title: Herpes simplex virus 1 glycoprotein B and US3 collaborate to inhibit CD1d antigen presentation and NKT cell function.
abstract: Herpes simplex viruses (HSVs) are prevalent human pathogens that establish latency in human neuronal cells and efficiently evade the immune system. It has been a major medical challenge to eradicate them and, despite intensive efforts, an effective vaccine is not available. We previously showed that upon infection of antigen-presenting cells, HSV type 1 (HSV-1) rapidly and efficiently downregulates the major histocompatibility complex class I-like antigen-presenting molecule, CD1d, and potently inhibits its recognition by CD1d-restricted natural killer T (NKT) cells. It suppresses CD1d expression primarily by inhibiting its recycling to the cell surface after endocytosis. We identify here the viral glycoprotein B (gB) as the predominant CD1d-interacting protein. gB initiates the interaction with CD1d in the endoplasmic reticulum and stably associates with it throughout CD1d trafficking. However, an additional HSV-1 component, the serine-threonine kinase US3, is required for optimal CD1d downregulation. US3 expression in infected cells leads to gB enrichment in the trans-Golgi network (TGN) and enhances the relocalization of both gB and CD1d to this compartment, suggesting that following internalization CD1d is translocated from the endocytic pathway to the TGN by its association with gB. Importantly, both US3 and gB are required for efficient inhibition of CD1d antigen presentation and NKT cell activation. In summary, our results suggest that HSV-1 uses gB and US3 to rapidly inhibit NKT cell function in the initial antiviral response.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Rao
authors.forename: Hong Thanh
authors.initials: HT
authors.lastname: Pham
authors.forename: Arpita
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Xueqiao
authors.initials: X
authors.lastname: Liu
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
authors.forename: Peter
authors.initials: P
authors.lastname: Cresswell
authors.forename: Weiming
authors.initials: W
authors.lastname: Yuan
mesh_terms: D017951:Antigen Presentation; D055610:Antigens, CD1d / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism / Q000821:virology
chemical_list: D055610:Antigens, CD1d; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C040495:glycoprotein B, Simplexvirus; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1