Viruses that lie low inside cells after infection come under attack by the immune system when they reawaken and resume multiplying. Hislop et al. (page 1863) now reveal the mechanism used by the Epstein-Barr virus (EBV) to dodge host immunity during this reactivation phase.
EBV initially infects and replicates within oral epithelial cells but later quietly hides out in B cells. During this latent phase, EBV-infected B cells avoid the immune system by expressing very little viral antigen. To ensure viral spread and survival, however, EBV must reenter the replicative, or lytic, phase and invade new epithelial tissues.
Previous studies suggested that this herpesvirus also avoids the attention of the immune system during its reawakening. During the lytic phase, EBV-infected B cells dial down the activity of their transporters associated with antigen processing (TAPs)—transmembrane channel proteins that shuttle antigenic peptides into the ER, where they find their HLA partners. Infected B cells thus display few viral antigens at the cell surface.
Known herpesviruses genes encoding TAP-inhibiting proteins were not found in the EBV genome. The authors therefore compared herpesvirus genomes to find a lytic phase TAP inhibitor gene in EBV and its closest relatives. Cloning and expression of candidate genes uncovered BNLF2a, which encodes a protein that blocked both the peptide-binding and ATP-binding sites on TAPs and thereby prevented it from translocating peptides into the ER.
This mechanism differs from those used by all other herpesvirus TAP inhibitors. The team is currently investigating how the relatively small BNLF2a protein blocks access to two distant sites on TAP.