Epstein–Barr virus in the multiple sclerosis brain – An evasive culprit

Abstract

The fundamental question now in multiple sclerosis (MS) is whether Epstein–Barr virus (EBV) is present in the brain and, if so, what is it doing there. The answer is important because it could radically transform the prevention and treatment of MS. A large body of evidence indicates that infection with EBV has a role in the pathogenesis of MS (Ascherio and Munger, 2010; Santiago et al., 2010; Pender, 2011). Recently a workshop was held in Vienna to address the highly controversial question of whether EBV is present in the brain in MS (Lassmann et al., 2011). To appreciate how EBV might contribute to the development of MS it is necessary to understand some key features of EBV infection. EBV is a ubiquitous human herpesvirus that has the unique ability to infect, activate and latently persist in B lymphocytes for the lifetime of the infected individual. During primary infection EBV transmitted via saliva infects naive B cells in the tonsil. EBV drives the infected B cell out of the resting state to become an activated B blast and then exploits the normal pathways of B cell differentiation so that the B blast progresses through a germinal center reaction to become a memory B cell which exits from the tonsil and circulates in the blood (Thorley-Lawson and Gross, 2004). The EBV-infected memory B cell expresses no viral proteins except during cell division, when it expresses only EBV nuclear antigen 1 (EBNA1), which engages the host cell DNA polymerase and ensures transmission of the viral genome to the daughter cells. The lack of viral protein expression allows the virus to evade the immune system and persist in memory B cells despite a healthy immune response. Latently infected memory B cells returning to the tonsil can terminally differentiate into plasma cells, which initiates the lytic (replicative) cycle with the production of infectious virus (Laichalk and Thorley-Lawson, 2005). The resulting free virions infect tonsil epithelial cells where the virus replicates at a high rate and is continuously shed into saliva for transmission to new hosts (Hadinoto et al., 2009).