Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 9, 81
eCollection

Viral-Targeted Strategies Against EBV-Associated Lymphoproliferative Diseases

Affiliations
Review

Viral-Targeted Strategies Against EBV-Associated Lymphoproliferative Diseases

Kwai Fung Hui et al. Front Oncol.

Abstract

Epstein-Barr virus (EBV) is strongly associated with a spectrum of EBV-associated lymphoproliferative diseases (EBV-LPDs) ranging from post-transplant lymphoproliferative disorder, B cell lymphomas (e.g., endemic Burkitt lymphoma, Hodgkin lymphoma, and diffuse large B cell lymphoma) to NK or T cell lymphoma (e.g., nasal NK/T-cell lymphoma). The virus expresses a number of latent viral proteins which are able to manipulate cell cycle and cell death processes to promote survival of the tumor cells. Several FDA-approved drugs or novel compounds have been shown to induce killing of some of the EBV-LPDs by inhibiting the function of latent viral proteins or activating the viral lytic cycle from latency. Here, we aim to provide an overview on the mechanisms by which EBV employs to drive the pathogenesis of various EBV-LPDs and to maintain the survival of the tumor cells followed by a discussion on the development of viral-targeted strategies based on the understanding of the patho-mechanisms.

Keywords: EBV latency; Epstein-Barr virus; histone deacetylase inhibitors; lymphoproliferative diseases; lytic cycle reactivation; proteasome inhibitors; viral-targeted strategies.

Figures

Figure 1
Figure 1
EBV latency in EBV-LPDs. No EBV protein is expressed in Latency 0. Only EBNA-1, EBERs, and BARTs are expressed in Latency I which is associated with endemic BL. The transcription of EBNA-1 is initiated at the BamHI Q promoter. 15% of endemic BL is found to be Wp-restricted latency in which EBNA-LP, EBNA-1, EBNA-3A, -3B, and -3C are transcribed from the BamHI W promoter. HL, nasal NK/T-cell lymphoma and DLBCL are detected in type II latency that EBNA-1, EBNA-LP, latent membrane protein (LMP)-1, -2A, and -2B, EBERs and BARTs are expressed. AIDS-associated B-cell lymphoma, PTLD and lymphoblastoid cell line (LCL), an in vitro model of EBV-LPDs are observed in type III latency. All EBV nuclear antigens (EBNA-1, -2, -LP, -3A, -3B, and -3C), latent membrane proteins (LMP-1, -2A, and -2B), EBERs and BARTs are expressed.
Figure 2
Figure 2
Schematic diagram representing the sequential events occur during EBV lytic reactivation. EBV Z/R promoters are activated upon diverse stimulants e.g., B-cell receptor crosslinking, chemical inductions and cellular stresses, resulting in the expression of immediate early lytic proteins, Zta and Rta. These key drivers of EBV lytic reactivation subsequently induce EBV viral DNA replication and the expression of an array of viral lytic proteins including early lytic proteins e.g., BALF1 and BHRF1 and late lytic proteins e.g., gp350 and VCA-p18. Viral DNA is then being packaged with the help from structural proteins and is assembled into mature virion. Finally, EBV is released via exocytosis.
Figure 3
Figure 3
Immunity against EBV-LPDs. (IFN)-γ and other functional cytokines [(TNF)-α and IL-2] are produced from EBV-specific polyfunctional T cells (PFCs) to control the proliferation of EBV-infected B cell during long-term infection. There are increase responses of CD4+ and CD8+ PFCs in infectious mononucleosis (IM) patients. (CD56dimNKG2A+KIR) NK cells also control EBV infection in acute IM patients and kill LCLs.
Figure 4
Figure 4
Effects of EBV latent and lytic proteins on the regulation of cell cycle. EBNA-3C interacts with cyclin A/CDK2 and promotes the proteasomal degradation of p27KIP1 to assist the EBV-infected cells to progress to enter S phase and M phase. EBNA-3C mediates the ubiquitin-proteasome degradation of pRb, increasing the transcription of E2F-dependent cyclin/CDK complexes (cyclin-D1/CDK-4/-6 and cyclin-A/-E/CDK-2), to allow the cells to enter G1 phase from G0 phase and enter S phase from G1 phase, respectively. EBNA-3C stabilizes Pim-1 protein to promote the phosphorylation and subsequent proteasomal degradation of p21WAF1 for the cells to enter S phase from G1 phase. EBNA-3C also promotes the proteasomal degradation of Bcl-6 which subsequently releases cyclin-D1 for the transition of G1 to S phase. EBNA-3A and -3C co-operate in epigenetic repression of p14ARF and p16INK4a to facilitate the transformation and proliferation of EBV-LPDs through bypassing the G2/M checkpoint regulation upon stimulation by various cytotoxic stresses.
Figure 5
Figure 5
Effects of EBV latent and lytic proteins on inhibition of apoptosis. EBNA-1 interacts with the HAUSP to destabilize and degrade p53. EBNA-2 antagonizes TGF-β-mediated growth arrest in LCLs. LMP-1 upregulates Bcl-2 and promotes the growth of BL through the activation of NF-kB signaling pathway. EBNA-3A upregulates Hsp70 chaperones to suppress the apoptosis in exposure to cytotoxic agents. EBNA-3C can suppress p53-dependent apoptosis through repressing the transcription of p53 and promoting its degradation. EBNA-3C also hinders the E2F1-mediated apoptosis induced by DNA damage response through inhibiting the DNA binding activity of E2F1 and promoting its proteolysis. EBNA-3C also interacts with Bcl-6 and releases the Bcl-2 to suppress apoptosis. EBNA-3A and -3C can co-operate to repress the expression of p16INK4a and Bim to promote cell proliferation. Zta can induce the expression of vascular endothelial growth factor (VEGF) to promote the growth of LCL.
Figure 6
Figure 6
Effects of EBV latent and lytic proteins on immune evasion. Glycine-alanine repeats (GAr) of EBNA-1 render it not be processed and presented to CD8+ T cells via the class I MHC. BDLF3, can promote the degradation of MHC class I and II molecules, impairing the immune recognition by EBV-specific CD4+ and CD8+ T cells. BGLF4 can suppress the host innate immune through the inhibition of interferon regulatory factor 3 (IRF3) and STAT1. BCRF1 suppresses INF-γ synthesis from human peripheral blood mononuclear cells, thus allowing the tumor cells to evade from the host immune surveillance.
Figure 7
Figure 7
Cellular events associated with EBV lytic reactivation and the rationale of lytic induction therapy. A diverse array of EBV lytic proteins is being expressed during lytic cycle reactivation. Subsequent occurrence of various cellular events include cell cycle arrest, inhibition of apoptosis, tumorigenesis and immune evasion. Expression of viral protein kinase BGLF4 converts antiviral drug e.g., ganciclovir (GCV) from a prodrug to its cytotoxic form, shaping the basis of lytic induction therapy.
Figure 8
Figure 8
Targeted survival pathways in EBV latency. Several EBV protein-induced survival pathways, such as inhibition of apoptosis and cell cycle arrest through epigenetic repression and/or proteasomal degradation of tumor suppressors for lymphomagenesis can be targeted by novel drugs or drug combinations.
Figure 9
Figure 9
Signaling pathways activated by different chemical lytic inducers for EBV lytic reactivation. EBV lytic reactivation can be achieved through the activation of different cellular signaling pathways e.g., PKC, p38/MAPK, ERK1/2, JNK, PI3K/AKT, DDR, ROS, hypoxia, ATM signaling pathways as well as inhibition of Ikaros and chromatin remodeling. 5-FU, fluorouracil; MTX, methotrexate; 5-AZA, 5-azacytidine; SAHA, suberoylanilide hydroxamic acid; TPA, 12-O-tetradecanoylphorbol-13-acetate; CQ, chloroquine; PKC, protein kinase C; p38/MAPK, P38 mitogen-activated protein kinases; ERK1/2, extracellular signal-regulated protein kinases 1 and 2; JNK, c-Jun N-terminal kinase; C/EBP, CCAAT/enhancer binding proteins; PI3K/AKT, phosphatidylinositol 3-kinase/AKT; TG, thapsigargin; MNNG, methylnitronitrosoguanidine; DDR, DNA damage response; ROS, reactive oxygen species; ER stress, endoplasmic reticulum stress; UPR, unfolded protein response.
Figure 10
Figure 10
Novel drugs or drug combination targeting EBV latency. EZH2 inhibitior (GSK126), DNA methyltransferase inhibitor (5-AZA) or HDAC inhibitor (SAHA) is used to inhibit the epigenetic repression of Bim, STK39, p14ARF, p15INK4b, and p16INK4a triggered by EBNA-3A and/or EBNA-3C. Proteasome inhibitor (bortezomib) can inhibit proteasomal degradation of tumor suppressors induced by EBNA-1, EBNA-3A, EBNA-3C, LMP-1, or LMP-2A. There are some EBNA-1 inhibitors, including gH/gL-EBNA1 vaccine, L2P4, LB7, SC11 and SC19, while gB-LMP2 vaccine is found to inhibit LMP-2A. Several downstream molecules, such as Lyn, mTOR, and MDM2 can be targeted by tyrosine kinase inhibitor (Dasatinib), mTOR inhibitor (rapamycin), and MDM2 inhibitor (Nutlin-3a), respectively.

