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

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.

Epstein–Barr Virus Infection in Cancer

“…Deng, Y. [ 12 ] published an article that examined how EBV-lytic products and co-infections such as Plasmodium falciparum, KSHV, and HIV interact with EBV, modify its immune control, and shape its tumorigenesis.…”

MicroRNA-focused CRISPR/Cas9 screen identifies miR-142 as a key regulator of Epstein-Barr virus reactivation

“…Periodic reactivation, which induces lytic viral gene expression and production of viral progeny, is necessary for cell-to-cell spread, host-to-host transmission, and replenishing the latent reservoir of infected cells [ 7 , 8 ]. Mounting evidence suggests that lytic replication is a key contributor to viral oncogenesis [ 9 , 10 ]. Lytic gene products can be detected in EBV-associated tumors [ 11 ], increased EBV DNA loads correlate with BL disease progression in children [ 12 ], and elevated antibody titers to EBV lytic antigens often precede onset of cancers such as NPC [ 13 , 14 ].…”

The Dual Functions of Andrographolide in the Epstein–Barr Virus-Positive Head-and-Neck Cancer Cells: The Inhibition of Lytic Reactivation of the Epstein–Barr Virus and the Induction of Cell Death

“…BZLF1 is a lytic gene of EBV that plays a critical role in transcriptional transactivation to regulate the switching of EBV from latency to lytic replication [7]. The Zta, a product of the BZLF1 gene, contributes to the oncogenesis of EBV-associated malignancies by inducing genome instability, inflammation, cell proliferation, and inhibiting cell death through the activation of several signaling pathways [11][12][13]. In addition, Rta, a product of the BRLF1 gene, can also promote the oncogenesis of EBV-associated malignancies by inducing cell migration via the activation of the IL6/JAK/STAT3 signaling pathway [14].…”