Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling.
Animals
Cystatin C
/ genetics
HIV Infections
/ genetics
HIV-1
/ genetics
Humans
Receptors, G-Protein-Coupled
/ genetics
Receptors, Peptide
/ genetics
Receptors, Virus
/ genetics
Signal Transduction
/ genetics
Simian Acquired Immunodeficiency Syndrome
/ genetics
Simian Immunodeficiency Virus
/ genetics
T-Lymphocytes
/ metabolism
Virus Internalization
G protein-coupled receptors
GPR15
chemokines
cystatin C
immunodeficiency viruses
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
19 01 2021
19 01 2021
Historique:
entrez:
12
1
2021
pubmed:
13
1
2021
medline:
13
5
2021
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 33431697
pii: 2023776118
doi: 10.1073/pnas.2023776118
pmc: PMC7826402
pii:
doi:
Substances chimiques
Cystatin C
0
GPR15 protein, human
0
Receptors, G-Protein-Coupled
0
Receptors, Peptide
0
Receptors, Virus
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI050529
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI114266
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI126620
Pays : United States
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
Références
Venkatakrishnan A. J., et al. Molecular signatures of G-protein-coupled receptors. Nature. 2013;494:185–194.
Heng B. C., Aubel D., Fussenegger M.. An overview of the diverse roles of G-protein coupled receptors (GPCRs) in the pathophysiology of various human diseases. Biotechnol. Adv.. 2013;31:1676–1694.
Deng H., et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996;381:661–666.
Feng Y., Broder C. C., Kennedy P. E., Berger E. A.. HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272:872–877.
Dragic T., et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996;381:667–673.
Alkhatib G., et al. CC CKR5: A RANTES, MIP-1, MIP-1 receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996;272:1955–1958.
Choe H., et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996;85:1135–1148.
Doranz B. J., et al. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996;85:1149–1158.
Bosso M., Ständker L., Kirchhoff F., Münch J.. Exploiting the human peptidome for novel antimicrobial and anticancer agents. Bioorg. Med. Chem.. 2018;26:2719–2726.
Münch J., Ständker L., Forssmann W.-G., Kirchhoff F.. Discovery of modulators of HIV-1 infection from the human peptidome. Nat. Rev. Microbiol.. 2014;12:715–722.
Detheux M., et al. Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and CCR5 agonist with anti-HIV properties. J. Exp. Med.. 2000;192:1501–1508.
Münch J., et al. Hemofiltrate CC chemokine 1[9-74] causes effective internalization of CCR5 and is a potent inhibitor of R5-tropic human immunodeficiency virus type 1 strains in primary T cells and macrophages. Antimicrob. Agents Chemother.. 2002;46:982–990.
Zirafi O., et al. Discovery and characterization of an endogenous CXCR4 antagonist. Cell Rep.. 2015;11:737–747.
Mörner A., et al. Primary human immunodeficiency virus type 2 (HIV-2) isolates, like HIV-1 isolates, frequently use CCR5 but show promiscuity in coreceptor usage. J. Virol.. 1999;73:2343–2349.
Pöhlmann S., et al. Simian immunodeficiency virus utilizes human and sooty mangabey but not rhesus macaque STRL33 for efficient entry. J. Virol.. 2000;74:5075–5082.
Riddick N. E., et al. Simian immunodeficiency virus SIVagm efficiently utilizes non-CCR5 entry pathways in African green monkey lymphocytes: Potential role for GPR15 and CXCR6 as viral coreceptors. J. Virol.. 2015;90:2316–2331.
Farzan M., et al. Two orphan seven-transmembrane segment receptors which are expressed in CD4-positive cells support simian immunodeficiency virus infection. J. Exp. Med.. 1997;186:405–411.
Owen S. M., et al. Genetically divergent strains of human immunodeficiency virus type 2 use multiple coreceptors for viral entry. J. Virol.. 1998;72:5425–5432.
Deng H. K., Unutmaz D., KewalRamani V. N., Littman D. R.. Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature. 1997;388:296–300.
Riddick N. E., et al. A novel CCR5 mutation common in sooty mangabeys reveals SIVsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in vivo. PLoS Pathog.. 2010;6:e1001064.
Kim S. V., et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science. 2013;340:1456–1459.
Nguyen L. P., et al. Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nat. Immunol.. 2015;16:207–213.
Suply T., et al. A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia. Sci. Signal.. 2017;10:eaal0180.
Ocón B., et al. A mucosal and cutaneous chemokine ligand for the lymphocyte chemoattractant receptor GPR15. Front. Immunol.. 2017;8:1111.
