PMID- 32817296 OWN - NLM STAT- MEDLINE DCOM- 20211210 LR - 20240402 IS - 2470-9468 (Electronic) IS - 2470-9468 (Linking) VI - 5 IP - 50 DP - 2020 Aug 14 TI - HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses. LID - 10.1126/sciimmunol.aax2454 [doi] LID - eaax2454 AB - 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, DeltagD-2, induces primarily non-neutralizing antibodies that activate Fcgamma receptors (FcgammaRs) 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 DeltagD-2 resulted in significant reduction in HSV-specific IgG2 antibodies, the subclass associated with FcgammaR 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 DeltagD-2-vaccinated Hvem(-/-) mice fail to protect wild-type mice but transfer of immune serum from DeltagD-2-vaccinated wild-type mice failed to protect Hvem(-/-) mice. Immune cells isolated from Hvem(-/-) mice were impaired in FcgammaR activation, and, conversely, addition of gD protein or anti-HVEM antibodies to in vitro murine or human FcgammaR 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. CI - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Burn Aschner, Clare AU - Burn Aschner C AUID- ORCID: 0000-0001-8940-5423 AD - Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Loh, Lip Nam AU - Loh LN AD - Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Galen, Benjamin AU - Galen B AUID- ORCID: 0000-0001-8172-258X AD - Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Delwel, Isabel AU - Delwel I AUID- ORCID: 0000-0001-6671-3669 AD - Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Jangra, Rohit K AU - Jangra RK AUID- ORCID: 0000-0002-3119-0869 AD - Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Garforth, Scott J AU - Garforth SJ AD - Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Chandran, Kartik AU - Chandran K AD - Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Almo, Steven AU - Almo S AD - Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Jacobs, William R Jr AU - Jacobs WR Jr AUID- ORCID: 0000-0003-3321-3080 AD - Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Ware, Carl F AU - Ware CF AD - Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. FAU - Herold, Betsy C AU - Herold BC AUID- ORCID: 0000-0001-9974-0786 AD - Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. betsy.herold@einsteinmed.org. AD - Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. LA - eng GR - R01 AI117321/AI/NIAID NIH HHS/United States GR - R37 AI026170/AI/NIAID NIH HHS/United States GR - R01 AI067890/AI/NIAID NIH HHS/United States GR - R25 GM104547/GM/NIGMS NIH HHS/United States GR - R01 AI134824/AI/NIAID NIH HHS/United States GR - P01 CA177322/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Sci Immunol JT - Science immunology JID - 101688624 RN - 0 (Receptors, Tumor Necrosis Factor, Member 14) RN - 0 (Viral Vaccines) SB - IM MH - Animals MH - *Antibody-Dependent Cell Cytotoxicity MH - Female MH - Herpes Simplex/*immunology/prevention & control MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Receptors, Tumor Necrosis Factor, Member 14/genetics/*immunology MH - Signal Transduction MH - Simplexvirus/*immunology MH - Viral Vaccines/*administration & dosage PMC - PMC7673108 MID - NIHMS1641481 COIS- Competing interests: WRJ and BCH receive support for development of the DeltagD-2 vaccine from X-Vax Technology, which holds the license for its development, and serve as scientific advisors for the company. WRJ and CW have equity interests in X-Vax Technology. WRJ and BCH are co-inventors on US patent number 9,999,665 B2 with a title of "RECOMBINANT HERPES SIMPLEX VIRUS 2 (HSV-2) VACCINE VECTORS." CBA and BCH are co-inventors on a pending patent application entitled "METHOD OF ENHANCING ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC)." The other authors declare that they have no competing interests. EDAT- 2020/08/21 06:00 MHDA- 2021/12/15 06:00 PMCR- 2021/02/14 CRDT- 2020/08/21 06:00 PHST- 2019/03/06 00:00 [received] PHST- 2020/01/20 00:00 [revised] PHST- 2020/07/23 00:00 [accepted] PHST- 2020/08/21 06:00 [entrez] PHST- 2020/08/21 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/02/14 00:00 [pmc-release] AID - 5/50/eaax2454 [pii] AID - 10.1126/sciimmunol.aax2454 [doi] PST - ppublish SO - Sci Immunol. 2020 Aug 14;5(50):eaax2454. doi: 10.1126/sciimmunol.aax2454.