The Immunomodulatory Capacity of an Epstein-Barr Virus Abortive Lytic Cycle: Potential Contribution to Viral Tumorigenesis

Abstract

Epstein-Barr virus (EBV) is characterized by a bipartite life cycle in which latent and lytic stages are alternated. Latency is compatible with long-lasting persistency within the infected host, while lytic expression, preferentially found in oropharyngeal epithelial tissue, is thought to favor host-to-host viral dissemination. The clinical importance of EBV relates to its association with cancer, which we think is mainly a consequence of the latency/persistency mechanisms. However, studies in murine models of tumorigenesis/lymphomagenesis indicate that the lytic cycle also contributes to cancer formation. Indeed, EBV lytic expression is often observed in established cell lines and tumor biopsies. Within the lytic cycle EBV expresses a handful of immunomodulatory (BCRF1, BARF1, BNLF2A, BGLF5 & BILF1) and anti-apoptotic (BHRF1 & BALF1) proteins. In this review, we discuss the evidence supporting an abortive lytic cycle in which these lytic genes are expressed, and how the immunomodulatory mechanisms of EBV and related herpesviruses Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV) result in paracrine signals that feed tumor cells. An abortive lytic cycle would reconcile the need of lytic expression for viral tumorigenesis without relaying in a complete cycle that would induce cell lysis to release the newly formed infective viral particles.

Keywords: EBV; HCMV; KSHV; abortive lytic cycle; autocrine/paracrine signaling; immunomodulation; oncomodulation; tumorigenesis.

Figure 1

Lytic cycle proteins contribution to tumor initiation and tumor maintenance through enhanced survival, inflammation and immunomodulation. BHRF1 & BALF1, two viral orthologues of cellular Bcl-2, display anti-apoptotic functions protecting infected cells from death signals. Immunoevasion occurs through several mechanisms: BCRF1 (encoding a viral IL-10) and BARF1 contribute to reduced natural killer (NK) and cytotoxic T lymphocyte (CTL) responses as well as suppression of T cell activity through inhibition of IFN-γ. BILF1, BGLF5 and BNLF2a deregulate the HLA pathway to evade elimination of EBV infected cells. Also, BILF1 displays an interfering regulatory role upon CXCL12-dependent activation of CXCR4. Viral reactivation genes also importantly contribute to inflammation. Zta directly or indirectly enhances levels of IL-13, IL-8, CXC chemokine GRO, CCL4, IL-6, and IL-10. IL-6 and IL-10 are also increased by Rta. BLLF3 increases secretion of pro-inflammatory Th1 and Th17 cytokines and of IL-10. The resulting inflammatory microenvironment promotes tumor growth through autocrine/paracrine stimulation.

Figure 2

The cell transformation mediated by EBV is dependent on latent, lytic and abortive lytic infection. Evidence supports that lytic cycle gene expression contributes to the EBV-induced tumorigenesis. In EBV positive tumors, the abortive lytic cycle expression induces an inflammatory microenvironment that nurtures the tumor. This inflammatory microenvironment promotes tumor growth, survival and angiogenesis.