scholarly journals CD8+ immunodominance among Epstein-Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells

2005 ◽  
Vol 201 (3) ◽  
pp. 349-360 ◽  
Author(s):  
Victoria A. Pudney ◽  
Alison M. Leese ◽  
Alan B. Rickinson ◽  
Andrew D. Hislop
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lytic Replication ◽  
Lytic Cycle ◽  
E Proteins ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr ◽  
L Proteins

Antigen immunodominance is an unexplained feature of CD8+ T cell responses to herpesviruses, which are agents whose lytic replication involves the sequential expression of immediate early (IE), early (E), and late (L) proteins. Here, we analyze the primary CD8 response to Epstein-Barr virus (EBV) infection for reactivity to 2 IE proteins, 11 representative E proteins, and 10 representative L proteins, across a range of HLA backgrounds. Responses were consistently skewed toward epitopes in IE and a subset of E proteins, with only occasional responses to novel epitopes in L proteins. CD8+ T cell clones to representative IE, E, and L epitopes were assayed against EBV-transformed lymphoblastoid cell lines (LCLs) containing lytically infected cells. This showed direct recognition of lytically infected cells by all three sets of effectors but at markedly different levels, in the order IE > E ≫ L, indicating that the efficiency of epitope presentation falls dramatically with progress of the lytic cycle. Thus, EBV lytic cycle antigens display a hierarchy of immunodominance that directly reflects the efficiency of their presentation in lytically infected cells; the CD8+ T cell response thereby focuses on targets whose recognition leads to maximal biologic effect.

scholarly journals Cooperation between Epstein-Barr Virus Immune Evasion Proteins Spreads Protection from CD8+ T Cell Recognition across All Three Phases of the Lytic Cycle

2014 ◽  
Vol 10 (8) ◽  
pp. e1004322 ◽  
Author(s):  
Laura L. Quinn ◽  
Jianmin Zuo ◽  
Rachel J. M. Abbott ◽  
Claire Shannon-Lowe ◽  
Rosemary J. Tierney ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Evasion ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lytic Cycle ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Barr Virus ◽  
Epstein Barr ◽  
Three Phases

scholarly journals Negative Autoregulation of Epstein-Barr Virus (EBV) Replicative Gene Expression by EBV SM Protein

2009 ◽  
Vol 83 (16) ◽  
pp. 8041-8050 ◽  
Author(s):  
Dinesh Verma ◽  
Chen Ling ◽  
Eric Johannsen ◽  
Tirumuru Nagaraja ◽  
Sankar Swaminathan
Keyword(s):  
Epstein Barr Virus ◽  
Feedback Regulation ◽  
Lytic Replication ◽  
Lytic Cycle ◽  
Immediate Early ◽  
Mrna Levels ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr ◽  
Sm Protein

ABSTRACT The Epstein-Barr virus (EBV) SM protein is essential for lytic EBV DNA replication and virion production. When EBV replication is induced in cells infected with an SM-deleted recombinant EBV, approximately 50% of EBV genes are expressed inefficiently. When EBV replication is rescued by transfection of SM, SM enhances expression of these genes by direct and indirect mechanisms. While expression of most EBV genes is either unaffected or enhanced by SM, expression of several genes is decreased in the presence of SM. Expression of BHRF1, a homolog of cellular bcl-2, is particularly decreased in the presence of SM. Investigation of the mechanism of BHRF1 downregulation revealed that SM downregulates expression of the immediate-early EBV transactivator R. In EBV-infected cells, R-responsive promoters, including the BHRF1 and SM promoters, were less active in the presence of SM, consistent with SM inhibition of R expression. SM decreased spliced R mRNA levels, supporting a posttranscriptional mechanism of R inhibition. R and BHRF1 expression were also found to decrease during later stages of EBV lytic replication in EBV-infected lymphoma cells. These data indicate that feedback regulation of immediate-early and early genes occurs during the lytic cycle of EBV regulation.

scholarly journals Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle

2015 ◽  
Vol 90 (2) ◽  
pp. 947-958 ◽  
Author(s):  
Luke R. Williams ◽  
Laura L. Quinn ◽  
Martin Rowe ◽  
Jianmin Zuo
Keyword(s):  
B Cells ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Cell Killing ◽  
Lytic Replication ◽  
Lytic Cycle ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACTEpstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replicationin vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses.IMPORTANCEThis report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor.

