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Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with B cell lymphomas. EBV glycoprotein 42 (gp42) binds HLA class II and activates membrane fusion with B cells. We isolated gp42-specific monoclonal antibodies (mAbs), A10 and 4C12, which use distinct mechanisms to neutralize virus infection. mAb A10 was more potent than the only known neutralizing gp42 mAb, F-2-1, in neutralizing EBV infection and blocking binding to HLA class II. mAb 4C12 was similar to mAb A10 in inhibiting glycoprotein-mediated B cell fusion but did not block receptor binding, and it was less effective in neutralizing infection. Crystallographic structures of gH/gL/gp42/A10 and gp42/4C12 complexes revealed two distinct sites of vulnerability on gp42 for receptor binding and B cell fusion. Passive transfer of mAb A10 into humanized mice conferred nearly 100% protection from viremia and EBV lymphomas after EBV challenge. These findings identify vulnerable sites on EBV that may facilitate therapeutics and vaccines. [Display omitted] • Isolated mAbs to EBV gp42, which is required for the fusion of the virus to B cells • gp42 mAbs A10 and 4C12 use different mechanisms to inhibit EBV fusion to B cells • Two distinct sites were identified on gp42 for receptor binding and for fusion to B cells • gp42 mAb A10 prevented viremia and EBV lymphoma in humanized mice challenged with virus EBV glycoprotein gp42 is essential for B cell entry, and identifying sites of vulnerability is important for rational vaccine design. Bu et al. isolated two gp42 mAbs that neutralize EBV infection and block fusion with B cells by distinct mechanisms, defining unique sites of vulnerability. Passive transfer of one mAb prevented viremia and EBV lymphoma in EBV-challenged humanized mice. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is nearly ubiquitous in adults. EBV causes infectious mononucleosis and is associated with B cell lymphomas, epithelial cell malignancies, and multiple sclerosis. The EBV gH/gL glycoprotein complex facilitates fusion of virus membrane with host cells and is a target of neutralizing antibodies. Here, we examined the sites of vulnerability for virus neutralization and fusion inhibition within EBV gH/gL. We developed a panel of human monoclonal antibodies (mAbs) that targeted five distinct antigenic sites on EBV gH/gL and prevented infection of epithelial and B cells. Structural analyses using X-ray crystallography and electron microscopy revealed multiple sites of vulnerability and defined the antigenic landscape of EBV gH/gL. One mAb provided near-complete protection against viremia and lymphoma in a humanized mouse EBV challenge model. Our findings provide structural and antigenic knowledge of the viral fusion machinery, yield a potential therapeutic antibody to prevent EBV disease, and emphasize gH/gL as a target for herpesvirus vaccines and therapeutics. [Display omitted] • Six human mAbs target five distinct sites on EBV gH/gL • Some of these antigenic sites match sites of vulnerability on other herpesviruses • Each mAb neutralizes EBV infection and blocks virus-cell fusion • mAb 769B10 inhibits viremia and prevents lymphoma in an animal EBV challenge model EBV is associated with several malignancies. Chen and colleagues identify six human monoclonal antibodies (mAbs) that target five distinct sites on EBV gH/gL, neutralize virus infection, and inhibit virus-cell fusion. mAb 769B10 reduces viremia and prevents lymphoma in mice challenged with EBV and may be useful as a therapeutic. [ABSTRACT FROM AUTHOR]

Background: Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists., Methods: Two patients with inborn errors of immunity, X- linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T cell (NST) response, B cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant setting (HSCT) before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing., Results: The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in one patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-vs-host-disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T cell compartments which recognized multiple norovirus structural and non-structural viral antigens. T cell responses were minimal during active CNI but detectable after resolution. Mapping of norovirus-specific T cell responses between the patient with DOCK8 and his matched sibling donor were nearly identical. B cell reconstitution or new endogenous antibody production for IgA or IgG were not observed., Conclusion: This report is the first to demonstrate reconstitution of norovirus-specific T cell immunity after HSCT closely temporally aligned with clearance of CNI suggesting that cellular immunity is sufficient for norovirus clearance., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)