This ubiquitous virus employs the oropharyngeal epithelium as its primary entry point and subsequently infiltrates circulating B cells, establishing a state of latency within memory B cells.
The age at which primary infection occurs varies, largely influenced by socioeconomic conditions (1, 2). While primary infection usually proceeds subclinically, it can manifest as infectious mononucleosis (IM) in adolescents and young adults (1, 3).
Infectious Mononucleosis: The EBV-Driven Proliferation
Infectious mononucleosis represents an EBV-induced proliferation of B lymphocytes, regulated by both humoral and cellular immune responses (1, 3). Notably, a robust T cell response, primarily featuring activated CD8+ cytotoxic T cells specific for lytic and latent viral antigens expressed on EBV-infected B cells, characterizes this condition (3, 4).
In immunocompetent individuals, EBV persists in a latent state for most of their lives. However, the viral load in saliva can fluctuate over time, with virions continually being released into saliva due to the viral reactivation process, marking the transition from latency to the lytic cycle of the virus (5).
Furthermore, a connection between terminal cell differentiation and EBV reactivation has been established (6), revealing that viral reactivation primarily occurs when the infected memory B cell undergoes differentiation into a plasma cell (7). Interestingly, the transcription factors responsible for maintaining the memory B cell differentiation stage act as repressors of lytic activation (8).
EBV: A Well-Adapted Human Pathogen with Oncogenic Potential
EBV is a ubiquitous herpesvirus well-adapted to the human species, typically leading to benign clinical outcomes. However, despite not being part of its natural replicative cycle, EBV is etiologically associated with the development of several neoplasms, supported by robust epidemiological and molecular evidence (9).
Both solid and lymphoid neoplasms can be associated with EBV, including nasopharyngeal carcinoma, gastric carcinoma, classical Hodgkin lymphoma, Burkitt lymphoma, post-transplant lymphoproliferative disease, extranodal NK/T-cell lymphoma (ENKTCL), and EBV-positive nodal T- and NK-cell lymphoma (NKTCL) (1, 10–12).
It is estimated that around 200,000 new cases of EBV-associated tumors are diagnosed globally each year, leading the International Agency for Research on Cancer (IARC) to classify EBV as a group 1 carcinogen (9).
The epidemiology of EBV-associated neoplasms is complex and may depend on various factors, including age, sex, socioeconomic status, ethnographic customs, and host and viral genetic background (1, 6, 10, 13–15).
EBV and Its Role in B Cell Lymphomas
There is a well-established causal relationship between EBV infection of B cells and the development of B cell lymphomas such as classical Hodgkin lymphoma and Burkitt lymphoma (1, 12–14, 16, 17). Tremendous progress has been made in understanding how EBV transforms B cells and contributes to their oncogenesis (1, 16–18).
EBV’s Lesser-Known Role in T and NK Cell Lymphomagenesis
In contrast to the extensive research on EBV’s role in B cell lymphomas, less information is available regarding its involvement in T and NK cell lymphomagenesis (19). However, EBV has been associated with various lymphoid proliferations of T and NK cells, including ENKTCL, NKTCL, angioimmunoblastic- and follicular-type of nodal T-follicular helper cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, as well as EBV-positive T- and NK-cell lymphoid proliferations, such as severe mosquito bite allergy, hydroa vacciniforme lymphoproliferative disorder, and systemic chronic active EBV disease (11, 18).
ENKTCL and NKTCL: A Genetic Predisposition?
In this comprehensive review, we will delve into the genetic characteristics of EBV and explore its potential role in the oncogenesis of ENKTCL and NKTCL, two lymphomas predominantly affecting mature T and NK cells. Additionally, we will highlight the main distinctions between these two lymphomas, shedding light on the intricate relationship between EBV and lymphoid malignancies. Understanding these connections is crucial for developing effective strategies for diagnosis, treatment, and prevention of EBV-associated lymphomas.
In conclusion, despite the well-established molecular, clinical, and immunohistological differences between Extranodal Natural Killer/T-Cell Lymphoma (ENKTCL) and Natural Killer/T-Cell Lymphoma (NKTCL), the precise etiopathogenic role of Epstein-Barr virus (EBV) in these lymphomas continues to elude researchers. Rather than providing definitive answers, the current state of knowledge raises more questions about the intricate relationship between EBV and these malignancies.
