EBV lytic proteins and tumorigenic functions (summarized from Ref. [14]).
Abstract
The Epstein-Barr virus (EBV) reactivation corresponds to the activation of EBV global replication involving not only the origin of the latent viral replication but also that of the origin of lytic replication. During this reactivation, a minority of B cells infected with EBV in its latent form enter the lytic phase. During this phase, all EBV proteins are produced, enabling the assembly of complete virions that lysate their host cells and infect neighboring cells (lytic cycle). This horizontal EBV transmission seeks to increase the pool of EBV-infected B cells. This chapter seeks to review the role of the lytic EBV proteins (particularly that of the ZEBRA protein) in tumor development. This protein is the main transcription factor of EBV, expressed during the activation of the lytic cycle. Recently, we demonstrated that this immediate early protein can be detected in the soluble state (s-ZEBRA) in the serum of patients with posttransplant lymphoproliferative disorder. We highlighted the role of ZEBRA in EBV pathogenesis in transplanted subjects, not only as a key protein in the activation of EBV replication but also as a protein “toxoid” released into the extracellular milieu. This release could result in increased secretion of immunomodulatory cytokines and that of angiogenesis-promoting factors conducive to tumor progression.
Keywords
- tumor progression
- tumorigenesis
- EBV
- lytic cycle
- Zta/ZEBRA protein
- lymphoma
1. Introduction
Epstein-Barr virus (EBV) is a member of the herpesvirus family and only infects primates, with tropism for B cells and epithelial cells, which establishes a lifelong persistent infection in over 90% of the world’s population [1]. After the resolution of the primary infection episode, EBV enters a latent phase. Following primary infection, the virus establishes lifelong persistence within the host memory B-cell compartment utilizing restricted latent gene expression programs [2, 3, 4]. Like all herpesviruses, EBV can choose between two alternative lifestyles: latent or lytic replication. EBV lytic replication, which is required for horizontal spread of the virus from cell to cell, and from host to host, occurs in both epithelial cells and B cells [5, 6, 7]. During latency, EBV exists in a dormant state where only a viral gene subset is expressed, facilitating the episomal persistence of the viral genome [8]. However, under certain physiological conditions, both viruses undergo lytic reactivation leading to expression of the full lytic gene complement, followed by the assembly and egress of infectious virions [1].
Lytic replication is mediated by the virally encoded DNA polymerase using the oriLyt replication origin and results in the release of infectious viral particles [9]. In contrast, during latent viral infection, only a viral gene subset is expressed. The genome is replicated once per cell cycle using the cellular DNA polymerase and the oriP replication origin, and the progeny virus is not released. Latent EBV infection allows the virus to persist for the life of the host and to avoid detection by the immune system [1]. In immune-competent hosts, the outgrowth of EBV-immortalized B cells is prevented through a robust expansion of EBV-specific memory T cells directed toward both lytic and latent antigens [10]. Thus, EBV-positive individuals with either congenital or acquired immune deficiencies are highly susceptible to viral reactivation and malignant transformation. Furthermore, EBV-seropositive patients treated with immunosuppressive medications following organ/stem cell transplantation are at significant risk of developing posttransplant lymphoproliferative disorder (PTLD), an often fatal B-cell lymphoproliferative disease (LPD) [11, 12].
Importantly however, EBV (as other gammaherpesviruses, e.g., KSHV) can also undergo abortive lytic reactivation, resulting in the expression of early lytic genes without subsequent virion assembly and cell lysis [13]. Although numerous efforts to understand these disorders’ molecular basis have focused on viral latency, EBV lytic cycles are now widely accepted as major contributors to oncogenesis and could be important targets in the development of new therapeutic or diagnostic approaches [14, 15]. Thus, in this chapter, we will discuss how lytic replication, particularly via the immediate-early/early antigens or IEAs/EAs, augments the pathogenesis of EBV-associated malignancies, especially in the lymphoma setting or with respect to the treatments that potentially target the lytic replication cycle.
2. Arguments of the pathogenic role of lytic infection in EBV-associated malignancies
EBV establishes a lifelong infection in B lymphocytes achieved through a highly regulated viral gene expression program. Numerous studies have been focused on the contributions of EBV latent infection in the pathogenesis of EBV-induced malignancies. These studies have revealed that the membrane LMP1 protein is the major essential oncoprotein [1, 16]. In recent years, the viral lytic cycle was shown to play an essential role in carcinogenesis through several potential mechanisms. EBV lytic infection may increase the total number of latently infected cells by enhancing transmission of the virus from cell to cell and thus constitutes an essential aspect of viral pathogenesis. A small subset of lytically infected cells was detected in biopsies of EBV-associated malignancies [13, 17, 18, 19, 20, 21, 22], suggesting a potential role of viral lytic infection in promoting tumor growth in vivo. Furthermore, several studies have indicated that the viral lytic cycle in a fraction of B cells promotes the transformation of B lymphocytes in vitro [23] and growth of B-cell lymphoma in vivo [24, 25] through the release of paracrine growth factors and angiogenic factors [26]. Focusing on the study of NPC, Wu et al. revealed that recurrent EBV reactivation promotes genome instability, invasiveness, and tumorigenesis of NPC cells. Another Wu et al. finding was that the contribution of the lytic cycle is more marked than that of the latent infection [27, 28]. Additionally, lytic replication enhances in NPC cells the secretion of vascular endothelial growth factor (VEGF), a factor contributing to angiogenesis and subsequent nasopharyngeal carcinoma’s (NPC) metastasis or relapse after remission [29]. Clinical and epidemiological studies have revealed that individuals with elevated plasma EBV DNA load and antibody titers against the lytic viral capsid antigen (VCA) and early antigen (EA) display a high risk of NPC [30]. These studies have also shown that fluctuation of EBV antibody titers occurs prior to the onset of NPC [31, 32, 33, 34]. Attention has also focused on the diagnostic and prognostic value of IgG antibody against the IEA ZEBRA (see further) in patients with NPC [33, 34, 35, 36, 37] and in Hodgkin disease (HD) patients as well [38]. More recently we reported that the replicative form of EBV, as investigated using anti-ZEBRA IgG titers, correlates with poorer outcomes in women with breast cancer [39]. All in all, these studies investigating serological lytic EBV markers have emphasized the prominent role importance of the lytic infection in EBV malignancies. Recently, the identification by mass spectrometry of 44 different EBV proteins in Burkitt lymphoma cells undergoing EBV replication has increased the knowledge base on EBV lytic replication, possibly highlighting different targets for future therapeutic strategies [40].
