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

SummaryEpstein-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.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► 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