Human immunity against EBV-lessons from the clinic

Abstract

The mammalian immune system has evolved over many millennia to be best equipped to protect the host from pathogen infection. In many cases, host and pathogen have coevolved, each acquiring sophisticated ways of inducing or protecting from disease. Epstein-Barr virus (EBV) is a human herpes virus that infects >90% of individuals. Despite its ubiquity, infection by EBV is often subclinical; this invariably reflects the necessity of the virus to preserve its host, balanced with sophisticated host immune mechanisms that maintain viral latency. However, EBV infection can result in various, and often fatal, clinical sequelae, including fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, organomegaly, and/or malignancy. Such clinical outcomes are typically observed in immunosuppressed individuals, with the most extreme cases being Mendelian primary immunodeficiencies (PIDs). Although these conditions are rare, they have provided critical insight into the cellular, biochemical, and molecular requirements for robust and long-lasting immunity against EBV infection. Here, we review the virology of EBV, mechanisms underlying disease pathogenesis in PIDs, and developments in immune cell-mediated therapy to treat disorders associated with or induced by EBV infection.

Figure 1.

EBV infection and viral persistence in the tonsils of immunocompetent hosts. Early events of infection are poorly understood. However, there is accumulating evidence for a potential role for oral epithelial cells and/or infiltrating B cells. Orally transmitted virus is believed to establish lytic infection within the lymphoepithelium of the oropharynx, resulting in shedding of high levels of virus in the throat. Then, the virus switches to a growth-transforming latent infection (Lat III) of B cells within the local lymphoid tissues leading to proliferation of infected cells. However, viral persistence is largely achieved through the silent infection of memory B cells, where viral DNA is maintained in a circular form and no viral proteins are expressed. These virally infected memory B cells are believed to constantly recirculate between blood and oropharyngeal lymphoid tissues. Occasional reactivation of the virus within these lymphoid tissues may result in the production of new viral particles that could seed new foci of new infection of local B cells and also result in viral shedding from the throat. In immunocompetent hosts, tight immune control maintains virus during both lytic phase and latency. During primary infection as seen in IM, the vast array of antigenically rich EBV-lytic and -latent proteins induce priming and expansion of EBV-specific CD4⁺ and CD8⁺ T cells, as well as activation of NK cells. These effective immune responses bring the infection under control. Upon disease resolution, contraction of the T cell pool results in a small population of the memory T cell pool that persists both as tissue-resident memory cells (Trm cells) and circulating memory cells. Continuous immune surveillance by these resident and circulating memory cells is important for viral control. Black arrows denote movement of infected B cells.

Figure 2.

Signaling pathways responsible for generating cell-mediated EBV-specific immunity. The scheme highlights the key cell surface receptor-induced signaling pathways that, when mutated, manifest as PIDs characterized by increased susceptibility to EBV-induced disease. Genes found to be mutated in these conditions (SAP/SH12D1A, MAGT1, ITK, CD27, CD70, NFKB1, and RASGRP1) are highlighted by red boxes. XIAP is not included here, as the mechanism by which mutations in XIAP cause disease remains unknown.

Figure 3.

Schematic representation of the generation of EBV-specific T cells to treat EBV-associated disease. PBMCs are isolated from donors and stimulated using different approaches to generate EBV-specific T cells, which are then infused into patients after conditioning or immunosuppressive therapy.