3. The role of some lytic EBV proteins in the tumorigenesis and focusing onto the Zta/ZEBRA IE transactivator
The role of the lytic EBV proteins was highlighted in some recent reviews [13, 14]. Overall, the authors clearly demonstrated the role of these lytic EBV proteins in tumorigenesis. They also showed that EBV reactivation may aid virus transmission within the tumor microenvironment to establish latency and drive cellular proliferation. Having said that, the likely predominant role of the EBV lytic cycle is likely to provide the necessary paracrine, anti-apoptotic, and immunomodulatory signals required for tumorigenesis (Table 1). From this point on, we will focus on the critical role of the IE ZEBRA
EBV lytic gene | Cellular homologs | Lytic function | Mechanisms of oncogenesis | Oncogenic function | Clinical and diagnostic relevance (Ref) |
---|---|---|---|---|---|
ZEBRA (Zta, BZLF1) | c-Fos, c-Jun | IEA, transactivator in cooperation with Rta | Promotes secretion of proangiogenic factors, VEGF and cytokines (IL-6, IL-8, IL-10, IL-13), toxoid protein | Angiogenesis, B-cell growth, immunomodulation | Expression in PTLD, B-cell lymphomas, Hodgkin lymphomas, NPC, detection of s-ZEBRA in PTLD patients’ serum, specific antibodies in NPC/HD/PTLD patients [84] |
BHRF1 and BALF1 | Bcl-2 | EA, delay cell death | Inhibition of apoptosis | Cell survival | |
BILF1 | G protein-coupled receptor | EA immunoevasin | MHC class I downregulation | ||
BNRF1 | EA nucleocapsid trafficking | Interacts with centromeres to cause centrosome overduplication | Genome instability | ||
BALF3 | Terminase | EA DNA synthesis and incorporation into virions | DNA damage | Genome instability | |
BGLF4 | EA viral DNA replication and nuclear import | DNA damage | Genome instability | ||
BARF1 | C-fms receptor | EA immunomodulator | Modulates expression genes involved in apoptotic signaling | Cell survival | Most abundant EBV transcripts in NPC, detection of s-BARF1 in the NPC patients’ serum [110] and specific antibodies [111] |
BGLF5 | Host cell shutoff (DNase), TLR-9 downregulation | DNA damage | Genome instability | Expression in NPC biopsies [112]. Specific antibodies in NPC [113] patients | |
BcRF1 | Il-10 | Immunoevasin | Downregulates interferon gamma | Cell survival | Soluble vIL10 in NHL patients’ serum [114] |
Functions of ZEBRA protein | Target | Effect |
---|---|---|
ZEBRA mediates the switch from latent to lytic infection, in combination with the second transactivator Rta | Virus | ZEBRA and Rta induce expression of all early (E) lytic viral proteins, allowing the virus to replicate [45] |
ZEBRA is able to bind to the methylated DNA | Virus | Activation of EBV replication [48] |
ZEBRA exhibits cell-penetrating properties, like HIV-1 Tat and dengue virus NS1 | Host cell | Toxoid effect [82, 83, 84] |
Activation of immunomodulatory genes IL-10 and IL-13 | Host cell | ZEBRA contributes to the growth of latently infected cells by promoting the release B-cell growth factors [60, 61] |
Inhibition of antiviral cytokine signaling | Immune system | Immune subversion [57] |
High immunogenicity: ZEBRA elicits robust B- and T-cell responses that dominate the early immune responses in patients | Immune system | EBV homeostasis and immune control of EBV replication activation [67, 68, 69] Detection of specific IgG antibodies in EBV-associated diseases [34, 38, 75, 115, 116] |
ZEBRA promotes B-cell transformation and lymphomagenesis in a humanized NOD/LtSz-scid/IL2Rγnull mouse model of EBV-related disease (PTLD) | Animal model | ZEBRA might be a prominent factor in the development of EBV-associated malignancy [24, 62] |
ZEBRA expression (mainly through abortive cycles) was shown in EBV-associated tumors, including Hodgkin disease and PTLD | Host tissue | Pathogenesis and tumor progression in patients [13, 17, 94, 96] |
ZEBRA is also released in the extracellular milieu (as HIV-1 Tat) and detectable in the serum of transplant patients, particularly those with PTLD | Host tissue | Diagnostic and prognostic value [84] |
Scid/hu mice proved to be a good model to study the pathogenesis of posttransplant B-cell lymphomas [63, 64, 65]. Several recent studies emphasized the role of EBV lytic proteins (including ZEBRA) in promoting B-cell transformation and lymphomagenesis in a humanized NOD/LtSz-scid/IL2Rγnull mouse model of an EBV-related disease [24]: The authors modeled a humanized NOD/LtSz-scid/IL2Rγnull mouse that was reconstituted with CD34+ human hematopoietic progenitor cells isolated from fetal liver and also simultaneously xenotransplanted with fetal liver and thymus tissues [hNSG(thy)]. The hNSG(thy) mice were infected with EBV developing CD20-positive diffuse large B-cell lymphomas (DLBCL). To understand the contribution of the lytic cycle in lymphomagenesis, the hNSG(thy) mice were infected with a BZLF1 knockout EBV. Although no significant differences were apparent in the number of infected cells and in their tissue distribution, lymphomas were found in 6/11 (54.4%) of the mice infected with the wild-type virus and in only 2/14 (14.3%) of mice infected with the mutant virus. These data along with other studies support that the lytic cycle directly helps tumorigenic mechanisms rather than the lateral spread of viruses, thereby increasing the number of latently infected cells [66]. In line with this observation, lymphomas developing in the mice infected with wild-type viruses sometimes expressed ZEBRA and BMRF1 lytic proteins but never gp350/220 structural protein. Thus, these data support the participation of the abortive lytic cycle in lymphomagenesis (see below). Hong et al. made a similar observation [62]: This research group reported that when lymphoblastoid cell lines (LCLs) derived from wild type and virus knockout of BZLF1 and BRLF1 IE genes were transplanted into scid mice, both mutant LCLs were shown unable to induce lymphoproliferative disease, supporting a critical role of the lytic cycle in the EBV-induced lymphoproliferation [62].
