HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses

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, Delta gD-2, induces primarily non-neutralizing antibodies that activate Fc gamma receptors (Fc gamma Rs) 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 Delta gD-2 resulted in significant reduction in HSV-specific IgG2 antibodies, the subclass associated with Fc gamma R 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 Delta gD-2-vaccinated Hvem(-/-) mice fail to protect wild-type mice but transfer of immune serum from Delta gD-2-vaccinated wild-type mice failed to protect Hvem(-/-) mice. Immune cells isolated from Hvem(-/-) mice were impaired in Fc gamma R activation, and, conversely, addition of gD protein or anti-HVEM antibodies to in vitro murine or human Fc gamma R 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.