The herpesviridae family consists of eight viruses, most of which infect a majority in the human population. One of the less-studied members is Human Herpesvirus 6 (HHV-6, Roseolovirus) that causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by life-long latency. Reactivation frequently occurs in immune-compromised patients, such as those suffering from HIV infection, cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms HHV-6 utilizes to remain undetected by natural killer (NK) cells, 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 that trigger NKG2D, and B7-H6 that activates NKp30. Accordingly, this downregulation impaired NK cells’ ability 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.
Human Herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, like cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. Therefore, we aimed to understand how cells undergoing lytic HHV-6 infection are interacting with natural killer (NK) cells, an innate lymphocyte 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 natural killer (NK) cells, NKG2D and NKp30. In consequence, HHV-6 can replicate undetected by innate immune system and potentially spread infection throughout the body.This study advances the understanding of HHV-6 biology and its measures used to successfully escape immune elimination.