It appears clearly that ZEBRA expression is critical for viral activation, persistence, and disease pathogenesis. From an immunologic standpoint, ZEBRA expression is thus likely to represent a prime target of adaptive immune responses (T-cell and humoral responses) (Table 2). ZEBRA, highly immunogenic, elicits robust T-cell responses [10, 67, 68, 69, 70, 71, 72] that dominate the early immune responses in patients [70]. B-cell epitopes were additionally described; to illustrate, the DNA-binding domain of ZEBRA (basic region, including the so-called RAK epitope) is a major target antigen for IgM antibody response in EBV primary infection (45), whereas the N-terminus part (activation domain) is mainly recognized by IgG in patients with EBV reactivation [35, 73, 74, 75].
4. ZEBRA, a deleterious protein acting as a “toxoid”
ZEBRA appears to be a multifunctional protein controlling its own expression, virus replication, cell cycle arrest, and DNA damage response in the host cells [76, 77, 78, 79, 80]. The structure of the 245-amino acid ZEBRA protein has been resolved in its DNA-bound form [81]. Based on this finding, the protein appears divided into an N-terminal
In 2005, we demonstrated that this multifunctional protein not only binds DNA and controls virus replication but also has the ability to penetrate lymphoid cells [82]. Moreover, we also demonstrated that ZEBRA possesses a transduction domain (C-terminus), crosses the outer membrane of live cells, and accumulates in the nucleus of lymphocytes. The protein transduction mostly occurs via direct translocation through the lipid bilayer rather than by endocytosis [83]. Soluble ZEBRA has additionally been detected in the sera of posttransplant lymphoproliferative disease patients, suggesting a possible secretion of this protein into the circulating blood, with further evidence toward a “toxoid” role for this lytic protein [84]. This unusual property must be compared with those of other nonstructural viral proteins like HIV-1 Tat and dengue virus (DV) NS1 [85, 86]. Therefore, we hypothesized that ZEBRA is to be involved in tumorigenesis and tumor progression, not only as an essential protein for EBV replication activation but also as a “toxin” released in the extracellular milieu. We hypothesized that early abortive replication associated with fully lytic cycles may occur within the tumor or its environment, along with eventual ZEBRA release in the bloodstream (Figure 2). In the end, this phenomenon could lead to the secretion of cytokines and angiogenesis-promoting factors, further aggravating the immunosuppressive environment (Figure 3) [26, 87].
5. Evidence of abortive lytic cycle and their role in tumorigenesis
In the absence of other lytic genes, particularly those encoding late structural proteins, without the formation of infective viral particles, BZLF1 expression is termed the “abortive lytic cycle” (Figure 4) [13]. The existence of abortive cycles was demonstrated in EBV-associated malignancies through the detection of either the ZEBRA protein (via monoclonal antibodies) or mRNA: Hodgkin disease [17], Non-Hodgkin lymphoma (NHL) [18, 88], NPC [20], or Burkitt lymphoma [21]. Decades ago, we revealed the early stages of EBV replication in lymphomas in scid/hu mice, assessed by the expression of ZEBRA expression, whereas the VCA expression late replicate protein proved to be weak [89]. In a recent review, the authors discussed evidence supporting an abortive lytic cycle with several lytic genes expressed, such as immunomodulatory (BCRF1, BARF1, BNLF2A, BGLF5, and BILF1) and anti-apoptotic (BHRF1 and BALF1) proteins. In their paper, the authors also discussed how the EBV immunomodulatory mechanisms result in paracrine signals that feed tumor cells. The existence of such abortive lytic cycles would reconcile the requirement of lytic expression in view of viral tumorigenesis without relying on a complete cycle that would induce cell lysis, thus releasing the newly formed infective viral particles [13].
6. Consequences in terms of diagnosis and therapy
The observation of ZEBRA transduction properties and abortive cycles has prompted us to imagine the existence of a circulating ZEBRA form, especially in the serum of patients, particularly those with lymphoid tumors. Many articles have previously mentioned the existence of the lytic cycle, especially in transplant patients with PTLD. Studies conducted on EBV lytic proteins, especially the IE proteins like ZEBRA, in patients with PTLD or HIV-associated NHL are still scarce, mostly relating to the role of EBV proteins and gene products in neoplastic tissues [18, 40, 90, 91, 92, 93, 94, 95]. It must be pointed out that several authors exploring BZLF1 transcripts in the peripheral blood lymphocytes (PBL) of PTLD patients demonstrated that both a high EBV genome number and strong BZLF1 mRNA expression are sensitive markers of EBV-related PTLD [96]. In a previous study, we demonstrated ZEBRA expression in the whole peripheral blood mononuclear cells (PBMCs) from a patient exhibiting a LPD using flow cytometry. In these patients who underwent non-myeloablative allogeneic stem cell transplantation, the ZEBRA antigen was found in mostly 5% of PBMCs [97]. Moreover infected cells were detected in the peripheral blood at higher levels (e.g., 1–10 lytic-infected cells per 104 B lymphocytes [1, 98] versus 1 and 50 per 106 B cells in persistently infected healthy individuals) [99].
Recently we succeeded in detecting soluble ZEBRA (s-ZEBRA) protein in serum from transplant patients (measured by an antibody-based ELISA). The s-ZEBRA (>100 ng/mL) was predictive in 80% of PTLD patients within 10 weeks, prior to PTLD diagnosis (p < 0.0001) [84]. We applied this technique in both solid organ transplant patients and in hematopoietic stem cell (HSC) patients. During the HSCT patient follow-up, the availability of iterative serum samples enabled us to investigate the kinetics of s-ZEBRA appearance in comparison to that of EBV DNA qPCR and anti-ZEBRA IgG antibodies. As for patient follow-up, it was interesting to notice that the circulating ZEBRA protein could be detected during periods in which the viral DNA was not detectable by qPCR. This could be explained by certain inconsistencies observed between the qPCR and s-ZEBRA detection results (Figure 5). This discrepancy may be accounted for by the precocity of the ZEBRA signal measured over the course of EBV infection in this patient population. This precocity of s-ZEBRA detection (with respect to the qPCR) was independent of the PCR format, since we observed the same phenomenon in PTLD patients who were investigated by measuring the EBV load (expressed in copies/150,000 cells). In two PTLD patients, s-ZEBRA was detected at 2 and 6 weeks, respectively, prior to the PTLD episode and before the increase in qPCR signals [100]. It is interesting to note that the s-ZEBRA potentially correlated the symptomatology, as only one patient (#P3) (Figure 5) exhibited very high levels (3690 ng/mL) compared to the two others (#P4 and #P10) without any PTLD (162 and 300 ng/mL, respectively) (Table 3).
