title: OX40 and 4-1BB downregulate Kaposi’s  sarcoma-associated herpesvirus replication  in lymphatic endothelial cells, but 4-1BB and  not OX40 inhibits viral replication in B-cells.
abstract: Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the human gammaherpesvirus subfamily and is associated with malignancies of endothelial origin (Kaposi’s sarcoma, KS) and B-cell origin [primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD)]. Viral lytic replication is known to be required for KS and MCD. As KSHV-related tumours mostly develop in human subjects when the immune system is compromised by immunosuppressive regimen, human immunodeficiency virus infection or some genetic deficiencies, KSHV-specific immune responses are believed to be important in the control of KSHV replication. However, analysis of the roles of immune cells in viral pathogenesis has been difficult due to the lack of an adequate animal model. Recently, congenital OX40 deficiency, as determined by genome-wide exome sequencing, was shown to be associated with aggressive childhood KS in a patient, suggesting that disrupted OX40–OX40L interactions might be implicated in disease development. Here, we report that interaction of recombinant OX40 protein with OX40L expressed on endothelial cells severely impaired KSHV lytic replication. Furthermore, 4-1BB–4-1BBL interactions were also capable of efficiently inhibiting viral replication in B-cells and endothelial cells. To the best of our knowledge, this is the first direct evidence that ligation of tumour necrosis factor superfamily members and their cognate receptors is important for the control of viral lytic replication. These data are likely to pave the way for the development of KSHV-specific therapies for KS and MCD, in which viral lytic replication is a disease-determining factor.
authors.affiliation: Korea Zoonosis Research Institute and Division of Biotechnology, Advanced Institute of Environment and Bioscience, College of Environmental and Bioresource Sciences, Chonbuk National University, Jeonju 561-756, Republic of Korea.
authors.forename: Min
authors.initials: M
authors.lastname: Cho
authors.affiliation: Korea Zoonosis Research Institute and Division of Biotechnology, Advanced Institute of Environment and Bioscience, College of Environmental and Bioresource Sciences, Chonbuk National University, Jeonju 561-756, Republic of Korea.|Department of Bioactive Material Sciences, New Drug Development Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
authors.forename: Jinjong
authors.initials: J
authors.lastname: Myoung
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000502:physiology / Q000821:virology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology / Q000821:virology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology / Q000821:virology*; D005786:Gene Expression Regulation / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D014066:Palatine Tonsil / Q000166:cytology; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
chemical_list: D053330:4-1BB Ligand; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human