EBV’s ability to infect T and NK cells during primary infection is well-documented. However, it appears that this infection alone may not be the sole trigger for lymphomagenesis in vivo, similar to its impact on EBV-infected B cells. Instead, EBV might act as an initiating agent that has the potential to transform the cells it infects. However, additional cellular events or genetic mutations may be necessary for the development of a fully malignant phenotype (Figure 1) (1, 154). The precise sequence of events leading to the development of ENKTCL and NKTCL remains a mystery.
One intriguing question is whether EBV-infected T and NK cells with persistent latency patterns II or III are more susceptible to oncogenic events. For instance, ENKTCL is characterized by an abundance of transcripts of latent EBV genes such as LMP1/2A/2B, as well as transcripts of lytic genes like BNRF1, BILF1, BALF5/4/3/2, and BNLF2b (85). These genes have the potential to interfere with host cell machinery. Could recombination or mutation events within the EBV genome in certain T and NK cells be responsible for initiating oncogenesis, or at least the initial steps thereof? Specific T cell epitope mutations of EBV that favor immune evasion have been identified in ENKTCL (117). Furthermore, it remains unclear whether the molecular profile of EBV in neoplastic cells of ENKTCL and NKTCL matches that of non-neoplastic EBV-infected cells within the same host.
The genetic characteristics of the host, especially those related to the anti-EBV immune response, also require more comprehensive investigation in the context of ENKTCL and NKTCL. Is it possible that an inability of the immune system to recognize and destroy EBV-infected T and NK cells in persistent latency patterns other than 0 plays a significant role in lymphomagenesis? Immunodeficiency, such as immunesenescence, has been noted at the time of NKTCL diagnosis (11).
Nearly six decades since the discovery of EBV, this virus remains an enigma. The complexities of its interactions with host cells, its role in lymphomagenesis, and the precise mechanisms involved continue to challenge our understanding. Further research is needed to unveil the intricate dance between EBV and the immune system, as well as the genetic and environmental factors that contribute to the development of ENKTCL and NKTCL. Only then can we hope to fully unravel the mysteries of these aggressive lymphomas and develop more effective diagnostic and therapeutic strategies.
Figure 1 Schematic representation of two hypotheses related with the Epstein-Barr virus (EBV) infection and lymphomagenesis in T/NK cells. In the light purple background, a possible scenario is shown, where EBV infects “healthy” T/NK cells and stablishes a latent infection (cell in blue). It is possible that some of these infected cells are eliminated by the immune system or go into apoptosis (cell in brown). Viral reactivation phases with virus entry into the lytic cycle may occur in infected T/NK cells (red arrows), just as they happen in infected B cells. Mutational events in one EBV-infected T/NK cell may take place later, resulting in the fully malignant phenotype (grey background). In this context, EBV would act as an initiating agent. In the light green background, another hypothesis is presented. The EBV-infection occurs in a previously mutated T/NK cell (initiated cell) and the viral machinery would trigger the fully malignant phenotype (grey background). In this context, EBV would serve as a promoting agent.
The Epstein-Barr virus (EBV), also known as human gammaherpesvirus 4 (HHV-4), is a member of the herpesvirus family. It is a ubiquitous virus found worldwide and is associated with a variety of human cancers. This article explores the complex nature of EBV, its role in cancer development, and the intricate interplay between the virus and the human immune system.
Discovery and Early Understanding
EBV was first identified in 1964 and was initially considered a potential oncovirus. However, it took several years to establish its definitive role in human cancers. Today, we know that EBV is causally linked to lymphoproliferative diseases of both B-cell and T-cell origins, as well as certain carcinomas. This diverse range of cancers reflects EBV’s ability to infect various cell types.
Viral Latency Patterns
EBV’s lifecycle involves different phases of latency, during which the virus expresses specific genes and proteins. These latency patterns are crucial for the virus’s survival and persistence within the host.
- Latency III: In this phase, characterized by the expression of several nuclear antigens, latent membrane proteins, untranslatable RNAs, and clusters of microRNAs, the virus is actively replicating. It can be found in conditions like infectious mononucleosis (IM) and post-transplant lymphoproliferative diseases.
- Latency IIb: This transitional phase between latency III and IIa involves the expression of specific genes, including some nuclear antigens, latent membrane proteins, and RNAs. It is also observed in IM and post-transplant lymphoproliferative diseases.
