Epstein-Barr virus: the mastermind of immune chaos

Abstract

The Epstein-Barr virus (EBV) is a ubiquitous human pathogen linked to various diseases, including infectious mononucleosis and multiple types of cancer. To control and eliminate EBV, the host's immune system deploys its most potent defenses, including pattern recognition receptors, Natural Killer cells, CD8⁺ and CD4⁺ T cells, among others. The interaction between EBV and the human immune system is complex and multifaceted. EBV employs a variety of strategies to evade detection and elimination by both the innate and adaptive immune systems. This demonstrates EBV's mastery of navigating the complexities of the immunological landscape. Further investigation into these complex mechanisms is imperative to advance the development of enhanced therapeutic approaches with heightened efficacy. This review provides a comprehensive overview of various mechanisms known to date, employed by the EBV to elude the immune response, while establishing enduring latent infections or instigate its lytic replication.

Keywords: EBV; acquired immunity; evasion; herpesvirus; innate immunity.

Figure 1

EBV’s impact on apoptosis inhibition and the stimulation of infected cell proliferation. Apoptosis inhibition primarily occurs via two mechanisms (1): Latency proteins LMP1 and LMP2 modulate various molecules and transcriptional pathways, suppressing host cell apoptosis to facilitate EBV latency persistence; and (2) Infection in nasopharyngeal epithelial cells prompts LMP1 accumulation and p53 phosphorylation, inhibiting apoptosis. Additionally, cell proliferation and B cell survival are predominantly induced by (1): EBER1 enhances mitochondrial activity and calcium influx; and (2) LMP1 induces different transcription factors associated with promoting cell proliferation and B cell survival. EBV miRNAs, particularly miR-BART20-5p and miR-BART11-5p, play a pivotal role in both inhibiting apoptosis and promoting cell proliferation.

Figure 2

EBV-Mediated Mechanisms of Immune Evasion. EBV evades the immune response by interfering with key molecular pattern receptors (PRRs) and the nuclear factor kappa B (NF-κB) pathway. EBV molecules, proteins and miRNAs play roles in suppressing the activity of Toll-like receptors (TLRs) (left), cyclic GMP-AMP synthase (cGAS) and retinoic acid-inducible gene I (RIG-I) (center left), in the NF-κB pathway (center right) and the NOD-like receptor (NLR) (right). Furthermore, EBV disrupts the production of products resulting from these pathways, directly or indirectly.

Figure 3

Roles of EBV genes and proteins in evading the adaptive immune response. EBV miRNAs negatively regulate the transporter complex associated with antigen processing (TAP), affecting antigen presentation by MHC class I. EBV lytic and latency proteins disrupt HLA I and II presentation in host cells, inhibiting the activation of CD4⁺ and CD8⁺ T cells.