Epstein-Barr virus: Biology and clinical disease

Abstract

Epstein-Barr virus (EBV) is a ubiquitous, oncogenic virus that is associated with a number of different human malignancies as well as autoimmune disorders. The expression of EBV viral proteins and non-coding RNAs contribute to EBV-mediated disease pathologies. The virus establishes life-long latency in the human host and is adept at evading host innate and adaptive immune responses. In this review, we discuss the life cycle of EBV, the various functions of EBV-encoded proteins and RNAs, the ability of the virus to activate and evade immune responses, as well as the neoplastic and autoimmune diseases that are associated with EBV infection in the human population.

Figure 1.. EBV Viral Entry.

Virion binding, attachment, and entry into the host cell is depicted. EBV can enter either through endocytosis or fusion with the plasma membrane. After the viral genome is injected into the nucleus, the virus can either enter latency or lytic replication depending on the cell type and environmental cues.

Figure 2.. Molecular interactions and activation of cell signaling pathways by LMP1 and LMP2.

(A) Latent membrane protein 1 (LMP1). LMP1 is located within lipid rafts and associates with proteins that facilitate exosome secretion (CD63) and function (galectin 9). The carboxy terminal activating domains, CTAR1 and CTAR2, and the interacting TRAF molecules are denoted. The resultant effects on cellular signaling complexes with activation of kinases and distinct forms of NFκB are indicated. (B) Latent membrane protein 2 (LMP2). Schematic representation of specific domains including the SH2 Src kinase binding domain, the ITAM Syk binding site, and PPY binding site for Nedd4 ubiquitin ligases. The critical pathways that are activated through these interactions and the inhibition of the B-cell receptor (BCR) are indicated.

Figure 3.. EBV modulation of the infected cell.

EBV is a master regulator of the infected cell. EBV genes can inhibit apoptotic pathways (LMP1, EBNA1, BARTs) and enhance cell proliferation and transformation pathways (LMP1, LMP2A, EBNA1, EBNA2, EBERs), angiogenesis (LMP1, Z), as well as promote metastasis (LMP1, LMP2A). Several EBV genes also block growth suppressors (LMP1, EBNA3C, BARTs). Multiple EBV proteins (EBNA1, EBNA3C, LMP1, BALF3, BNRF1, BGLF5) have been demonstrated to induce genomic stability and dysregulate cell metabolic pathways (LMP1, LMP2A). EBV genes can also inhibit host innate and adaptive immune responses (EBNA1, EBERs, BARTs) and induce inflammatory cytokine and growth factor expression (LMP1, Z, R). Modulation of these pathways by EBV contribute to its oncogenic role in human malignancies. Additionally, EBV EBNA1 displays molecular mimicry with cellular proteins and contribute to EBV’s role in autoimmune diseases including multiple sclerosis.