Patients | Nr of serum samples | Means (m) | PTLD | ||
---|---|---|---|---|---|
s-ZEBRA (OD450 value) | anti-ZEBRA (IgG titer) | EBV DNA load (copies/mL) | |||
Immunocompetent Seronegative | 30 | 0.067 | NT | 0 | No |
Immunocompetent Seropositive | 25 | 0.092 | NT | NT | No |
Infectious mononucleosis | 50 | 0.238 | 24,000 | NT | No |
Hematopoietic stem cell transplant patients | |||||
P1 | 3 | 0.461 | 2833 | 93 | No |
P2 | 3 | 0.321 | 3333 | 28 | |
P3 (deceased) | 7 | 3.26 | 5214 | 1300 | Yes |
P4 | 3 | 0.92 | 2000 | 947 | No |
P5 | 4 | 0.274 | 2300 | 136 | No |
P6 | 3 | 0.255 | 200 | 2417 | No |
P7 | 2 | 0.24 | 2250 | 42 | No |
P8 | 2 | 0.201 | 4000 | 117 | No |
P9 | 2 | 0.248 | 4000 | NT | No |
P10 | 1 | 1.236 | 20,000 | 0 | No |
P11 | 1 | 0.323 | 20,000 | 0 | No |
31 | m = 0.727 | m = 6012 | m = 507.9 |
Therefore, s-ZEBRA detection could be a potential diagnostic marker for EBV follow-up in immunocompromised patients. Given this particular setting, our findings suggest that s-ZEBRA testing could help identify patients likely to develop severe outcomes during the critical posttransplant period. Based on our findings, we assume that the circulating ZEBRA form to be a useful target for the rapid and early diagnosis of PTLD, meaning that ZEBRA antigen-capture ELISA is likely to be a good confirmatory test for assessing EBV load in this patient population. Future evaluations of the prognostic value of ZEBRA detection should focus on the sampling time and clinical phase of lymphoproliferative disease. To improve the sensitivity and specificity of PTLD diagnosis [101, 102, 103], we hypothesize that combining approaches to detect both the circulating antigen and EBV load would be likely to increase the sensitivity and reliability of tests designed to identify such malignant EBV-related diseases.
These data focused on the relevance of the lytic cycle have already attracted the attention of the EBV community due to the potential usefulness of targeting certain lytic proteins (Figure 6). Investigations using both in vitro and in vivo systems revealed that FDA-approved leflunomide, a teriflunomide metabolite that targets EBV replication, inhibited the earliest step of lytic EBV reactivation (BZLF1 and BMRF1 expression) and thus prevented the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model [104]. More recently duvesilib (a molecule inhibiting the PIU3K/akt signaling pathway, thereby inhibiting BCR signaling) was shown to reduce the expression of EBV lytic genes like BZLF1 and gp350/220, in EBV-positive cell lines and cell growth, suggesting that this molecule was able to suppress the lytic EBV cycle induced by BCR signaling [105]. The histone acetylase and DNA methyl transferase inhibitors are possible avenues to suppress the ZEBRA expression and entire lytic cascade [106]. Immunotherapeutic approaches such as vaccination against IE proteins or IE-specific therapeutic monoclonal antibodies (mAbs) look likewise promising. A recent study demonstrated that vaccination of hu-PBL-SCID mice against the ZEBRA protein could enhance specific cellular immunity and significantly delay the development of lethal EBV-LPD [107]. Efforts are additionally being made to improve the quality of CD4+ T-cell line infusions responding to EBV lytic antigens [108]. Recently authors demonstrated the role of BARF1 as a novel EBV-specific antigen suitable for immunotherapeutic approach. These authors provided evidence that mABs anti-BARF1 are likely to be a potent tool for managing several EBV malignancies [109].
In conclusion, the relevance of the lytic cycle and, particularly, the role of ZEBRA in lymphomagenesis is a new paradigm pertaining to the prevention and treatment strategies for EBV-associated cancers. Therefore, it now appears relevant to investigate the lytic EBV infection in immunocompromised patients, such as organ transplant recipients, who are highly prone to developing EBV-associated malignancies. With respect to circulating s-ZEBRA, we have made the following assumptions: (i) it may be a marker of over-immunosuppression by triggering the expression of immunomodulating cytokines; (ii) it may thus consequently play a specific role in the oncogenic process, even tumor progression. More efforts should be invested to examine the potential of drugs that target EBV lytic proteins, especially the IE proteins, such as ZEBRA.
References
- 1.
Longnecker RM, Kieff E, Cohen JI. Epstein-Barr virus. In: Knipe DM, Howley PM, editors. Fields Virology. Philadelphia, Pa: Lippincott-Williams Wilkins Publishers; 2013. pp. 1898-1960 - 2.
Joseph AM, Babcock GJ, Thorley-Lawson DA. EBV persistence involves strict selection of latently infected B cells. Journal of Immunology. 2000; 165 :2975-2981 - 3.
Babcock GJ, Decker LL, Volk M, Thorley-Lawson DA. EBV persistence in memory B cells in vivo. Immunity. 1998; 9 :395-404 - 4.
Rowe M, Lear AL, Croom-Carter D, Davies AH, Rickinson AB. Three pathways of Epstein-Barr virus gene activation from EBNA1-positive latency in B lymphocytes. Journal of Virology. 1992; 66 :122-131 - 5.
Li QX, Young LS, Niedobitek G, Dawson CW, Birkenbach M, Wang F, et al. Epstein-Barr virus infection and replication in a human epithelial cell system. Nature. 1992; 356 :347-350 - 6.
Takada K, Shimizu N, Sakuma S, Ono Y. Trans activation of the latent Epstein-Barr virus (EBV) genome after transfection of the EBV DNA fragment. Journal of Virology. 1986; 57 :1016-1022 - 7.
Laichalk LL, Thorley-Lawson DA. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. Journal of Virology. 2005; 79 :1296-1307 - 8.
Kenney SC, Mertz JE. Regulation of the latent-lytic switch in Epstein-Barr virus. Seminars in Cancer Biology. 2014; 26 :60-68 - 9.
Tsurumi T, Fujita M, Kudoh A. Latent and lytic Epstein-Barr virus replication strategies. Reviews in Medical Virology. 2005; 15 :3-15 - 10.
Rickinson AB, Long HM, Palendira U, Munz C, Hislop AD. Cellular immune controls over Epstein-Barr virus infection: New lessons from the clinic and the laboratory. Trends in Immunology. 2014; 35 :159-169 - 11.
Cesarman E. Gammaherpesvirus and lymphoproliferative disorders in immunocompromised patients. Cancer Letters. 2011; 305 :163-174 - 12.
Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. The New England Journal of Medicine. 2018; 378 :549-562 - 13.
Morales-Sanchez A, Fuentes-Panana EM. The immunomodulatory capacity of an Epstein-Barr virus abortive lytic cycle: Potential contribution to viral tumorigenesis. Cancers (Basel). 2018; 10 :1-25 - 14.
Manners O, Murphy JC, Coleman A, Hughes DJ, Whitehouse A. Contribution of the KSHV and EBV lytic cycles to tumourigenesis. Current Opinion in Virology. 2018; 32 :60-70 - 15.
Jha HC, Banerjee S, Robertson ES. The role of gammaherpesviruses in Cancer pathogenesis. Pathogens. 2016; 5 :1-43 - 16.
Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nature Reviews. Cancer. 2004; 4 :757-768 - 17.
Brousset P, Knecht H, Rubin B, Drouet E, Chittal S, Meggetto F, et al. Demonstration of Epstein-Barr virus replication in Reed-Sternberg cells of Hodgkin's disease. Blood. 1993; 82 :872-876 - 18.
Brousset P, Drouet E, Schlaifer D, Icart J, Payen C, Meggetto F, et al. Epstein-Barr virus (EBV) replicative gene expression in tumour cells of AIDS-related non-Hodgkin's lymphoma in relation to CD4 cell number and antibody titres to EBV. AIDS. 1994; 8 :583-590 - 19.
Bibeau F, Brousset P, Knecht H, Meggetto F, Drouet E, Rubin B, et al. Epstein-Barr virus replication in Hodgkin disease. Bulletin du Cancer. 1994; 81 :114-118 - 20.
Martel-Renoir D, Grunewald V, Touitou R, Schwaab G, Joab I. Qualitative analysis of the expression of Epstein-Barr virus lytic genes in nasopharyngeal carcinoma biopsies. The Journal of General Virology. 1995; 76 (Pt 6):1401-1408 - 21.
Xue SA, Lu QL, Poulsom R, Karran L, Jones MD, Griffin BE. Expression of two related viral early genes in Epstein-Barr virus-associated tumors. Journal of Virology. 2000; 74 :2793-2803 - 22.
Cabras G, Decaussin G, Zeng Y, Djennaoui D, Melouli H, Broully P, et al. Epstein-Barr virus encoded BALF1 gene is transcribed in Burkitt’s lymphoma cell lines and in nasopharyngeal carcinoma's biopsies. Journal of Clinical Virology. 2005; 34 :26-34 - 23.
Katsumura KR, Maruo S, Takada K. EBV lytic infection enhances transformation of B-lymphocytes infected with EBV in the presence of T-lymphocytes. Journal of Medical Virology. 2012; 84 :504-510 - 24.
Ma SD, Hegde S, Young KH, Sullivan R, Rajesh D, Zhou Y, et al. A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. Journal of Virology. 2011; 85 :165-177 - 25.
Ma SD, Yu X, Mertz JE, Gumperz JE, Reinheim E, Zhou Y, et al. An Epstein-Barr virus (EBV) mutant with enhanced BZLF1 expression causes lymphomas with abortive lytic EBV infection in a humanized mouse model. Journal of Virology. 2012; 86 :7976-7987 - 26.
Dolcetti R, Dal Col J, Martorelli D, Carbone A, Klein E. Interplay among viral antigens, cellular pathways and tumor microenvironment in the pathogenesis of EBV-driven lymphomas. Seminars in Cancer Biology. 2013; 23 :441-456 - 27.
Fang CY, Lee CH, Wu CC, Chang YT, Yu SL, Chou SP, et al. Recurrent chemical reactivations of EBV promotes genome instability and enhances tumor progression of nasopharyngeal carcinoma cells. International Journal of Cancer. 2009; 124 :2016-2025 - 28.
Wu CC, Liu MT, Chang YT, Fang CY, Chou SP, Liao HW, et al. Epstein-Barr virus DNase (BGLF5) induces genomic instability in human epithelial cells. Nucleic Acids Research. 2010; 38 :1932-1949 - 29.
Hong GK, Kumar P, Wang L, Damania B, Gulley ML, Delecluse HJ, et al. Epstein-Barr virus lytic infection is required for efficient production of the angiogenesis factor vascular endothelial growth factor in lymphoblastoid cell lines. Journal of Virology. 2005; 79 :13984-13992 - 30.
Chien YC, Chen JY, Liu MY, Yang HI, Hsu MM, Chen CJ, et al. Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. The New England Journal of Medicine. 2001; 345 :1877-1882 - 31.
Ji MF, Wang DK, Yu YL, Guo YQ , Liang JS, Cheng WM, et al. Sustained elevation of Epstein-Barr virus antibody levels preceding clinical onset of nasopharyngeal carcinoma. British Journal of Cancer. 2007; 96 :623-630 - 32.
Cao SM, Liu Z, Jia WH, Huang QH, Liu Q , Guo X, et al. Fluctuations of Epstein-Barr virus serological antibodies and risk for nasopharyngeal carcinoma: A prospective screening study with a 20-year follow-up. PLoS One. 2011; 6 :e19100 - 33.
Dardari R, Hinderer W, Lang D, Benider A, El Gueddari B, Joab I, et al. Antibody responses to recombinant Epstein-Barr virus antigens in nasopharyngeal carcinoma patients: Complementary test of ZEBRA protein and early antigens p54 and p138. Journal of Clinical Microbiology. 2001; 39 :3164-3170 - 34.
Dardari R, Khyatti M, Benider A, Jouhadi H, Kahlain A, Cochet C, et al. Antibodies to the Epstein-Barr virus transactivator protein (ZEBRA) as a valuable biomarker in young patients with nasopharyngeal carcinoma. International Journal of Cancer. 2000; 86 :71-75 - 35.
Dardari R, Menezes J, Drouet E, Joab I, Benider A, Bakkali H, et al. Analyses of the prognostic significance of the Epstein-Barr virus transactivator ZEBRA protein and diagnostic value of its two synthetic peptides in nasopharyngeal carcinoma. Journal of Clinical Virology. 2008; 41 :96-103 - 36.
Yip TT, Ngan RK, Lau WH, Poon YF, Joab I, Cochet C, et al. A possible prognostic role of immunoglobulin-G antibody against recombinant Epstein-Barr virus BZLF-1 transactivator protein ZEBRA in patients with nasopharyngeal carcinoma. Cancer. 1994; 74 :2414-2424 - 37.