Onopiuk A., Tokarzewicz A., Gorodkiewicz E.. Cystatin C: A kidney function biomarker. Adv. Clin. Chem.. 2015;68:57–69.
Turk V., et al. Cysteine cathepsins: From structure, function and regulation to new frontiers. Biochim. Biophys. Acta. 2012;1824:68–88.
Villa P., Jiménez M., Soriano M.-C., Manzanares J., Casasnovas P.. Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients. Crit. Care. 2005;9:R139–R143.
Magister S., Kos J.. Cystatins in immune system. J. Cancer. 2013;4:45–56.
Sokol J. P., Schiemann W. P.. Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells. Mol. Cancer Res.. 2004;2:183–195.
Xu Y., Ding Y., Li X., Wu X.. Cystatin C is a disease-associated protein subject to multiple regulation. Immunol. Cell Biol.. 2015;93:442–451.
Zi M., Xu Y.. Involvement of cystatin C in immunity and apoptosis. Immunol. Lett.. 2018;196:80–90.
Schulz-Knappe P., et al. Peptide bank generated by large-scale preparation of circulating human peptides. J. Chromatogr. A. 1997;776:125–132.
Pöhlmann S., et al. Co-receptor usage of BOB/GPR15 in addition to CCR5 has no significant effect on replication of simian immunodeficiency virus in vivo. J. Infect. Dis.. 1999;180:1494–1502.
Richter R., et al. Composition of the peptide fraction in human blood plasma: Database of circulating human peptides. J. Chromatogr. B Biomed. Sci. Appl.. 1999;726:25–35.
Randers E., Kristensen J. H., Erlandsen E. J., Danielsen H.. Serum cystatin C as a marker of the renal function. Scand. J. Clin. Lab. Invest.. 1998;58:585–592.
Chahroudi A., Bosinger S. E., Vanderford T. H., Paiardini M., Silvestri G.. Natural SIV hosts: Showing AIDS the door. Science. 2012;335:1188–1193.
Sharp P. M., Hahn B. H.. Origins of HIV and the AIDS pandemic. Cold Spring Harb. Perspect. Med.. 2011;1:a006841.
Visseaux B., Damond F., Matheron S., Descamps D., Charpentier C.. Hiv-2 molecular epidemiology. Infect. Genet. Evol.. 2016;46:233–240.
Clavel F., et al. Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature. 1986;324:691–695.
Döring M., et al. A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support. Retrovirology. 2016;13:85.
Kong L. I., et al. West African HIV-2-related human retrovirus with attenuated cytopathicity. Science. 1988;240:1525–1529.
Kumar P., et al. Molecular characterization of an attenuated human immunodeficiency virus type 2 isolate. J. Virol.. 1990;64:890–901.
Gao F., et al. Genetic diversity of human immunodeficiency virus type 2: Evidence for distinct sequence subtypes with differences in virus biology. J. Virol.. 1994;68:7433–7447.
Ibe S., et al. HIV-2 CRF01_AB: First circulating recombinant form of HIV-2. J. Acquir. Immune Defic. Syndr.. 2010;54:241–247.
Connor R. I., Sheridan K. E., Ceradini D., Choe S., Landau N. R.. Change in coreceptor use correlates with disease progression in HIV-1–Infected individuals. J. Exp. Med.. 1997;185:621–628.
Xiao L., Rudolph D. L., Owen S. M., Spira T. J., Lal R. B.. Adaptation to promiscuous usage of CC and CXC-chemokine coreceptors in vivo correlates with HIV-1 disease progression. AIDS. 1998;12:F137–F143.
P Hlmann S., Krumbiegel M., Kirchhoff F.. Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human immunodeficiency virus type 1. J. Gen. Virol.. 1999;80:1241–1251.
Jiang C., et al. Primary infection by a human immunodeficiency virus with atypical coreceptor tropism. J. Virol.. 2011;85:10669–10681.
Neuhaus J., et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J. Infect. Dis.. 2010;201:1788–1795.
Odden M. C., et al. Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: The FRAM study. Arch. Intern. Med.. 2007;167:2213–2219.
Zaidi N., Kalbacher H.. Cathepsin E: A mini review. Biochem. Biophys. Res. Commun.. 2008;367:517–522.
Appelqvist H., Wäster P., Kågedal K., Öllinger K.. The lysosome: From waste bag to potential therapeutic target. J. Mol. Cell Biol.. 2013;5:214–226.
