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Review
. 2021 May 10;13(9):2275.
doi: 10.3390/cancers13092275.

Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein-Barr Virus

Yun Deng  1 , Christian Münz  1
Affiliations
Review

Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein-Barr Virus

Yun Deng et al. Cancers (Basel). .

Abstract

Epstein-Barr virus (EBV) is the prototypic human tumor virus whose continuous lifelong immune control is required to prevent lymphomagenesis in the more than 90% of the human adult population that are healthy carriers of the virus. Here, we review recent evidence that this immune control has not only to target latent oncogenes, but also lytic replication of EBV. Furthermore, genetic variations identify the molecular machinery of cytotoxic lymphocytes as essential for this immune control and recent studies in mice with reconstituted human immune system components (humanized mice) have begun to provide insights into the mechanistic role of these molecules during EBV infection. Finally, EBV often does not act in isolation to cause disease. Some of EBV infection-modulating co-infections, including human immunodeficiency virus (HIV) and Kaposi sarcoma-associated herpesvirus (KSHV), have been modeled in humanized mice. These preclinical in vivo models for EBV infection, lymphomagenesis, and cell-mediated immune control do not only promise a better understanding of the biology of this human tumor virus, but also the possibility to explore vaccine candidates against it.

Keywords: CD27; CD8+ T cells; Kaposi sarcoma-associated herpesvirus (KSHV); human immunodeficiency virus (HIV); humanized mice; malaria; natural killer cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Signaling pathways involved in genetic predispositions that abolish the function of cytotoxic lymphocytes against EBV-infected cells. The graph summarizes genetic mutations that predispose for EBV-associated diseases: MAGT1 and ITK can both mediate the T cell activation by regulating PLCγ1. This pathway is further regulated by RASGRP1, which is the main activator for the Ras/MAPK signaling pathway for T and NK cell activation. In addition, MAGT1 also interacts with NKG2D to regulate the cytotoxic effector function of CD8+ T cells and NK cells. By engaging the receptors for 2B4 and NTB-A, they facilitate the NFκB signaling pathway through the interaction with the SAP adaptor protein. Similar for CD27, the engagement of CD70 leads to the activation of NF-κB and c-Fos/c-Jun pathways. Recent studies have also shown HLA-DR15 and CD16 as genetic risk factors for attenuated EBV immune control but the underlying mechanisms remain to be further investigated.
Figure 2
Figure 2
Co-infections by Plasmodium falciparum (Pf), human immunodeficiency virus (HIV), and Kaposi sarcoma-associated herpesvirus (KSHV) modulate Epstein–Barr virus (EBV) pathogenesis. (A) Holoendemic Pf infection is associated with the development of EBV-positive endemic BL. Pf is thought to drive EBV-infected B cells more frequently into the germinal center reaction where translocation of the oncogene c-myc into the heavy or light immunoglobulin chain (IgH or IgL) locus occurs that is characteristic for BL and responsible for its proliferation. In addition, Pf attenuates EBV-specific T cell-mediated immune control, thereby increasing the number of EBV-infected B cells. (B) HIV infection compromises EBV-specific immune control, but at the same time can also infect EBV-positive B cells that then are better controlled by CD8+ T cells due to an upregulation of MHC class I-restricted antigen presentation. (C) KSHV co-infection drives increased EBV-associated lymphomagenesis by transactivating lytic EBV replication in double infected B cells. This results in plasma cell differentiated lymphomas with similarities to primary effusion lymphoma (PEL). This figure was created in part with modified Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 unported license: https://smart.servier.com (accessed on 01 April 2021).
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