Mathew A, Cheng HM, Sam CK, Joab I, Prasad U, Cochet C. A high incidence of serum IgG antibodies to the Epstein-Barr virus replication activator protein in nasopharyngeal carcinoma. Cancer Immunology, Immunotherapy. 1994; 38 :68-70 - 38.
Drouet E, Brousset P, Fares F, Icart J, Verniol C, Meggetto F, et al. High Epstein-Barr virus serum load and elevated titers of anti-ZEBRA antibodies in patients with EBV-harboring tumor cells of Hodgkin's disease. Journal of Medical Virology. 1999; 57 :383-389 - 39.
Marrao G, Habib M, Paiva A, Bicout D, Fallecker C, Franco S, et al. Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-alpha/IFN-gamma response. BMC Cancer. 2014; 14 :665 - 40.
Traylen C, Ramasubramanyan S, Zuo J, Rowe M, Almohammad R, Heesom K, et al. Identification of Epstein-Barr virus replication proteins in Burkitt's lymphoma cells. Pathogens. 2015; 4 :739-751 - 41.
Rooney CM, Rowe DT, Ragot T, Farrell PJ. The spliced BZLF1 gene of Epstein-Barr virus (EBV) transactivates an early EBV promoter and induces the virus productive cycle. Journal of Virology. 1989; 63 :3109-3116 - 42.
Farrell PJ, Rowe DT, Rooney CM, Kouzarides T. Epstein-Barr virus BZLF1 trans-activator specifically binds to a consensus AP-1 site and is related to c-fos. The EMBO Journal. 1989; 8 :127-132 - 43.
Speck SH, Chatila T, Flemington E. Reactivation of Epstein-Barr virus: Regulation and function of the BZLF1 gene. Trends in Microbiology. 1997; 5 :399-405 - 44.
Flemington E, Speck SH. Evidence for coiled-coil dimer formation by an Epstein-Barr virus transactivator that lacks a heptad repeat of leucine residues. Proceedings of the National Academy of Sciences of the United States of America. 1990; 87 :9459-9463 - 45.
Feederle R, Kost M, Baumann M, Janz A, Drouet E, Hammerschmidt W, et al. The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. The EMBO Journal. 2000; 19 :3080-3089 - 46.
Flemington E, Speck SH. Autoregulation of Epstein-Barr virus putative lytic switch gene BZLF1. Journal of Virology. 1990; 64 :1227-1232 - 47.
Lee S, Cho HJ, Park JJ, Kim YS, Hwang S, Sun R, et al. The ORF49 protein of murine gammaherpesvirus 68 cooperates with RTA in regulating virus replication. Journal of Virology. 2007; 81 :9870-9877 - 48.
Bhende PM, Seaman WT, Delecluse HJ, Kenney SC. The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nature Genetics. 2004; 36 :1099-1104 - 49.
Bhende PM, Seaman WT, Delecluse HJ, Kenney SC. BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. Journal of Virology. 2005; 79 :7338-7348 - 50.
Ernberg I, Falk K, Minarovits J, Busson P, Tursz T, Masucci MG, et al. The role of methylation in the phenotype-dependent modulation of Epstein-Barr nuclear antigen 2 and latent membrane protein genes in cells latently infected with Epstein-Barr virus. The Journal of General Virology. 1989; 70 (Pt 11):2989-3002 - 51.
Minarovits J, Minarovits-Kormuta S, Ehlin-Henriksson B, Falk K, Klein G, Ernberg I. Host cell phenotype-dependent methylation patterns of Epstein-Barr virus DNA. The Journal of General Virology. 1991; 72 (Pt 7):1591-1599 - 52.
Bird AP, Wolffe AP. Methylation-induced repression–Belts, braces, and chromatin. Cell. 1999; 99 :451-454 - 53.
Boyes J, Bird A. Repression of genes by DNA methylation depends on CpG density and promoter strength: Evidence for involvement of a methyl-CpG binding protein. The EMBO Journal. 1992; 11 :327-333 - 54.
Buschhausen G, Wittig B, Graessmann M, Graessmann A. Chromatin structure is required to block transcription of the methylated herpes simplex virus thymidine kinase gene. Proceedings of the National Academy of Sciences of the United States of America. 1987; 84 :1177-1181 - 55.
Clark SJ, Harrison J, Molloy PL. Sp1 binding is inhibited by (m)Cp(m)CpG methylation. Gene. 1997; 195 :67-71 - 56.
Doerfler W. DNA methylation and gene activity. Annual Review of Biochemistry. 1983; 52 :93-124 - 57.
Morrison TE, Mauser A, Wong A, Ting JP, Kenney SC. Inhibition of IFN-gamma signaling by an Epstein-Barr virus immediate-early protein. Immunity. 2001; 15 :787-799 - 58.
Morrison TE, Kenney SC. BZLF1, an Epstein-Barr virus immediate-early protein, induces p65 nuclear translocation while inhibiting p65 transcriptional function. Virology. 2004; 328 :219-232 - 59.
Zuo J, Thomas WA, Haigh TA, Fitzsimmons L, Long HM, Hislop AD, et al. Epstein-Barr virus evades CD4+ T cell responses in lytic cycle through BZLF1-mediated downregulation of CD74 and the cooperation of vBcl-2. PLoS Pathogens. 2011; 7 :e1002455 - 60.
Mahot S, Sergeant A, Drouet E, Gruffat H. A novel function for the Epstein-Barr virus transcription factor EB1/Zta: Induction of transcription of the hIL-10 gene. The Journal of General Virology. 2003; 84 :965-974 - 61.
Tsai SC, Lin SJ, Chen PW, Luo WY, Yeh TH, Wang HW, et al. EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines. Blood. 2009; 114 :109-118 - 62.
Hong GK, Gulley ML, Feng WH, Delecluse HJ, Holley-Guthrie E, Kenney SC. Epstein-Barr virus lytic infection contributes to lymphoproliferative disease in a SCID mouse model. Journal of Virology. 2005; 79 :13993-14003 - 63.
Cannon MJ, Pisa P, Fox RI, Cooper NR. Epstein-Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice. The Journal of Clinical Investigation. 1990; 85 :1333-1337 - 64.
Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988; 335 :256-259 - 65.
Rowe M, Young LS, Crocker J, Stokes H, Henderson S, Rickinson AB. Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: Implications for the pathogenesis of EBV-positive lymphomas in man. The Journal of Experimental Medicine. 1991; 173 :147-158 - 66.
