title: Stepwise release of biologically active HMGB1 during HSV-2 infection.
abstract: BACKGROUND
  High mobility group box 1 protein (HMGB1) is a major endogenous danger signal that triggers inflammation and immunity during septic and aseptic stresses. HMGB1 recently emerged as a key soluble factor in the pathogenesis of various infectious diseases, but nothing is known of its behaviour during herpesvirus infection. We therefore investigated the dynamics and biological effects of HMGB1 during HSV-2 infection of epithelial HEC-1 cells.
  
  
  RESULTS
  Despite a transcriptional shutdown of HMGB1 gene expression during infection, the intracellular pool of HMGB1 protein remained unaffected, indicating its remarkable stability. However, the dynamics of HMGB1 was deeply modified in infected cells. Whereas viral multiplication was concomitant with apoptosis and HMGB1 retention on chromatin, a subsequent release of HMGB1 was observed in response to HSV-2 mediated necrosis. Importantly, extracellular HMGB1 was biologically active. Indeed, HMGB1-containing supernatants from HSV-2 infected cells induced the migration of fibroblasts from murine or human origin, and reactivated HIV-1 from latently infected T lymphocytes. These effects were specifically linked to HMGB1 since they were blocked by glycyrrhizin or by a neutralizing anti-HMGB1 antibody, and were mediated through TLR2 and the receptor for Advanced Glycation End-products (RAGE). Finally, we show that genital HSV-2 active infections also promote HMGB1 release in vivo, strengthening the clinical relevance of our experimental data.
  
  
  CONCLUSIONS
  These observations target HMGB1 as an important actor during HSV-2 genital infection, notably in the setting of HSV-HIV co-infection.
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Université Paris Descartes, INSERM, UMRS872, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Borde
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Barnay-Verdier
authors.forename: Claire
authors.initials: C
authors.lastname: Gaillard
authors.forename: Hakim
authors.initials: H
authors.lastname: Hocini
authors.forename: Vincent
authors.initials: V
authors.lastname: Maréchal
authors.forename: Joël
authors.initials: J
authors.lastname: Gozlan
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D015897:Comorbidity; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D005347:Fibroblasts / Q000166:cytology; D015658:HIV Infections / Q000150:complications*; D024243:HMGB1 Protein / Q000378:metabolism* / Q000502:physiology; D006558:Herpes Genitalis / Q000150:complications / Q000378:metabolism*; D018258:Herpesvirus 2, Human; D006801:Humans; D051379:Mice
chemical_list: D024243:HMGB1 Protein