Human Complement Receptor Type 1/CD35 Is an Epstein-Barr Virus Receptor

• Published in: Cell reports (Cambridge) 2013-02, Vol.3 (2), p.371-385
• Main Authors: Ogembo, Javier G., Kannan, Lakshmi, Ghiran, Ionita, Nicholson-Weller, Anne, Finberg, Robert W., Tsokos, George C., Fingeroth, Joyce D.
• Format: Article
• Language: English
• Subjects: Antigens, CD19 - metabolism; Cell Line; Epstein-Barr virus; Herpesvirus 4, Human - metabolism; Humans; K562 Cells; Mutation; Precursor Cells, B-Lymphoid - immunology; Precursor Cells, B-Lymphoid - metabolism; Protein Binding; Receptors, Complement 3b - genetics; Receptors, Complement 3b - metabolism; Receptors, Complement 3d - genetics; Receptors, Complement 3d - metabolism; Temperature; Transfection; Viral Matrix Proteins - metabolism; Virus Attachment; Virus Internalization
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.01.023

Epstein-Barr virus (EBV) attachment to primary B cells initiates virus entry. Although CD21 is the only known receptor for EBVgp350/220, a recent report documents EBV-infected B cells from a patient genetically deficient in CD21. On normal resting B cells, CD21 forms two membrane complexes: one with CD19 and another with CD35. Whereas the CD21/CD19 complex is widely retained on immortalized and B cell tumor lines, the related complement-regulatory protein CD35 is lost. To determine the role(s) of CD35 in initial infection, we transduced a CD21-negative pre-B cell and myeloid leukemia line with CD35, CD21, or both. Cells expressing CD35 alone bound gp350/220 and became latently infected when the fusion receptor HLA II was coexpressed. Temporal, biophysical, and structural characteristics of CD35-mediated infection were distinct from CD21. Identification of CD35 as an EBV receptor uncovers a salient role in primary infection, addresses unsettled questions of virus tropism, and underscores the importance of EBVgp350/220 for vaccine development. [Display omitted] ► Human CD35, like CD21, binds EBVgp350/220, the major virion envelope glycoprotein ► CD35 mediates latent EBV infection when the fusion coreceptor HLA II is expressed ► Temperature, tempo, structure, and regulation distinguish CD35-mediated infection ► CD35 is a physiologically relevant EBV receptor Epstein-Barr virus (EBV) infection begins upon attachment of EBVgp350/220 to CD21 on normal B cells where CD21 forms two complexes: one with CD19, another with CD35. The CD21/CD19 complex persists on immortalized and B cell tumor lines, whereas CD35 is lost. To investigate CD35’s role, Fingeroth and colleagues transduced cells with CD35, CD21, or both. Strikingly, CD35+ cells bound gp350/220 and were latently infected when HLA II was coexpressed. These findings identify a receptor and underscore the importance of EBVgp350/220 for vaccine development.