HVEM Signaling Promotes Protective Antibody-Dependent Cellular Cytotoxicity (ADCC) Vaccine Responses to Herpes Simplex Viruses.

Herpes simplex virus glycoprotein D allows viral evasion of protective host ADCC responses by interfering with LIGHT-HVEM signaling. Subversion of ADCC by herpes viruses Antibodies to viruses produced after infection or vaccination can protect the host by virus neutralization or through antibody-dependent cellular cytotoxicity (ADCC). The strong ADCC response elicited by an HSV-2 vaccine strain lacking glycoprotein D (∆gD-2) provides robust protection against wild-type HSV-2 challenge in mice. Burn Aschner et al. tested the hypothesis that HSV-2 gD binding to the HVEM entry receptor interferes with host immunity by blocking an HVEM-dependent signaling pathway needed to achieve a protective ADCC response. They found that the ∆gD-2 vaccine–induced ADCC response in mice requires HVEM and its ligand LIGHT during the inductive phase and HVEM and the FcγIV receptor during the effector phase. This research provides a deeper understanding of the host signaling pathways that support the establishment of ADCC. Herpes simplex virus (HSV) glycoprotein D (gD) not only is required for virus entry and cell-to-cell spread but also binds the host immunomodulatory molecule, HVEM, blocking interactions with its ligands. Natural infection primarily elicits neutralizing antibodies targeting gD, but subunit protein vaccines designed to induce this response have failed clinically. In contrast, preclinical studies demonstrate that an HSV-2 single-cycle strain deleted in gD, ΔgD-2, induces primarily non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC). These studies were designed to test the hypothesis that gD interferes with ADCC through engagement of HVEM. Immunization of Hvem−/− mice with ΔgD-2 resulted in significant reduction in HSV-specific IgG2 antibodies, the subclass associated with FcγR activation and ADCC, compared with wild-type controls. This translated into a parallel reduction in active and passive vaccine protection. A similar decrease in ADCC titers was observed in Hvem−/− mice vaccinated with an alternative HSV vaccine candidate (dl5-29) or an unrelated vesicular stomatitis virus–vectored vaccine. Unexpectedly, not only did passive transfer of immune serum from ΔgD-2–vaccinated Hvem−/− mice fail to protect wild-type mice but transfer of immune serum from ΔgD-2–vaccinated wild-type mice failed to protect Hvem−/− mice. Immune cells isolated from Hvem−/− mice were impaired in FcγR activation, and, conversely, addition of gD protein or anti-HVEM antibodies to in vitro murine or human FcγR activation assays inhibited the response. These findings uncover a previously unrecognized role for HVEM signaling in generating and mediating ADCC and an additional HSV immune evasion strategy.