Acute Infection with Epstein-Barr Virus Targets and Overwhelms the Peripheral Memory B-Cell Compartment with Resting, Latently Infected Cells

Abstract

In this paper we demonstrate that during acute infection with Epstein-Barr virus (EBV), the peripheral blood fills up with latently infected, resting memory B cells to the point where up to 50% of all the memory cells may carry EBV. Despite this massive invasion of the memory compartment, the virus remains tightly restricted to memory cells, such that, in one donor, fewer than 1 in 10 4 infected cells were found in the naive compartment. We conclude that, even during acute infection, EBV persistence is tightly regulated. This result confirms the prediction that during the early phase of infection, before cellular immunity is effective, there is nothing to prevent amplification of the viral cycle of infection, differentiation, and reactivation, causing the peripheral memory compartment to fill up with latently infected cells. Subsequently, there is a rapid decline in infected cells for the first few weeks that approximates the decay in the cytotoxic-T-cell responses to viral replicative antigens. This phase is followed by a slower decline that, even by 1 year, had not reached a steady state. Therefore, EBV may approach but never reach a stable equilibrium.The B-lymphotropic herpesvirus Epstein-Barr virus (EBV) is a ubiquitous human virus (reviewed in references 23 and 45) that establishes a lifelong persistent infection in memory B lymphocytes (3). It is an important pathogen because of its association with several human neoplasias (reviewed in references 38 and 45). However, no good animal model exists for the study of EBV. The murine gammaherpesvirus 68 (MHV68) is a related virus which has tropism for B lymphocytes (44) and also persists in memory B cells (12, 50). However, it appears to lack the specific latency transcription programs of EBV and persistence is not dependent on B lymphocytes (49). Primate homologues of EBV are known (7,11,42), but these are not useful because of financial constraints and the lack of virological and immunological reagents for these systems. Despite this limitation, EBV has emerged as an excellent system for studying persistent infection in humans. There are two primary reasons for this. First, EBV infects resting B cells in culture and transforms them into continuously proliferating, latently infected lymphoblasts (35,36). This provides a readily manipulable in vitro system for studying the functions of the latency-associated proteins. Second, the major sites of viral persistence, the peripheral blood and Waldeyer's ring (29), are relatively accessible for study. Taking together information from both in vitro and in vivo studies we have developed a unified model of how EBV establishes and maintains a persistent infection (46) (Fig. 1). The key underlying theme of the model is that EBV uses its latent proteins to provide signals to the infected B cell that cause it to become activated and then differentiate, through a mechanism analogous to the germinal center reaction (30, 31), into a resting memory cell. We have provided evidence that these events occur in the lymphoid tissue o...

EBV and Systemic Lupus Erythematosus: A New Perspective

“…We have detected BZLF1 expression in the blood of patients with infectious mononucleosis, but the frequency of infected cells expressing this lytic gene was considerably less (0.02 to Ͻ0.001%; n ϭ 5) (data published in Ref. 41) than those in the two lupus patients. These findings confirm that BZLF1, and probably LMP1, are abnormally regulated in some patients with SLE.…”

Boolean monomial control systems

“…It is associated with an initial acute phase in which a large fraction (up to 50%) of circulating memory B cells may be latently infected [50]. This induces the broad T lymphocyte immune response characteristic of acute EBV infection.…”

“…Exactly how persistent infection is sustained is unclear. It is even unclear whether the virus actually establishes a steady state during persistence or continues to decay, albeit at an ever slower rate [50]. A diagrammatic version of the biological model is presented in the left panel of Figure 6.1.…”

Abortive lytic Epstein–Barr virus replication in tonsil-B lymphocytes in infectious mononucleosis and a subset of the chronic fatigue syndrome

“…30,31 Quantitative studies of EBV replication during IM indicate lytic replication in the tonsils is in the minority, and abortive lytic replication is dominant. 25 …”

“…3 Remarkably, too, a low level of EBV lytic replication continues in B-lymphocytes, in the tonsils, which have differentiated into plasma cells during the entire lifetime of every individual. 25,26 After primary EBV infection in the tonsils, naïve B-lymphocytes in the tonsil differentiate into activated blasts and express the growth transcription programs EBNA 1, 2, 3A, 3C, LP, LMP1, and LMP2. These activated EBV-infected B-lymphocytes migrate to an adjacent oligoclonal germinal center, where they differentiate into memory B-cells [27][28][29] ( Figure 1).…”