Immunity & infection
HSV glycoprotein D (gD) is an immunodominant envelope glycoprotein required for entry, but also competitively binds the costimulatory molecule, HVEM (TNFRSF14), which is expressed on immune cells. Natural infection elicits neutralizing antibodies (nAbs) targeting gD, but vaccines designed to elicit gD-specific nAbs have failed clinically. We constructed a single-cycle HSV-2 vaccine deleted in gD, DgD-2. This vaccine induces non-neutralizing antibodies that activate the Fc gamma receptor (FcgRIV) and mediate ADCC. Active or passive immunization protects in mice and prevents the establishment of latency. We hypothesize that gD blocks the generation of ADCC through interactions with HVEM. Wild-type mice were immunized with DgD-2; dl5-29, a replication-defective HSV-2 strain that expresses gD, or adjuvanted gD protein (rgD-Alum/MPL) prior to challenge with HSV. ΔgD-2 protected 100% of mice from disease and latency following challenge with clinical isolates of HSV, while dl5-29 and rgD-2/AS04 provided incomplete protection. Protection correlated with ADCC, not nAb titer. Immunization of HVEM-/- or LIGHT-/- (an HVEM ligand) mice resulted in a significant reduction in ADCC and loss of protection. Surprisingly, transfer of immune serum from wild-type mice also failed to protect HVEM-/- mice, suggesting a role for HVEM in generating and mediating ADCC responses. Immune cells isolated from HVEM-/- mice were impaired in mediating cell killing. Addition of gD protein or anti-HVEM antibodies inhibited FcgR activation with mouse or human immune serum. These findings uncover a previously unrecognized function of HVEM in generating and mediating ADCC and suggest that gD blocks HVEM signaling as an immune evasion strategy.