Research Article: The Epstein-Barr Virus Glycoprotein gp150 Forms an Immune-Evasive Glycan Shield at the Surface of Infected Cells

Date Published: April 14, 2016

Publisher: Public Library of Science

Author(s): Anna M. Gram, Timo Oosenbrug, Marthe F. S. Lindenbergh, Christian Büll, Anouskha Comvalius, Kathryn J. I. Dickson, Joop Wiegant, Hans Vrolijk, Robert Jan Lebbink, Ron Wolterbeek, Gosse J. Adema, Marieke Griffioen, Mirjam H. M. Heemskerk, David C. Tscharke, Lindsey M. Hutt-Fletcher, Emmanuel J. H. J. Wiertz, Rob C. Hoeben, Maaike E. Ressing, Klaus Früh.


Cell-mediated immunity plays a key role in host control of viral infection. This is exemplified by life-threatening reactivations of e.g. herpesviruses in individuals with impaired T-cell and/or iNKT cell responses. To allow lifelong persistence and virus production in the face of primed immunity, herpesviruses exploit immune evasion strategies. These include a reduction in viral antigen expression during latency and a number of escape mechanisms that target antigen presentation pathways. Given the plethora of foreign antigens expressed in virus-producing cells, herpesviruses are conceivably most vulnerable to elimination by cell-mediated immunity during the replicative phase of infection. Here, we show that a prototypic herpesvirus, Epstein-Barr virus (EBV), encodes a novel, broadly acting immunoevasin, gp150, that is expressed during the late phase of viral replication. In particular, EBV gp150 inhibits antigen presentation by HLA class I, HLA class II, and the non-classical, lipid-presenting CD1d molecules. The mechanism of gp150-mediated T-cell escape does not depend on degradation of the antigen-presenting molecules nor does it require gp150’s cytoplasmic tail. Through its abundant glycosylation, gp150 creates a shield that impedes surface presentation of antigen. This is an unprecedented immune evasion mechanism for herpesviruses. In view of its likely broader target range, gp150 could additionally have an impact beyond escape of T cell activation. Importantly, B cells infected with a gp150-null mutant EBV displayed rescued levels of surface antigen presentation by HLA class I, HLA class II, and CD1d, supporting an important role for iNKT cells next to classical T cells in fighting EBV infection. At the same time, our results indicate that EBV gp150 prolongs the timespan for producing viral offspring at the most vulnerable stage of the viral life cycle.

Partial Text

Viruses are exceptionally well equipped to adjust processes in infected host cells to support their own replication and survival. Especially in persistent infections, they must withstand many layers of anti-viral activities exerted by the host immune system. Cell-mediated immunity, in particular that mediated by antigen (Ag)-specific T cells, is essential for elimination of virus-infected cells, reducing viral replication, and stimulating other immune effector functions.

Cell-mediated immunity by HLA I and II-restricted cytotoxic and helper T cells as well as by CD1d-restricted iNKT cells is critical in the defence against many viruses [1]. Especially persistent viruses, such as herpesviruses, have acquired strategies to permit their escape from elimination by these immune cells. In this study, we report that EBV infection, even in its late productive phase, substantially reduced display of CD1d, HLA I, and HLA II complexes at the surface of human B cells. Reduced detection of these antigen-presenting molecules was observed with Abs that can block TCR binding. This effect is functionally important, because HLA downregulation results in reduced T cell activation. For transmission to other target cells or hosts, new viral particles need to be produced through EBV reactivation from latently infected B cells, the primary natural targets for EBV infection. At the late stage of viral replication, up to 100 EBV genes are expressed, thus resulting in a wide array of Ags presented at the surface of infected cells to T cells. EBV-specific T cells are generated upon primary infection [6]. Therefore, immune escape strategies targeting Ag-presenting molecules including HLA I, II, and CD1d might allow EBV-producing B cells to effectively evade T and iNKT cell surveillance in vivo, prolonging the timespan for the production of viral offspring. Indeed, patients with reduced functional T and iNKT cell numbers are known to have life-threatening complications upon encountering EBV [6].




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