- Latency IIa: This pattern, found in classic Hodgkin lymphoma and nasopharyngeal carcinoma, involves the expression of a different set of genes, enabling EBV-infected B cells to survive within the germinal center.
- Latency 0: After differentiation into memory B cells, EBV-infected cells enter latency 0, characterized by minimal gene expression, only involving the presence of untranslatable RNAs.
- Latency I: Occurring during homeostatic proliferation of EBV-infected memory B cells, latency I involves the expression of a limited set of genes, including nuclear antigens and specific RNAs.
These different latency phases allow EBV to adapt to its host environment and ensure its persistence.
EBV’s ability to reactivate from latency is not fully understood, but it appears to occur when infected memory B cells are stimulated to differentiate into plasma cells. This process involves the activation of key transcription factors, such as XPB-1 and BLIMP1, which, in turn, activate lytic genes. This results in the production of new viral particles, which can infect new immature B cells and epithelial cells. Viral reactivation is also responsible for fluctuations in viral load in saliva.
The human immune system plays a crucial role in controlling EBV infection. CD8+ T cells primarily target and control EBV-infected cells. The strength of the immune response varies, with certain viral proteins, such as EBNA3A, EBNA3B, and EBNA3C, and lytic cycle antigens, including BZLF1 and BRLF1, eliciting the strongest responses. These responses help control cells expressing the more immunogenic latency III pattern, reducing the risk of cancer development.
Molecular Characteristics of EBV
EBV’s genome is a stable double-stranded DNA of approximately 172 kb. It encodes over 80 proteins and various small RNAs. The genome contains repeated sequences, both internally and at the ends, which play roles in latency and gene regulation.
EBV shares genes with other herpesviruses, but it also has unique genes, some of which bear similarities to host genes. Variations in these genes have been associated with specific diseases and populations.
EBV can be categorized into two main genotypes: type 1 and type 2. These genotypes differ in their sequences of certain genes. While they are not directly linked to specific diseases, their prevalence can vary geographically due to host immune responses.
EBV Infection of T and NK Cells
While B cells are the primary target of EBV infection, T cells and natural killer (NK) cells can also become infected. It’s worth noting that EBV primarily infects CD8+ T cells over CD4+ T cells. The fate of EBV-infected T and NK cells, whether they serve as a viral reservoir or are eliminated by the immune system, is still under investigation.
A Possible Role of Epstein-Barr Virus (EBV) in the Oncogenesis of Extranodal Natural Killer/T-Cell Lymphoma (ENKTCL) and Natural Killer/T-Cell Lymphoma (NKTCL)
Epstein-Barr virus (EBV), a gammaherpesvirus, was first identified as a potential human oncogenic virus in 1964. Since then, extensive research has revealed its involvement in various human cancers. EBV is known to be causally associated with lymphoproliferations of both B and T-cell origins, as well as certain carcinomas, a reflection of its diverse cell tropism. This article explores the potential role of EBV in the oncogenesis of Extranodal Natural Killer/T-Cell Lymphoma (ENKTCL) and Natural Killer/T-Cell Lymphoma (NKTCL), shedding light on the complex relationship between this virus and these aggressive lymphomas.
EBV Latency Patterns
EBV exhibits intricate survival and persistence dynamics within the host, characterized by its ability to express different sets of genes at different stages of infection. These gene expression profiles, referred to as latency patterns, are central to understanding EBV’s role in oncogenesis.
- Latency III (III)
- Characterized by the expression of six nuclear antigens (EBNA-1, -2, -3A, -3B, -3C, and leader protein), three latent membrane proteins (LMP-1, -2A, and -2B), two untranslatable RNAs (EBER1 and EBER2), and two clusters of microRNAs (BART and BHRF).
- Seen in conditions like Infectious Mononucleosis (IM), lymphoblastoid cell lines, and post-transplant lymphoproliferative diseases.
- Latency IIb (IIb)
- Observed during the transitional phase between latency III and IIa.
- Characterized by the expression of EBNA1, EBNA2, EBNA3A, EBNA3C, EBERs, BART miRNAs, and BHRF miRNAs.
- Also found in IM and post-transplant lymphoproliferative diseases.
- Latency IIa (IIa)
- Involves the expression of EBNA1, LMPs, EBERs, and BART miRNAs.
