Academic Journal
Structural basis for complement receptor engagement and virus neutralization through Epstein-Barr virus gp350.
| Τίτλος: | Structural basis for complement receptor engagement and virus neutralization through Epstein-Barr virus gp350. |
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| Συγγραφείς: | Joyce MG; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD 20817, USA; Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. Electronic address: gjoyce@eidresearch.org., Bu W; Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Chen WH; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD 20817, USA; Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA., Gillespie RA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Andrews SF; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Wheatley AK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Tsybovsky Y; Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Jensen JL; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD 20817, USA; Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA., Stephens T; Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Prabhakaran M; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Fisher BE; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Narpala SR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Bagchi M; Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., McDermott AB; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Nabel GJ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Kwong PD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Mascola JR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Cohen JI; Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Kanekiyo M; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: kanekiyom@nih.gov. |
| Πηγή: | Immunity [Immunity] 2025 Feb 11; Vol. 58 (2), pp. 295-308.e5. Date of Electronic Publication: 2025 Feb 04. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Intramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge, MA : Cell Press Original Publication: Cambridge, Mass. : Cell Press, c1994- |
| Ιατρικοί όροι (MeSH): | Herpesvirus 4, Human*/immunology , Antibodies, Neutralizing*/immunology , Antibodies, Neutralizing*/metabolism , Epstein-Barr Virus Infections*/immunology , Receptors, Complement 3d*/metabolism , Receptors, Complement 3d*/chemistry , Receptors, Complement 3d*/immunology , Viral Matrix Proteins*/immunology , Viral Matrix Proteins*/chemistry , Viral Matrix Proteins*/metabolism, Antibodies, Viral/immunology ; Antibodies, Viral/metabolism ; Complement C3d/metabolism ; Complement C3d/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/virology ; Animals ; Humans ; Protein Binding ; Binding Sites ; Models, Molecular ; Macaca ; Molecular Mimicry |
| Περίληψη: | Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with malignancies in humans. Viral infection of B cells is initiated by the viral glycoprotein 350 (gp350) binding to complement receptor 2 (CR2). Despite decades of effort, no vaccines or curative agents have been developed, partly due to lack of atomic-level understanding of the virus-host interface. Here, we determined the 1.7 Å structure of gp350 in complex with CR2. CR2 binding of gp350 utilized the same set of Arg residues required for recognition of its natural ligand, complement C3d. We further determined the structures of gp350 in complex with three potently neutralizing antibodies (nAbs) obtained from vaccinated macaques and EBV-infected individuals. Like the CR2 interaction, these nAbs targeted the acidic pocket within the CR2-binding site on gp350 using Arg residues. Our results illustrate two axes of molecular mimicry-gp350 versus C3d and CR2 versus EBV nAbs-offering insights for EBV vaccines and therapeutics development. (Published by Elsevier Inc.) |
| Competing Interests: | Declaration of interests M.G.J., W.B., J.I.C., and M.K. are listed as inventors on a patent application based on the studies presented in this paper, which have been filed by the Department of Health and Human Services and the Henry M. Jackson Foundation. At the time that the research described in this paper was initiated, G.J.N. was an employee of Sanofi, which has filed patent applications on EBV vaccines. G.J.N and J.R.M. are current employees of ModeX Therapeutics, which develops EBV vaccines. A.B.M. is a current employee of Sanofi. |
| Grant Information: | HHSN261200800001E United States CA NCI NIH HHS; P30 GM124165 United States GM NIGMS NIH HHS; S10 OD021527 United States OD NIH HHS |
| Contributed Indexing: | Keywords: CR2; EBV; Epstein-Barr virus; Herpesvirus; antibody therapeutics; gp350; human complement receptor 2; mAb; molecular mimicry; sites of vulnerability |
| Molecular Sequence: | ClinicalTrials.gov NCT04645147, NCT05683834 PDB 8SM0, 8SMI, 8SEF, 8SGA, 8SGG, 8SGN, 8SIC GENBANK PQ539149, PQ539150, PQ539151, PQ539152, PQ539289, PQ539290, PQ539291, PQ539292, PQ539293, PQ539294, PQ539295, PQ539296, PQ539297, PQ539298, PQ539299, PQ539300, PQ539301, PQ539302, PQ539303, PQ539304, PQ539305, PQ539306, PQ539307, PQ539308 |
| Substance Nomenclature: | 0 (Antibodies, Neutralizing) 0 (Receptors, Complement 3d) 0 (Antibodies, Viral) 80295-45-0 (Complement C3d) 0 (Viral Matrix Proteins) |
| Entry Date(s): | Date Created: 20250205 Date Completed: 20250506 Latest Revision: 20260605 |
| Update Code: | 20260606 |
| DOI: | 10.1016/j.immuni.2025.01.010 |
| PMID: | 39909035 |
| Βάση Δεδομένων: | MEDLINE |
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