scholarly journals A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates

2007 ◽  
Vol 204 (8) ◽  
pp. 1863-1873 ◽  
Author(s):  
Andrew D. Hislop ◽  
Maaike E. Ressing ◽  
Daphne van Leeuwen ◽  
Victoria A. Pudney ◽  
Daniëlle Horst ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lytic Cycle ◽  
Class I ◽  
Cell Recognition ◽  
Old World ◽  
T Cell Recognition ◽  
Barr Virus ◽  
Epstein Barr

γ1-Herpesviruses such as Epstein-Barr virus (EBV) have a unique ability to amplify virus loads in vivo through latent growth-transforming infection. Whether they, like α- and β-herpesviruses, have been driven to actively evade immune detection of replicative (lytic) infection remains a moot point. We were prompted to readdress this question by recent work (Pudney, V.A., A.M. Leese, A.B. Rickinson, and A.D. Hislop. 2005. J. Exp. Med. 201:349–360; Ressing, M.E., S.E. Keating, D. van Leeuwen, D. Koppers-Lalic, I.Y. Pappworth, E.J.H.J. Wiertz, and M. Rowe. 2005. J. Immunol. 174:6829–6838) showing that, as EBV-infected cells move through the lytic cycle, their susceptibility to EBV-specific CD8+ T cell recognition falls dramatically, concomitant with a reductions in transporter associated with antigen processing (TAP) function and surface human histocompatibility leukocyte antigen (HLA) class I expression. Screening of genes that are unique to EBV and closely related γ1-herpesviruses of Old World primates identified an early EBV lytic cycle gene, BNLF2a, which efficiently blocks antigen-specific CD8+ T cell recognition through HLA-A–, HLA-B–, and HLA-C–restricting alleles when expressed in target cells in vitro. The small (60–amino acid) BNLF2a protein mediated its effects through interacting with the TAP complex and inhibiting both its peptide- and ATP-binding functions. Furthermore, this targeting of the major histocompatibility complex class I pathway appears to be conserved among the BNLF2a homologues of Old World primate γ1-herpesviruses. Thus, even the acquisition of latent cycle genes endowing unique growth-transforming ability has not liberated these agents from evolutionary pressure to evade CD8+ T cell control over virus replicative foci.

scholarly journals Epitope-specific Evolution of Human CD8+ T Cell Responses from Primary to Persistent Phases of Epstein-Barr Virus Infection

2002 ◽  
Vol 195 (7) ◽  
pp. 893-905 ◽  
Author(s):  
Andrew D. Hislop ◽  
Nicola E. Annels ◽  
Nancy H. Gudgeon ◽  
Alison M. Leese ◽  
Alan B. Rickinson
Keyword(s):  
T Cell ◽  
Virus Infection ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Lytic Cycle ◽  
Phenotypic Change ◽  
Barr Virus ◽  
Epstein Barr

Primary virus infection often elicits a large CD8+ T cell response which subsequently contracts to a smaller memory T cell pool; the relationship between these two virus-specific populations is not well understood. Here we follow the human CD8+ T cell response to Epstein-Barr virus (EBV) from its primary phase in infectious mononucleosis (IM) through to the persistent carrier state. Using HLA-A2.1 or B8 tetramers specific for four lytic cycle and three latent cycle epitopes, we find marked differences in the epitope-specific composition of the T cell populations between the two phases of infection. The primary response is dominated by lytic epitope specificities which are severely culled (and in one case extinguished) with resolution of the acute infection; in contrast latent epitope specificities are less abundant, if present at all, in acute IM but often then increase their percentage representation in the CD8 pool. Even comparing epitopes of the same type, the relative size of responses seen in primary infection does not necessarily correlate with that seen in the longer term. We also follow the evolution of phenotypic change in these populations and show that, from a uniform CD45RA−RO+CCR7− phenotype in IM, lytic epitope responses show greater reversion to a CD45RA+RO− phenotype whereas latent epitope responses remain CD45RA−RO+ with a greater tendency to acquire CCR7. Interestingly these phenotypic distinctions reflect the source of the epitope as lytic or latent, and not the extent to which the response has been amplified in vivo.

scholarly journals MHC II tetramers visualize human CD4+ T cell responses to Epstein–Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response

