Interplay among viral antigens, cellular pathways and tumor microenvironment in the pathogenesis of EBV-driven lymphomas

Abstract

Epstein–Barr virus (EBV) is a ubiquitous human γ-herpes virus that has established an elegant strategy to persist as a life-long asymptomatic infection in memory B lymphocytes. EBV has potent transforming properties for B lymphocytes and it is pathogenically associated with a variety of lymphomas of B or NK/T cell origin. The viral latency programs expressed can hijack or deregulate cellular pathways critical for cell proliferation and survival, while impairing anti-viral immune responses. Similar effects may also be induced by EBV-encoded micro-RNAs, which may have a pathogenic role particularly in lymphomas showing a restricted expression of viral proteins. Of note, recent data have challenged the view that only the EBV latency is relevant for lymphomagenesis, suggesting that lytic EBV replication may also contribute to the development of EBV-associated lymphoproliferations. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion are providing the rationale for innovative and tailored treatment approaches for EBV-driven lymphomas.

Introduction

The Epstein–Barr virus (EBV) is a ubiquitous human gamma-herpesvirus able to establish a lifelong infection in more than 90% of individuals [1]. It was originally discovered in cultured Burkitt lymphoma cells in 1964 and in 1997 it has been included among the “carcinogenic agents” by the World Health Organization (WHO) on the basis of its direct transforming potential and close association with human malignancies, mainly lymphomas. Primary infection is usually asymptomatic and only when it is delayed until adolescence or adulthood, which occurs mainly in developed countries, it can cause a self-limiting lymphoproliferative disorder, known as infectious mononucleosis (IM). The main target of EBV infection is the B lymphocyte, although T, NK, and epithelial cells may be also infected in vivo, as indicated by the occurrence of EBV-carrying malignancies that originate from these cells. B lymphocytes are infected through interaction of the virus with the complement receptor-2/CD21 expressed at the cell surface. The infection is usually non-productive, latent, whereas intermittent reactivation and virus replication at epithelial surfaces allows the spreading of EBV to new hosts. Under physiological conditions, EBV-seropositive adults carry 1–50 EBV-infected B lymphocytes per million cells in the peripheral blood [2]. These resting memory B lymphocytes show no or limited expression of virally encoded genes [2], [3] and are considered the reservoir of EBV latency. EBV reaches the memory B cell compartment through its ability to elegantly exploit the B-cell differentiation pathway. After initial infection of naïve B lymphocytes, EBV may establish different programs of latency that may be sequentially expressed according to the type, differentiation and activation status of infected cells, finally reaching the memory B-cell compartment. Shortly after infection, EBV activates a program that includes the full set of latency proteins, the six EBV nuclear antigens (EBNAs) and three latent membrane proteins (LMP-1, LMP-2A, LMP-2B). This broad latency pattern (type III latency) activates and induces proliferation of B lymphocytes, which can be initiated in vitro in continuously growing lymphoblastoid cell lines (LCL). A second latency program (type II) occurs in the germinal centers of lymphoid follicles where EBV-carrying B lymphoblasts migrate, as normal B lymphocytes do after having encountered the cognate antigen [4]. These cells express only EBNA-1 and the LMPs (type II latency), a so-called “rescue” program that provides signals allowing EBV-infected cells to survive and differentiate into memory B lymphocytes [5]. Cells leaving the germinal center as resting memory B lymphocytes silence the expression of all EBV latency proteins (type 0 latency) or may express EBNA-1 upon cell division (type I latency), a strict requirement for replication of the viral genome and its maintenance within the cell. This elegant strategy allows EBV-carrying cells to escape immune surveillance while establishing lifelong persistence in humans. In several experimental systems, an additional latency program was detected in which the nuclear antigens EBNAs, but no LMP-1, are expressed. This program, denoted as type IIb latency, does not induce proliferation and thus probably does not contribute to tumor development [6].

In all forms of latency, EBV expresses the EBERs, small non-polyadenylated, non-coding double-strand RNAs, which may also contribute to EBV-driven B-cell immortalization [7]. EBV may activate the lytic replication program upon terminal differentiation of EBV-infected memory B lymphocytes into antibody-secreting plasma cells [5]. Although well equipped to promote the growth of B lymphocytes, EBV may drive the proliferation of these cells only transiently in immunocompetent hosts. This is due to the existence of a complex, strictly regulated immunological control involving various humoral and cellular effectors of immunity. Through the long time evolutionary adaptation in humans, the virus has evolved several potent mechanisms by which the type III B lymphocytes that express the “growth program” evade the immune response. This may also explain why only a limited proportion of EBV-seropositive individuals develop EBV-associated lymphomas, even in the setting of immune deficiency. In rare cases, therefore, a derangement of the normal differentiation pathway may prevent infected B lymphocytes from entering into a resting state, allowing thus EBV to fully manifest its transforming potential.