Figure. Mechanism of γ-herpesvirus gB-mediated membrane fusion and the potential neutralization mechanism of Fab5.

Supported by grants from the National Natural Science Foundation of China (Nos. U24A20743, 32441094, 82402614), a collaborative research team led by Prof. Zeng Musheng and Assoc. Prof. Sun Cong from Sun Yat-sen University Cancer Center, together with the group of Prof. Liu Zheng from Southern University of Science and Technology, has achieved a breakthrough in the development of broad-spectrum intervention strategies against γ-herpesviruses. The study, entitled “A broadly protective antibody targeting γ-herpesvirus gB”, was published in Nature on February 2, 2026 (DOI: https://doi.org/10.1038/s41586-026-10192-5).

γ-herpesviruses infect a wide range of mammalian species, including humans. Notably, Epstein–Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are major human oncogenic viruses linked to several malignancies and autoimmune disorders. The high genetic heterogeneity among different γ-herpesviruses genera and host-adapted variants has posed a long-standing challenge for developing cross-genus and cross-species broad-spectrum vaccines and neutralizing antibodies.

As enveloped viruses, γ-herpesviruses enter host cells through a membrane-fusion process mediated by the conserved fusion glycoprotein B (gB). Building on their earlier work on an EBV chimeric nanoparticle vaccine, the team employed antigen-specific single B-cell sorting and sequencing to isolate and characterize a monoclonal antibody, designated Fab5, targeting gB. Protein-binding and cell-based assays demonstrated that Fab5 potently binds gB from multiple γ-herpesvirus—including EBV, rhLCV, and MHV68—and effectively blocks viral infection in vitro (see Figure). In vivo studies using mouse, nonhuman primate, and humanized mouse models consistently showed that Fab5 confers significant protection against infection by susceptible γ-herpesvirus.

High-resolution cryo-electron microscopy structures of Fab5 in complex with gB from several γ-herpesviruses revealed that Fab5 engages Domain I of gB, a region exhibiting marked conformational conservation across the γ-herpesvirus family. Epitope mapping based on sequence-structure analysis indicated that the Domain I epitope recognized by Fab5 is functionally conserved despite partial sequence variation among different γ-herpesviruses. This domain remains structurally stable and solvent-accessible in both pre-fusion and post-fusion conformations of gB, constituting a conserved neutralizing site. The findings suggest that Fab5 likely neutralizes γ-herpesviruses broadly by interfering with key conformational transitions of gB during membrane fusion or by disrupting the gHgL–gB signaling cascade required for fusion progression.

In summary, this work identifies a broad-spectrum neutralizing antibody, Fab5, against γ-herpesviruses and elucidates its conserved binding epitope within gB Domain I. These results offer a promising therapeutic strategy for combating γ-herpesvirus infections, particularly those driven by oncogenic viruses, and provide a structural framework for the rational design of next-generation broad-spectrum herpesvirus vaccines and antibody-based therapeutics.