2013 ◽  
Vol 210 (5) ◽  
pp. 933-949 ◽  
Author(s):  
Heather M. Long ◽  
Odette L. Chagoury ◽  
Alison M. Leese ◽  
Gordon B. Ryan ◽  
Eddie James ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Lytic Cycle ◽  
Cd4 T Cell ◽  
Barr Virus ◽  
Mhc Ii ◽  
Cell Responses ◽  
Epstein Barr

Virus-specific CD4+ T cells are key orchestrators of host responses to viral infection yet, compared with their CD8+ T cell counterparts, remain poorly characterized at the single cell level. Here we use nine MHC II–epitope peptide tetramers to visualize human CD4+ T cell responses to Epstein–Barr virus (EBV), the causative agent of infectious mononucleosis (IM), a disease associated with large virus-specific CD8+ T cell responses. We find that, while not approaching virus-specific CD8+ T cell expansions in magnitude, activated CD4+ T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4+ T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4+ T cell priming.

scholarly journals Epstein–Barr Virus Permissively Infects Human Syncytiotrophoblastsin Vitroand Induces Replication of Human T Cell Leukemia-Lymphoma Virus Type I in Dually Infected Cells

Virology ◽  
1997 ◽  
Vol 229 (2) ◽  
pp. 400-414 ◽  
Author(s):  
Ferenc D. Tóth ◽  
George Aboagye-Mathiesen ◽  
József Nemes ◽  
Xiangdong Liu ◽  
István Andirkó ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Epstein Barr Virus ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Barr Virus ◽  
Human T Cell ◽  
Infected Cells ◽  
Epstein Barr

scholarly journals Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Tiffany R. Frey ◽  
Jozan Brathwaite ◽  
Xiaofan Li ◽  
Sandeepta Burgula ◽  
Ibukun A. Akinyemi ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Human Herpesvirus ◽  
Lytic Cycle ◽  
Barr Virus ◽  
Viral Spread ◽  
Cellular Genes ◽  
Latently Infected ◽  
Infected Cells ◽  
Host Shutoff ◽  
Epstein Barr

ABSTRACT Lytic activation from latency is a key transition point in the life cycle of herpesviruses. Epstein-Barr virus (EBV) is a human herpesvirus that can cause lymphomas, epithelial cancers, and other diseases, most of which require the lytic cycle. While the lytic cycle of EBV can be triggered by chemicals and immunologic ligands, the lytic cascade is activated only when expression of the EBV latent-to-lytic switch protein ZEBRA is turned on. ZEBRA then transcriptionally activates other EBV genes and, together with some of those gene products, ensures completion of the lytic cycle. However, not every latently infected cell exposed to a lytic trigger turns on the expression of ZEBRA, resulting in responsive and refractory subpopulations. What governs this dichotomy? By examining the nascent transcriptome following exposure to a lytic trigger, we find that several cellular genes are transcriptionally upregulated temporally upstream of ZEBRA. These genes regulate lytic susceptibility to various degrees in latently infected cells that respond to mechanistically distinct lytic triggers. While increased expression of these cellular genes defines a prolytic state, such upregulation also runs counter to the well-known mechanism of viral-nuclease-mediated host shutoff that is activated downstream of ZEBRA. Furthermore, a subset of upregulated cellular genes is transcriptionally repressed temporally downstream of ZEBRA, indicating an additional mode of virus-mediated host shutoff through transcriptional repression. Thus, increased transcription of a set of host genes contributes to a prolytic state that allows a subpopulation of cells to support the EBV lytic cycle. IMPORTANCE Transition from latency to the lytic phase is necessary for herpesvirus-mediated pathology as well as viral spread and persistence in the population at large. Yet, viral genomes in only some cells in a population of latently infected cells respond to lytic triggers, resulting in subpopulations of responsive/lytic and refractory cells. Our investigations into this partially permissive phenotype of the herpesvirus Epstein-Barr virus (EBV) indicate that upon exposure to lytic triggers, certain cellular genes are transcriptionally upregulated, while viral latency genes are downregulated ahead of expression of the viral latent-to-lytic switch protein. These cellular genes contribute to lytic susceptibility to various degrees. Apart from indicating that there may be a cellular “prolytic” state, our findings indicate that (i) early transcriptional upregulation of cellular genes counters the well-known viral-nuclease-mediated host shutoff and (ii) subsequent transcriptional downregulation of a subset of early upregulated cellular genes is a previously undescribed mode of host shutoff.

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