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. 2025 Feb 11;58(2):295-308.e5.
doi: 10.1016/j.immuni.2025.01.010. Epub 2025 Feb 4.

Structural basis for complement receptor engagement and virus neutralization through Epstein-Barr virus gp350

M Gordon Joyce  1 , Wei Bu  2 , Wei-Hung Chen  3 , Rebecca A Gillespie  4 , Sarah F Andrews  4 , Adam K Wheatley  4 , Yaroslav Tsybovsky  5 , Jaime L Jensen  3 , Tyler Stephens  5 , Madhu Prabhakaran  4 , Brian E Fisher  4 , Sandeep R Narpala  4 , Meghna Bagchi  2 , Adrian B McDermott  4 , Gary J Nabel  4 , Peter D Kwong  4 , John R Mascola  4 , Jeffrey I Cohen  2 , Masaru Kanekiyo  6
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Free article

Structural basis for complement receptor engagement and virus neutralization through Epstein-Barr virus gp350

M Gordon Joyce et al. Immunity. .
Free article

Abstract

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.

Keywords: CR2; EBV; Epstein-Barr virus; Herpesvirus; antibody therapeutics; gp350; human complement receptor 2; mAb; molecular mimicry; sites of vulnerability.

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Conflict of interest statement

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.

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