The Cycle of EBV Infection Explains Persistence, the Sizes of the Infected Cell Populations and Which Come under CTL Regulation

Abstract

Previous analysis of Epstein-Barr virus (EBV) persistent infection has involved biological and immunological studies to identify and quantify infected cell populations and the immune response to them. This led to a biological model whereby EBV infects and activates naive B-cells, which then transit through the germinal center to become resting memory B-cells where the virus resides quiescently. Occasionally the virus reactivates from these memory cells to produce infectious virions. Some of this virus infects new naive B-cells, completing a cycle of infection. What has been lacking is an understanding of the dynamic interactions between these components and how their regulation by the immune response produces the observed pattern of viral persistence. We have recently provided a mathematical analysis of a pathogen which, like EBV, has a cycle of infected stages. In this paper we have developed biologically credible values for all of the parameters governing this model and show that with these values, it successfully recapitulates persistent EBV infection with remarkable accuracy. This includes correctly predicting the observed patterns of cytotoxic T-cell regulation (which and by how much each infected population is regulated by the immune response) and the size of the infected germinal center and memory populations. Furthermore, we find that viral quiescence in the memory compartment dictates the pattern of regulation but is not required for persistence; it is the cycle of infection that explains persistence and provides the stability that allows EBV to persist at extremely low levels. This shifts the focus away from a single infected stage, the memory B-cell, to the whole cycle of infection. We conclude that the mathematical description of the biological model of EBV persistence provides a sound basis for quantitative analysis of viral persistence and provides testable predictions about the nature of EBV-associated diseases and how to curb or prevent them.

EBV Persistence—Introducing the Virus

“…From cell surface phenotyping of fractionated tonsil cells, it is clear that the B cells replicating the virus in the lymphoepithelium of the tonsils are plasma cells (CD38hi, CD10−, CD19−, CD20lo, slg−, and clg+) (Laichalk and Thorley-Lawson 2005), a conclusion consistent with histological observations (Niedobitek et al 2000; Anagnostopoulos et al 1995). Quantitative estimates suggest that somewhere in the region of −250 cells are undergoing replication in Waldeyer’s ring at any one time (Hawkins et al 2013; Laichalk and Thorley-Lawson 2005). However, sequentially fewer cells express the immediate early, early, and then late antigens of the lytic cycle such that only −10 % of the cells complete the replicative cycle.…”

The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells

“…In normal healthy individuals, the EBV-infected B blasts are targets for EBV-specific cytotoxic lymphocytes (CTLs) that can recognise and destroy these latently infected cells. Stable persistence depends, therefore, on the equilibrium established between the proliferation of B blasts-on the one hand-and immune elimination or differentiation to the resting memory compartment on the other (Babcock et al 1999;Hawkins et al 2013). …”

Role of ATM in the Formation of the Replication Compartment during Lytic Replication of Epstein-Barr Virus in Nasopharyngeal Epithelial Cells

“…While EBV readily establishes latent infection in B lymphocytes, infection of primary oropharyngeal epithelial cells is primarily lytic in nature (3). It has been proposed that acute replication of EBV in infected oropharyngeal epithelium in vivo is the main source of virus in saliva for transmission (4). During latent infection of EBV, multiple copies of the EBV genome (around 170 kb in size) are maintained as circular, chromatin-like DNA structures called episomes.…”