Similar articles

See all similar articles

Cited by 3 PubMed Central articles

References

    1. Epstein A. Why and how Epstein-Barr virus was discovered 50 years ago. Curr Top Microbiol Immunol. (2015) 390(Pt1):3–15. 10.1007/978-3-319-22822-8_1 - DOI - PubMed
    1. Hui KF, Chan TF, Yang W, Shen JJ, Lam KP, Kwok H, et al. . High risk Epstein-Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma. Int J Cancer (2018). 10.1002/ijc.32049. [Epub ahead of print]. - DOI - PubMed
    1. Rickinson AB, Kieff E. In: Fields B, Knipe DM, Howley PM, editors. editors. Epstein-Barr Virus. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; (2001). p. 2575–627.
    1. Hochberg D, Middeldorp JM, Catalina M, Sullivan JL, Luzuriaga K, Thorley-Lawson DA. Demonstration of the Burkitt's lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cells in vivo. Proc Natl Acad Sci USA. (2004) 101:239–44. 10.1073/pnas.2237267100 - DOI - PMC - PubMed
    1. Kelly GL, Stylianou J, Rasaiyaah J, Wei W, Thomas W, Croom-Carter D, et al. . Different patterns of Epstein-Barr virus latency in endemic Burkitt lymphoma (BL) lead to distinct variants within the BL-associated gene expression signature. J Virol. (2013) 87:2882–94. 10.1128/JVI.03003-12 - DOI - PMC - PubMed

LinkOut - more resources

Feedback