Functional Peptidomics, Ulm University Medical Center, 89081 Ulm, Germany;
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  • ORCID record for Ludger Ständker
Sebastian Wiese
cCore Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany;
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  • ORCID record for Sebastian Wiese
Christina M. Stürzel
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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Mirja Harms
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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Rüdiger Gross
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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  • ORCID record for Rüdiger Gross
Christoph Jung
fInstitute of Electrochemistry, Ulm University, 89081 Ulm, Germany;
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  • ORCID record for Christoph Jung
Miriam Kiene
gInfection Biology Unit, German Primate Center–Leibniz Institute for Primate Research, 37077 Göttingen, Germany;
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Timo Jacob
fInstitute of Electrochemistry, Ulm University, 89081 Ulm, Germany;
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  • ORCID record for Timo Jacob
Stefan Pöhlmann
gInfection Biology Unit, German Primate Center–Leibniz Institute for Primate Research, 37077 Göttingen, Germany;
hFaculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany;
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Wolf-Georg Forssmann
dPHARIS Biotec GmbH, 30625 Hannover, Germany;
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Jan Münch
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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  • ORCID record for Jan Münch
Konstantin M. J. Sparrer
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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  • ORCID record for Konstantin M. J. Sparrer
Klaus Seuwen
eNovartis Institutes for Biomedical Research, 4056 Basel, Switzerland;
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  • ORCID record for Klaus Seuwen
Beatrice H. Hahn
iDepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076;
jDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076
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  • For correspondence: bhahn@pennmedicine.upenn.edu frank.kirchhoff@uni-ulm.de
Frank Kirchhoff
aInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;
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  • For correspondence: bhahn@pennmedicine.upenn.edu frank.kirchhoff@uni-ulm.de
  1. Contributed by Beatrice H. Hahn, December 5, 2020 (sent for review November 16, 2020; reviewed by Shibo Jiang and Wesley I. Sundquist)

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Significance

G protein-coupled receptors (GPCRs) are involved in many physiological processes and important drug targets. However, most therapeutic agents targeting GPCRs, such as the coreceptors of HIV-1 CCR5 and CXCR4, also interfere with their signaling function. Here, we used primate lentiviruses as tools to discover novel endogenous ligands of GPR15, a coreceptor for HIV-2 and SIV proposed to play a role in mucosal immunity. We found that C-terminal fragments of cystatin C generated by immune-activated proteases inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L chemokine signaling. Thus, we identified an endogenous bioactive peptide that specifically prevents the detrimental activity of a GPCR (i.e. virus infection) without compromising its physiological signaling function.

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.

  • G protein-coupled receptors
  • GPR15
  • immunodeficiency viruses
  • chemokines
  • cystatin C

Footnotes

  • ↵1M. Hayn and A.B. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: bhahn{at}pennmedicine.upenn.edu or frank.kirchhoff{at}uni-ulm.de.
  • Author contributions: A.B., L.S., S.W., S.P., K.M.J.S., K.S., and F.K. designed research; M. Hayn, A.B., A.R., S.V., N.P., S.W., C.M.S., M. Harms, R.G., C.J., M.K., and T.J. performed research; C.M.S., W.-G.F., J.M., and B.H.H. contributed new reagents/analytic tools; M. Hayn, A.B., A.R., L.S., S.W., C.J., T.J., S.P., K.M.J.S., K.S., and F.K. analyzed data; and B.H.H. and F.K. wrote the paper.

  • Reviewers: S.J., Fudan University; and W.I.S., University of Utah Medical Center.

  • The authors declare no competing interest.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2023776118/-/DCSupplemental.

Data Availability.

All data generated in this study are included in the paper and SI Appendix.

  • Copyright © 2021 the Author(s). Published by PNAS.

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling
Manuel Hayn, Andrea Blötz, Armando Rodríguez, Solange Vidal, Nico Preising, Ludger Ständker, Sebastian Wiese, Christina M. Stürzel, Mirja Harms, Rüdiger Gross, Christoph Jung, Miriam Kiene, Timo Jacob, Stefan Pöhlmann, Wolf-Georg Forssmann, Jan Münch, Konstantin M. J. Sparrer, Klaus Seuwen, Beatrice H. Hahn, Frank Kirchhoff
Proceedings of the National Academy of Sciences Jan 2021, 118 (3) e2023776118; DOI: 10.1073/pnas.2023776118

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Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling
Manuel Hayn, Andrea Blötz, Armando Rodríguez, Solange Vidal, Nico Preising, Ludger Ständker, Sebastian Wiese, Christina M. Stürzel, Mirja Harms, Rüdiger Gross, Christoph Jung, Miriam Kiene, Timo Jacob, Stefan Pöhlmann, Wolf-Georg Forssmann, Jan Münch, Konstantin M. J. Sparrer, Klaus Seuwen, Beatrice H. Hahn, Frank Kirchhoff
Proceedings of the National Academy of Sciences Jan 2021, 118 (3) e2023776118; DOI: 10.1073/pnas.2023776118
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Proceedings of the National Academy of Sciences: 118 (3)
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