title: Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells.
abstract: The Herpesviridae family consists of eight viruses, most of which infect a majority of the human population. One of the less-studied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination.
  
  
  OBJECTIVE
  Human herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination.
authors.affiliation: Lautenberg Center for General and Tumor Immunology, BioMedical Research Institute Israel-Canada, Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmiedel
authors.affiliation: Lautenberg Center for General and Tumor Immunology, BioMedical Research Institute Israel-Canada, Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Julie
authors.initials: J
authors.lastname: Tai
authors.affiliation: Pharmacology and Experimental Therapeutics Unit, Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Francesca
authors.initials: F
authors.lastname: Levi-Schaffer
authors.affiliation: Central Virology Laboratory, Chaim Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dovrat
authors.affiliation: Lautenberg Center for General and Tumor Immunology, BioMedical Research Institute Israel-Canada, Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel oferm@ekmd.huji.ac.il.
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology*; D015654:Herpesvirus 6, Human / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D055607:Receptors, Natural Killer Cell / Q000276:immunology; D018406:Virus Physiological Phenomena / Q000276:immunology
chemical_list: D008024:Ligands; D055607:Receptors, Natural Killer Cell