期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：32
DOI：10.1073/pnas.2202371119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Epstein-Barr virus (EBV) accounts for 200,000 new epithelial and B cell malignancy cases and 140,000 deaths annually. Glycoprotein B (gB) is the sole fusogen that is highly conserved and essential for all herpesvirus entry into target cells and thus, is attracting attention to identify potent antibodies to neutralize viral infection. Here, we discovered two anti-EBV gB neutralizing antibodies, 3A3 and 3A5, that effectively neutralized EBV infection of both B and epithelial cells. They also potently protected against EBV-induced lymphoproliferative disorders in humanized mice. Importantly, the 3A3 and 3A5 epitopes identified here represent the neutralizing antigenic sites to block EBV infection and membrane fusion. They are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans.
Epstein-Barr virus (EBV) infects more than 90% of the world’s adult population and accounts for a significant cancer burden of epithelial and B cell origins. Glycoprotein B (gB) is the primary fusogen essential for EBV entry into host cells. Here, we isolated two EBV gB-specific neutralizing antibodies, 3A3 and 3A5; both effectively neutralized the dual-tropic EBV infection of B and epithelial cells. In humanized mice, both antibodies showed effective protection from EBV-induced lymphoproliferative disorders. Cryoelectron microscopy analyses identified that 3A3 and 3A5 bind to nonoverlapping sites on domains D-II and D-IV, respectively. Structure-based mutagenesis revealed that 3A3 and 3A5 inhibit membrane fusion through different mechanisms involving the interference with gB-cell interaction and gB activation. Importantly, the 3A3 and 3A5 epitopes are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans, providing potential targets for antiviral therapies and vaccines.
