A Linear Epitope in the N-Terminal Domain of CCR5 and Its Interaction with Antibody

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Jun 2

PMID 26030924

Citations 7

Authors

Benny Chain

Jack Arnold

Samia Akthar

Michael Brandt

David Davis

Mahdad Noursadeghi

Thabo Lapp

Changhua Ji

Surya Sankuratri

Yanjing Zhang

Lata Govada

Emmanuel Saridakis

Naomi Chayen

Affiliations

Soon will be listed here.

Abstract

The CCR5 receptor plays a role in several key physiological and pathological processes and is an important therapeutic target. Inhibition of the CCR5 axis by passive or active immunisation offers one very selective strategy for intervention. In this study we define a new linear epitope within the extracellular domain of CCR5 recognised by two independently produced monoclonal antibodies. A short peptide encoding the linear epitope can induce antibodies which recognise the intact receptor when administered colinear with a tetanus toxoid helper T cell epitope. The monoclonal antibody RoAb 13 is shown to bind to both cells and peptide with moderate to high affinity (6x10^8 and 1.2x107 M-1 respectively), and binding to the peptide is enhanced by sulfation of tyrosines at positions 10 and 14. RoAb13, which has previously been shown to block HIV infection, also blocks migration of monocytes in response to CCR5 binding chemokines and to inflammatory macrophage conditioned medium. A Fab fragment of RoAb13 has been crystallised and a structure of the antibody is reported to 2.1 angstrom resolution.

Citing Articles

Identification of the Binding Epitope of an Anti-Mouse CCR6 Monoclonal Antibody (CMab-13) Using 1× Alanine Scanning.

Tanaka T, Tawara M, Suzuki H, Kaneko M, Kato Y Antibodies (Basel). 2023; 12(2).

PMID: 37218898 PMC: 10204553. DOI: 10.3390/antib12020032.

X-ray crystallographic studies of RoAb13 bound to PIYDIN, a part of the N-terminal domain of C-C chemokine receptor 5.

Govada L, Saridakis E, Kassen S, Bin-Ramzi A, Morgan R, Chain B IUCrJ. 2021; 8(Pt 4):678-683.

PMID: 34258015 PMC: 8256702. DOI: 10.1107/S2052252521005340.

The Expanding Therapeutic Perspective of CCR5 Blockade.

Vangelista L, Vento S Front Immunol. 2018; 8:1981.

PMID: 29375583 PMC: 5770570. DOI: 10.3389/fimmu.2017.01981.

The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection.

Venuti A, Pastori C, Lopalco L Front Immunol. 2017; 8:1358.

PMID: 29163468 PMC: 5670346. DOI: 10.3389/fimmu.2017.01358.

Opportunities for therapeutic antibodies directed at G-protein-coupled receptors.

Hutchings C, Koglin M, Olson W, Marshall F Nat Rev Drug Discov. 2017; 16(9):787-810.

PMID: 28706220 DOI: 10.1038/nrd.2017.91.

References

Chain B, Noursadeghi M, Gardener M, Tsang J, Wright E . HIV blocking antibodies following immunisation with chimaeric peptides coding a short N-terminal sequence of the CCR5 receptor. Vaccine. 2008; 26(45):5752-9. PMC: 2670972. DOI: 10.1016/j.vaccine.2008.08.025. View

Pastori C, Diomede L, Venuti A, Fisher G, Jarvik J, Bomsel M . Induction of HIV-blocking anti-CCR5 IgA in Peyers's patches without histopathological alterations. J Virol. 2014; 88(7):3623-35. PMC: 3993546. DOI: 10.1128/JVI.03663-13. View

Farzan M, Mirzabekov T, Kolchinsky P, Wyatt R, Cayabyab M, Gerard N . Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell. 1999; 96(5):667-76. DOI: 10.1016/s0092-8674(00)80577-2. View

