Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Contributed by Beatrice H. Hahn, December 5, 2020 (sent for review November 16, 2020; reviewed by Shibo Jiang and Wesley I. Sundquist)
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.
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).
Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling
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- Biological Sciences
- Immunology and Inflammation
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