Stress-Induced Epstein-Barr Virus Reactivation

Abstract

Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough understanding of this virus, and the interplay between stress and the immune system, is essential to establish effective treatment. This review will provide a summary of the interaction between both psychological and cellular stressors resulting in EBV reactivation. It will examine mechanisms by which EBV establishes and maintains latency and will conclude with a brief overview of treatments targeting EBV.

Keywords: EBV; latency; reactivation; stress; vaccination.

Figure 1

EBV Latency Types. EBV has four gene expression profiles during latent infection: type 0, type I, type II, and type III. In type 0 latency EBV, few, if any, proteins are expressed. Epstein-Barr nuclear antigen (EBNA)-1 is the only protein expressed during type I latency. Latent membrane protein (LMP) 1, LMP2, and EBNA-1 are all expressed during type II latency. All genes associated with latency are expressed in type III latency, including EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP (leader protein), LMP1, and LMP2. These proteins play important roles in maintaining latency. Notably, non-canonical latency expression profiles have also been documented. For example, infected cells expressing a type I latency profile may also express LMP1 or LMP2A, and infected cells expressing a type III latency profile may not express EBNA-2.

Figure 2

B Cell Receptor Signaling and EBV Reactivation. B cell receptor signaling begins when an antigen binds to the B cell receptor. Binding causes SRC kinases to phosphorylate CD 79, which stimulates SYK. SYK stimulation results in the formation of a signalosome comprised of PI3K, Btk, BLNK, PLCγ2, and PKCβ. Signalosome activation results in the activation of molecules that influence gene expression including NF-κB, NFAT, ERK, and SRF. Stimulation of the B cell receptor leads to plasma cell differentiation and can trigger EBV reactivation. Notably, activation of PI3K has been shown to stimulate EBV reactivation.

Figure 3

Summary of Factors Involved in Latency and Reactivation. Factors associated with latency and reactivation are categorized by source.