Panina-Bordignon P, Tan A, Termijtelen A, Demotz S, Corradin G, Lanzavecchia A . Universally immunogenic T cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur J Immunol. 1989; 19(12):2237-42. DOI: 10.1002/eji.1830191209. View

Dyson H, Lerner R, Wright P . The physical basis for induction of protein-reactive antipeptide antibodies. Annu Rev Biophys Biophys Chem. 1988; 17:305-24. DOI: 10.1146/annurev.bb.17.060188.001513. View

Ji C, Brandt M, Dioszegi M, Jekle A, Schwoerer S, Challand S . Novel CCR5 monoclonal antibodies with potent and broad-spectrum anti-HIV activities. Antiviral Res. 2006; 74(2):125-37. DOI: 10.1016/j.antiviral.2006.11.003. View

Misumi S, Nakayama D, Kusaba M, Iiboshi T, Mukai R, Tachibana K . Effects of immunization with CCR5-based cycloimmunogen on simian/HIVSF162P3 challenge. J Immunol. 2005; 176(1):463-71. DOI: 10.4049/jimmunol.176.1.463. View

Evans P . Scaling and assessment of data quality. Acta Crystallogr D Biol Crystallogr. 2005; 62(Pt 1):72-82. DOI: 10.1107/S0907444905036693. View

Bogers W, Bergmeier L, Oostermeijer H, ten Haaft P, Wang Y, Kelly C . CCR5 targeted SIV vaccination strategy preventing or inhibiting SIV infection. Vaccine. 2004; 22(23-24):2974-84. DOI: 10.1016/j.vaccine.2004.02.050. View

10.

Samson M, Libert F, Doranz B, Rucker J, Liesnard C, Farber C . Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996; 382(6593):722-5. DOI: 10.1038/382722a0. View

11.

Leslie A, Powell H, Winter G, Svensson O, Spruce D, McSweeney S . Automation of the collection and processing of X-ray diffraction data -- a generic approach. Acta Crystallogr D Biol Crystallogr. 2002; 58(Pt 11):1924-8. DOI: 10.1107/s0907444902016864. View

12.

Afonine P, Grosse-Kunstleve R, Echols N, Headd J, Moriarty N, Mustyakimov M . Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr D Biol Crystallogr. 2012; 68(Pt 4):352-67. PMC: 3322595. DOI: 10.1107/S0907444912001308. View

13.

Lee B, Sharron M, Blanpain C, Doranz B, Vakili J, Setoh P . Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. J Biol Chem. 1999; 274(14):9617-26. DOI: 10.1074/jbc.274.14.9617. View

14.

Griffith J, Sokol C, Luster A . Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol. 2014; 32:659-702. DOI: 10.1146/annurev-immunol-032713-120145. View

15.

Noursadeghi M, Tsang J, Haustein T, Miller R, Chain B, Katz D . Quantitative imaging assay for NF-kappaB nuclear translocation in primary human macrophages. J Immunol Methods. 2007; 329(1-2):194-200. PMC: 2225449. DOI: 10.1016/j.jim.2007.10.015. View

16.

Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E . Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2010; 117(10):2791-9. DOI: 10.1182/blood-2010-09-309591. View

17.

Jones K, Maguire J, Davenport A . Chemokine receptor CCR5: from AIDS to atherosclerosis. Br J Pharmacol. 2010; 162(7):1453-69. PMC: 3057285. DOI: 10.1111/j.1476-5381.2010.01147.x. View

18.

Weitzenfeld P, Ben-Baruch A . The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett. 2013; 352(1):36-53. DOI: 10.1016/j.canlet.2013.10.006. View

19.

Li L, Tian J, Yang K, Zhang P, Jia W . Humanized PA14 (a monoclonal CCR5 antibody) for treatment of people with HIV infection. Cochrane Database Syst Rev. 2014; (7):CD008439. PMC: 7173721. DOI: 10.1002/14651858.CD008439.pub3. View

20.

Murshudov G, Vagin A, Dodson E . Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 3):240-55. DOI: 10.1107/S0907444996012255. View