CryoEM and X-ray structures shed light on the mechanism of Epstein-Barr Virus neutralizing antibody AMMO1

Infecting more than 95% of adults, Epstein-Barr virus (EBV) is part of the Herpesviridae family of DNA viruses. Primary infection by EBV often starts asymptomatically in children but can manifest into lymphoproliferative (excess white blood cell) disorders. In young adults, EBV is most widely known as the causative agent of infectious mononucleosis or the ‘kissing disease’. Due to links to various forms of cancer, strategies for prevention of EBV infection are greatly needed.

Although there has been little progress in the development of a successful vaccine, major attempts have focused on the abundant and surface exposed glycoprotein 350 (gp350).  Other important targets include glycoproteins gH, gL, gB and gp42 involved in the dual-tropic (dual receptor mediated) infection of B cells and epithelial cells. Few known monoclonal antibodies (mAbs) have been able to prevent both B cell and epithelial cell entry. However, recent progress on neutralizing antibodies by the Veesler lab at the University of Washington and the McGuire lab at the Fred Hutch, in partnership with the Seattle Structural Genomics Center for Infectious Disease (SSGCID), may contribute to improved vaccine design.

As reported in Snijder et al. (2018), researchers have isolated a human anti-gH/gL mAb called AMMO1 that effectively neutralized both B cell and epithelial infections by disrupting activation of the EBV fusion machinery. A cryoEM structure of the gH/gL-gp42-AMMO1 complex was determined (PDB: 6C5V) along with an X-ray structure of AMMO1 (PDB: 6BLA) revealing the intricacies of the antibody binding mode. AMMO1 is the first antibody isolated from natural infections in humans and the first molecule capable of inhibiting infections of both epithelial cells and B cells, the two major targets of EBV infections. AMMO1 recognizes a discontinuous epitope at the Domain-I/Domain-II interface between gH and gL and blocks membrane fusion and viral entry, as supported by cell-cell fusion assays.

Overall, these results identify a key epitope recognized by AMMO1 on the EBV viral glycoproteins which is important for activation of the fusion machinery. More significantly, AMMO1 was isolated during the humoral immune response phase of EBV-infected individuals and was able to neutralize both B cell and epithelial cell infection, presenting a more promising and stable alternative in the development of new treatments for patients.

CryoEM structure of the gH/gL-gp42-AMMO1 complex was determined (PDB: 6C5V) along with an X-ray structure of AMMO1 (PDB: 6BLA).
This image has been rendered by Abigail S Wall and David Veesler.


Snijder J, Ortego MS, Weidle C, Stuart AB, Gray MD, McElrath MJ, Pancera M, Veesler D, McGuire AT. An antibody targeting the fusion machinery neutralizes dual-tropic infection and define a site of vulnerability on Epstein-Barr virus. Immunity 2018 Apr; 48: 799-811. doi: 10.1016/j.immuni.2018.03.026.

Link to PDB entries: 6BLA, 6C5V, 5W0K

Showcase written by Jenny Phan, Beryllium

Featured Structures

Overlay of 3 Bartonella BID domains

Bartonella BID

Recent Tweets