Li H, Liu S, Hu J, Luo X, Li N, Bode AM, et al. Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis. International Journal of Biological Sciences. 2016; 12 :1309-1318 - 67.
Bogedain C, Wolf H, Modrow S, Stuber G, Jilg W. Specific cytotoxic T lymphocytes recognize the immediate-early transactivator Zta of Epstein-Barr virus. Journal of Virology. 1995; 69 :4872-4879 - 68.
Hislop AD, Taylor GS, Sauce D, Rickinson AB. Cellular responses to viral infection in humans: Lessons from Epstein-Barr virus. Annual Review of Immunology. 2007; 25 :587-617 - 69.
Rist MJ, Neller MA, Burrows JM, Burrows SR. T cell epitope clustering in the highly immunogenic BZLF1 antigen of Epstein-Barr virus. Journal of Virology. 2015; 89 :703-712 - 70.
Scherrenburg J, Piriou ER, Nanlohy NM, van Baarle D. Detailed analysis of Epstein-Barr virus-specific CD4+ and CD8+ T cell responses during infectious mononucleosis. Clinical and Experimental Immunology. 2008; 153 :231-239 - 71.
Precopio ML, Sullivan JL, Willard C, Somasundaran M, Luzuriaga K. Differential kinetics and specificity of EBV-specific CD4+ and CD8+ T cells during primary infection. Journal of Immunology. 2003; 170 :2590-2598 - 72.
Pudney VA, Leese AM, Rickinson AB, Hislop AD. CD8+ immunodominance among Epstein-Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells. The Journal of Experimental Medicine. 2005; 201 :349-360 - 73.
Drouet E, Chapuis-Cellier C, Bosshard S, Verniol C, Niveleau A, Touraine JL, et al. Oligo-monoclonal immunoglobulins frequently develop during concurrent cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections in patients after renal transplantation. Clinical and Experimental Immunology. 1999; 118 :465-472 - 74.
Niveleau A, Bruno C, Drouet E, Brebant R, Sergeant A, Troalen F. Grafting peptides onto polystyrene microplates for ELISA. Journal of Immunological Methods. 1995; 182 :227-234 - 75.
Drouet E, Chapuis-Cellier C, Garnier JL, Touraine JL. Early detection of EBV infection and meaning in transplant patients. In: Touraine JL, editor. Cancer in Transplantation: Prevention and Treatment. Lyon: Kluwer Academic Publishers; 1996. pp. 201-207 - 76.
Sinclair AJ. bZIP proteins of human gammaherpesviruses. The Journal of General Virology. 2003; 84 :1941-1949 - 77.
Flemington EK. Herpesvirus lytic replication and the cell cycle: Arresting new developments. Journal of Virology. 2001; 75 :4475-4481 - 78.
Cayrol C, Flemington E. G0/G1 growth arrest mediated by a region encompassing the basic leucine zipper (bZIP) domain of the Epstein-Barr virus transactivator Zta. The Journal of Biological Chemistry. 1996; 271 :31799-31802 - 79.
Cayrol C, Flemington EK. The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors. The EMBO Journal. 1996; 15 :2748-2759 - 80.
Rodriguez A, Jung EJ, Yin Q , Cayrol C, Flemington EK. Role of c-myc regulation in Zta-mediated induction of the cyclin-dependent kinase inhibitors p21 and p27 and cell growth arrest. Virology. 2001; 284 :159-169 - 81.
Petosa C, Morand P, Baudin F, Moulin M, Artero JB, Muller CW. Structural basis of lytic cycle activation by the Epstein-Barr virus ZEBRA protein. Molecular Cell. 2006; 21 :565-572 - 82.
Mahot S, Fender P, Vives RR, Caron C, Perrissin M, Gruffat H, et al. Cellular uptake of the EBV transcription factor EB1/Zta. Virus Research. 2005; 110 :187-193 - 83.
Rothe R, Liguori L, Villegas-Mendez A, Marques B, Grunwald D, Drouet E, et al. Characterization of the cell-penetrating properties of the Epstein-Barr virus ZEBRA trans-activator. The Journal of Biological Chemistry. 2010; 285 :20224-20233 - 84.
Habib M, Buisson M, Lupo J, Agbalika F, Socie G, Germi R, et al. Lytic EBV infection investigated by detection of soluble Epstein-Barr virus ZEBRA in the serum of patients with PTLD. Scientific Reports. 2017; 7 :10479 - 85.
Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature. 1990; 345 :84-86 - 86.
Amorim JH, Alves RP, Boscardin SB, Ferreira LC. The dengue virus non-structural 1 protein: Risks and benefits. Virus Research. 2014; 181 :53-60 - 87.
Tosato G, Teruya-Feldstein J, Setsuda J, Pike SE, Jones KD, Jaffe ES. Post-transplant lymphoproliferative disease (PTLD): Lymphokine production and PTLD. Springer Seminars in Immunopathology. 1998; 20 :405-423 - 88.
Garnier JL, Cooper NR, Cannon MJ. Low expression of CD20 and CD23 in Epstein-Barr virus-induced B cell tumors in SCID/hu mice. The American Journal of Pathology. 1993; 142 :353-358 - 89.
Garnier JL, Blanc-Brunat N, Laurin D, Vivier G, Touraine JL, Sergeant A, et al. Lymphomas in the Scid/Hu mice: Effect of EBV on human B-cells in vivo. In: Touraine JL, editor. Cancer in Transplantation: Prevention and Treatment. Lyon: Kluwer Academic Publishers; 1996. pp. 209-213 - 90.
Montone KT, Hodinka RL, Salhany KE, Lavi E, Rostami A, Tomaszewski JE. Identification of Epstein-Barr virus lytic activity in post-transplantation lymphoproliferative disease. Modern Pathology. 1996; 9 :621-630 - 91.
Montone KT, Litzky LA, Wurster A, Kaiser L, Bavaria J, Kotloff R, et al. Analysis of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after lung transplantation. Surgery. 1996; 119 :544-551 - 92.
Rea D, Delecluse HJ, Hamilton-Dutoit SJ, Marelle L, Joab I, Edelman L, et al. Epstein-Barr virus latent and replicative gene expression in post-transplant lymphoproliferative disorders and AIDS-related non-Hodgkin's lymphomas. French Study Group of Pathology for HIV-associated Tumors. Annals of Oncology. 1994; 5 (Suppl 1):113-116 - 93.
Rea D, Fourcade C, Leblond V, Rowe M, Joab I, Edelman L, et al. Patterns of Epstein-Barr virus latent and replicative gene expression in Epstein-Barr virus B cell lymphoproliferative disorders after organ transplantation. Transplantation. 1994; 58 :317-324 - 94.