- Found in classic Hodgkin lymphoma and nasopharyngeal carcinoma.
- Latency 0 (0)
- Characterized by the presence of only EBERs.
- Observed in EBV-infected memory B cells after differentiation.
- Latency I (I)
- Detected during homeostatic proliferation of EBV-infected memory B cells.
- Involves EBNA1, EBERs, and BART miRNAs.
- Identified in Burkitt lymphoma and EBV-infected memory B cells during cell division.
EBV can persist in the host for years by maintaining a balance between latent and lytic cycles. Viral reactivation, which involves the switch from latency to the lytic cycle, is not fully understood but is thought to occur when EBV-infected memory B cells differentiate into plasma cells, triggered by various stimuli. This reactivation leads to the production of new viral particles that can infect other B cells, epithelial cells, and be released in saliva, potentially infecting other hosts.
Immune Response to EBV
The immune response against EBV plays a crucial role in controlling the virus and preventing the development of associated malignancies. CD8+ T cells are known to target specific EBV proteins, with the strongest responses against EBNA3A, EBNA3B, EBNA3C, BZLF1, BRLF1, and BMRF1. These responses help control cells expressing latency III, which have a higher transforming potential.
EBV Molecular Characteristics
EBV has a stable double-strand DNA genome of approximately 172 kb, encoding over 80 proteins and numerous small RNAs. While many EBV genes are conserved among herpesviruses, some are unique to the Gammaherpesvirinae subfamily. Additionally, some EBV genes bear similarity to host genes, potentially contributing to oncogenesis.
EBV is classified into two genotypes, type 1 and type 2, based on differences in EBNA-2 and EBNA-3 sequences. Type 1 EBV is more prevalent worldwide and has been associated with specific malignancies, such as AIDS-associated lymphomas in Southeast Asia.
EBV Infection of T and NK Cells
EBV infection of T and NK cells is less understood than its infection of B cells. Recent studies suggest that EBV can infect these cells through mechanisms such as trogocytosis and interactions between viral glycoproteins and HLA class II molecules. EBV-infected T cells have demonstrated unique oncogenic potential, distinct from that observed in B cells, and may be more permissive for the expression of immediate early viral genes.
EBV in ENKTCL and NKTCL
ENKTCL and NKTCL are characterized by the presence of EBV in nearly all cases. The specific latency patterns in these lymphomas are not well-established, with some evidence suggesting latent patterns I, II, and III. Additionally, studies have indicated potential viral replication in ENKTCL cases based on antibody profiles.
EBV type 1 appears to be associated with ENKTCL, but this may reflect population demographics rather than a direct link to the disease. The molecular characteristics of EBV in these lymphomas remain largely unexplored, and further research is needed to understand their implications in lymphomagenesis.
Viral Proteins as Targets for Targeted Therapy
Epitopes derived from EBV proteins serve as potential targets for immunotherapy in ENKTCL and NKTCL. Adoptive immunotherapy using antigen-specific cytotoxic T cells (CTL) has shown promise in clinical trials, with objective responses observed in some cases. Targeting LMP1- and LMP2-derived epitopes in CTL therapy appears to be a promising approach.
EBV Viral Load
The quantification of circulating EBV DNA has been utilized in the diagnosis and management of EBV-associated neoplasms. In ENKTCL, assessing viral load in plasma may reflect the tumor burden and predict clinical outcomes. However, the impact of EBV viral load on NKTCL management remains unclear.
Human Leukocyte Antigens in ENKTCL and NKTCL
Host genetic factors, including human leukocyte antigens (HLA), may influence the development of ENKTCL and NKTCL. Specific HLA haplotypes have been associated with altered risk in ENKTCL, emphasizing the role of the host immune response in these lymphomas. Further studies are needed to confirm these associations and explore the influence of host genetics in NKTCL.
The Epstein-Barr virus is a complex and intriguing virus that plays a significant role in the development of various human cancers. Its ability to establish different latency patterns, evade the immune system, and infect various cell types makes it a formidable pathogen. Understanding the intricacies of EBV’s biology and its interactions with the host immune system is crucial for developing effective strategies for preventing and treating EBV-associated diseases. Further research is needed to unravel the mysteries of this enigmatic virus and its role in cancer development.
reference link : https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1240359/full