Yamamoto K., Kawakubo T., Yasukochi A., Tsukuba T.. Emerging roles of cathepsin E in host defense mechanisms. Biochim. Biophys. Acta. 2012;1824:105–112.
Sun H., et al. Proteolytic characteristics of cathepsin D related to the recognition and cleavage of its target proteins. PLoS One. 2013;8:e65733.
Tissera H., et al. Chymase level is a predictive biomarker of dengue hemorrhagic fever in pediatric and adult patients. J. Infect. Dis.. 2017;216:1112–1121.
Bishop J. A., Sharma R., Illei P. B.. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum. Pathol.. 2010;41:20–25.
Verani A., Lusso P.. Chemokines as natural HIV antagonists. Curr. Mol. Med.. 2002;2:691–702.
Woolley M. J., Conner A. C.. Understanding the common themes and diverse roles of the second extracellular loop (ECL2) of the GPCR super-family. Mol. Cell. Endocrinol.. 2017;449:3–11.
Sauter D., Kirchhoff F.. Key viral adaptations preceding the AIDS pandemic. Cell Host Microbe. 2019;25:27–38.
Pandrea I., Sodora D. L., Silvestri G., Apetrei C.. Into the wild: Simian immunodeficiency virus (SIV) infection in natural hosts. Trends Immunol.. 2008;29:419–428.
de Sousa-Pereira P., et al. Evolution of C, D and S-type cystatins in mammals: An extensive gene duplication in primates. PLoS One. 2014;9:e109050.
Samson M., et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722–725.
Bleul C. C., et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996;382:829–833.
Oberlin E., et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996;382:833–835.
Donzella G. A., et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat. Med.. 1998;4:72–77.
Dorr P., et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob. Agents Chemother.. 2005;49:4721–4732.
Bhasin B., et al. HIV viremia and T-cell activation differentially affect the performance of glomerular filtration rate equations based on creatinine and cystatin C. PLoS One. 2013;8:e82028.
Longenecker C. T., et alAIDS Clinical Trials Group Study A5224s Team. Reductions in plasma cystatin C after initiation of antiretroviral therapy are associated with reductions in inflammation: ACTG A5224s. J. Acquir. Immune Defic. Syndr.. 2015;69:168–177.
Rodríguez A., Webster P., Ortego J., Andrews N. W.. Lysosomes behave as Ca2+-regulated exocytic vesicles in fibroblasts and epithelial cells. J. Cell Biol.. 1997;137:93–104.
Okajima F.. Regulation of inflammation by extracellular acidification and proton-sensing GPCRs. Cell. Signal.. 2013;25:2263–2271.
Rajamäki K., et al. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J. Biol. Chem.. 2013;288:13410–13419.
Compton A. A., Malik H. S., Emerman M.. Host gene evolution traces the evolutionary history of ancient primate lentiviruses. Philos. Trans. R. Soc. Lond. B Biol. Sci.. 2013;368:20120496.
Gifford R. J., et al. A transitional endogenous lentivirus from the genome of a basal primate and implications for lentivirus evolution. Proc. Natl. Acad. Sci. U.S.A.. 2008;105:20362–20367.
Münch J., et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell. 2007;129:263–275.
Forssmann W.-G., et al. Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci. Transl. Med.. 2010;2:63re3.
Harms M., et al. An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation. bioRxiv. 2020.
doi: 10.1101/2020.08.28.272781
Lobritz M. A., et al. Multifaceted mechanisms of HIV inhibition and resistance to CCR5 inhibitors PSC-RANTES and Maraviroc. Antimicrob. Agents Chemother.. 2013;57:2640–2650.
Steen A., Schwartz T. W., Rosenkilde M. M.. Targeting CXCR4 in HIV cell-entry inhibition. Mini Rev. Med. Chem.. 2009;9:1605–1621.
Golding H., et al. CCR5 N-terminal region plays a critical role in HIV-1 inhibition by Toxoplasma gondii-derived cyclophilin-18. J. Biol. Chem.. 2005;280:29570–29577.
Zhou N., et al. Structural and functional characterization of human CXCR4 as a chemokine receptor and HIV-1 co-receptor by mutagenesis and molecular modeling studies. J. Biol. Chem.. 2001;276:42826–42833.
Unutmaz D., KewalRamani V. N., Littman D. R.. G protein-coupled receptors in HIV and SIV entry: New perspectives on lentivirus-host interactions and on the utility of animal models. Semin. Immunol.. 1998;10:225–236.
Liu R., et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996;86:367–377.