Fink SE, Gandhi MK, Nourse JP, Keane C, Jones K, Crooks P, et al. A comprehensive analysis of the cellular and EBV-specific microRNAome in primary CNS PTLD identifies different patterns among EBV-associated tumors. American Journal of Transplantation. 2014; 14 :2577-2587 - 95.
Cohen M, Vistarop AG, Huaman F, Narbaitz M, Metrebian F, De Matteo E, et al. Epstein-Barr virus lytic cycle involvement in diffuse large B cell lymphoma. Hematological Oncology. 2018; 36 :98-103 - 96.
Vajro P, Lucariello S, Migliaro F, Sokal E, Gridelli B, Vegnente A, et al. Predictive value of Epstein-Barr virus genome copy number and BZLF1 expression in blood lymphocytes of transplant recipients at risk for lymphoproliferative disease. The Journal of Infectious Diseases. 2000; 181 :2050-2054 - 97.
Imbert-Marcille BM, Coste-Burel M, Robillard N, Foucaud-Gamen J, Billaudel S, Drouet E. Sequential use of paraformaldehyde and methanol as optimal conditions for the direct quantification of ZEBRA and rta antigens by flow cytometry. Clinical and Diagnostic Laboratory Immunology. 2000; 7 :206-211 - 98.
Babcock GJ, Decker LL, Freeman RB, Thorley-Lawson DA. Epstein-barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. The Journal of Experimental Medicine. 1999; 190 :567-576 - 99.
Miyashita EM, Yang B, Lam KM, Crawford DH, Thorley-Lawson DA. A novel form of Epstein-Barr virus latency in normal B cells in vivo. Cell. 1995; 80 :593-601 - 100.
Drouet E, Habib M, Agbalika F. Use of at least one biomarker for the in vitro prognosis or diagnosis of lymphoproliferative episodes associated with the Epstein-Barr virus (EBV). In: Joseph-Fourier U, editor. United States Patent Application Publication. France: Université Joseph-Fourier; 2014. pp. 1-17 - 101.
Oertel S, Trappe RU, Zeidler K, Babel N, Reinke P, Hummel M, et al. Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course. Annals of Hematology. 2006; 85 :478-484 - 102.
Wareham NE, Mocroft A, Sengelov H, Da Cunha-Bang C, Gustafsson F, Heilmann C, et al. The value of EBV DNA in early detection of post-transplant lymphoproliferative disorders among solid organ and hematopoietic stem cell transplant recipients. Journal of Cancer Research and Clinical Oncology. 2018; 144 :1569-1580 - 103.
Dharnidharka VR. Peripheral blood Epstein-Barr viral nucleic acid surveillance as a marker for posttransplant Cancer risk. American Journal of Transplantation. 2017; 17 :611-616 - 104.
Bilger A, Plowshay J, Ma S, Nawandar D, Barlow EA, Romero-Masters JC, et al. Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication. Oncotarget. 2017; 8 :44266-44280 - 105.
Kawada JI, Ando S, Torii Y, Watanabe T, Sato Y, Ito Y, et al. Antitumor effects of duvelisib on Epstein-Barr virus-associated lymphoma cells. Cancer Medicine. 2018; 7 :1275-1284 - 106.
Daskalogianni C, Pyndiah S, Apcher S, Mazars A, Manoury B, Ammari N, et al. Epstein-Barr virus-encoded EBNA1 and ZEBRA: Targets for therapeutic strategies against EBV-carrying cancers. The Journal of Pathology. 2015; 235 :334-341 - 107.
Hartlage AS, Liu T, Patton JT, Garman SL, Zhang X, Kurt H, et al. The Epstein-Barr virus lytic protein BZLF1 as a candidate target antigen for vaccine development. Cancer Immunology Research. 2015; 3 :787-794 - 108.
Adhikary D, Behrends U, Boerschmann H, Pfunder A, Burdach S, Moosmann A, et al. Immunodominance of lytic cycle antigens in Epstein-Barr virus-specific CD4+ T cell preparations for therapy. PLoS One. 2007; 2 :e583 - 109.
Turrini R, Merlo A, Martorelli D, Fae DA, Sommaggio R, Montagner IM, et al. A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors. Oncoimmunology. 2017; 6 :e1304338 - 110.
Houali K, Wang X, Shimizu Y, Djennaoui D, Nicholls J, Fiorini S, et al. A new diagnostic marker for secreted Epstein-Barr virus encoded LMP1 and BARF1 oncoproteins in the serum and saliva of patients with nasopharyngeal carcinoma. Clinical Cancer Research. 2007; 13 :4993-5000 - 111.
Hoebe EK, Hutajulu SH, van Beek J, Stevens SJ, Paramita DK, Greijer AE, et al. Purified hexameric Epstein-Barr virus-encoded BARF1 protein for measuring anti-BARF1 antibody responses in nasopharyngeal carcinoma patients. Clinical and Vaccine Immunology. 2011; 18 :298-304 - 112.
Sbih-Lammali F, Berger F, Busson P, Ooka T. Expression of the DNase encoded by the BGLF5 gene of Epstein-Barr virus in nasopharyngeal carcinoma epithelial cells. Virology. 1996; 222 :64-74 - 113.
Stolzenberg MC, Debouze S, Ng M, Sham J, Choy D, Bouguermouh A, et al. Purified recombinant EBV desoxyribonuclease in serological diagnosis of nasopharyngeal carcinoma. International Journal of Cancer. 1996; 66 :337-341 - 114.
Blay JY, Voorzanger N, Favrot M, Burdin N, Rousset F, Banchereau J. Presence of Epstein-Barr virus viral interleukin-10 in the serum of patients with non-human-immunodeficiency-virus-related diffuse large-cell non-Hodgkin's lymphomas. Blood. 1995; 86 :4702-4704 - 115.
Joab I, Nicolas JC, Schwaab G, de-The G, Clausse B, Perricaudet M, et al. Detection of anti-Epstein-Barr-virus transactivator (ZEBRA) antibodies in sera from patients with nasopharyngeal carcinoma. International Journal of Cancer. 1991; 48 :647-649 - 116.
Joab I, Triki H, de Saint MJ, Perricaudet M, Nicolas JC. Detection of anti-Epstein-Barr virus trans-activator (ZEBRA) antibodies in sera from patients with human immunodeficiency virus. The Journal of Infectious Diseases. 1991; 163 :53-56