Antibodies can kill virus-infected cells by interacting with viral proteins expressed on their surface. This process, called antibody-dependent cellular cytotoxicity (ADCC), is important for preventing HIV, influenza, and it may be critical for preventing herpes simplex virus (HSV) infections. Betsy Herold, M.D., William  Jacobs, Jr., Ph.D., and colleagues developed a vaccine called ΔgD-2 that provides superior protection against HSV-1 and HSV-2 in preclinical studies compared to prior vaccine efforts. This novel candidate vaccine, which lacks glycoprotein D, works primarily by generating these ADCC antibodies. This response is distinct from the immune response to natural HSV infection and to previous unsuccessful vaccine efforts, which generate neutralizing antibodies that target glycoprotein D.

In a study published online on August 14 in Science Immunology, Dr. Herold and colleagues used their ΔgD-2 vaccine to identify molecular pathways that promote production of ADCC antibodies. Glycoprotein D binds to an immunoregulatory molecule called herpesvirus entry mediator (HVEM), which is expressed by most immune cells; in doing so, glycoprotein D competes with molecules, referred to as ligands, that naturally bind to HVEM. The researchers hypothesized that glycoprotein D might enable the virus to evade host immunity by blocking an HVEM-ligand dependent signaling pathway needed to achieve a protective ADCC response. Production of antibodies that lead to ADCC was found to require HVEM and one of its ligands, LIGHT. These findings identify a previously unrecognized role for HVEM-LIGHT signaling in establishing ADCC as well as a novel viral immune evasion strategy.

Dr. Herold is professor of pediatrics, of microbiology & immunology, and of obstetrics & gynecology and women’s health at Einstein. Dr. Herold also holds the Harold and Muriel Block Chair in Pediatrics at Einstein and is chief of the division of pediatric infectious diseases and vice chair for research at both Children’s Hospital at Montefiore and Einstein. Dr. Jacobs is the Leo and Julia Forchheimer Chair in Microbiology and Immunology and a professor of genetics and of microbiology & immunology at Einstein.