The molecular mechanisms of Epstein-Barr virus persistence in the human organism

Abstract

This review describes advances in molecular aspects of EBV infection and disease. We discuss the spectrum of clinical illness due to EBV persistent infection. The main characteristic of Epstein-Barr virus (EBV) is that initial infection results in lifelong persistence. EBV infects nearly all humans by the time they reach adulthood. Healthy humans have approximately 1 to 50 infected cells per million leukocytes. EBV is one of the eight known human herpesviruses. EBV virions have a double-stranded linear DNA and 100 genes had been described in virus genome. Initial infection is thought to occur in the oral compartment. The host cells of EBV are mainly lymphocytes and epithelial cells. EBV attaches to B cells via binding of the viral gp350 protein to CD21 receptor. The consequence of EBV infection is cells proliferation and differentiation into memory B lymphocyte in the germinal center. Infected memory B cells are released into the peripheral circulation. EBV persists mostly in the memory B cell. Latency is the state of persistent viral infection without active viral production. In latently infected B cells EBV virus exist as episomes. During the latent phase episomal replication occurs via host DNA polymerase. Genes of the nuclear antigens (EBNA) and latent membrane proteins (LMP) are transcribed during latency. These include EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, EBNA leader protein (EBNALP), LMP1 and LMP2 genes. All nuclear antigens are transcription transactivators which bind to cis-regulatory DNA elements of cell or virus genomes directly or in complex with other proteins. LMP2A and LMP1 can function to coordinately mimic B-cell receptor and CD40 coreceptor signaling in latently infected B cells. LMP proteins activate cell signaling systems and as the consequence different gene expression programs. Characterization of gene expression patterns in different cell lines and pathologic conditions has revealed that there are at least three different latency programs. During I phase of latency latent EBV genomes can multiply in dividing memory B cells, during II phase of latency virus can induce and modulate B-cell differentiation, during III phase of latency virus can activate proliferation of the naïve B cells, during 0 phase of latency virus completely down regulates expression all protein coding genes. Latently infected B cells can occasionally be stimulated to reactivate EBV. Viral proteins BZLF1 and BRLF1 act as transactivators of the viral lytic program. The early reactivated virus gene products have such function as replication, metabolism and blockade of antigen processing. DNA polymerase replicates linear viral genome during the lytic phase. The late products code the structural proteins such as the viral capsid antigens (VCA) and gene products used for immune evasion. In healthy carriers virus exists in resting memory B lymphocytes in 0 phase of latency. The intensive virus reactivation in lytic replication phase or virus persistence in I, II and III latent phases promotes the development of such disease as lymphomas, rheumatoid arthritis, systemic erythematous lupus, chronic fatigue syndrome, etc. EBNA1 is expressed in the type I latency program, which is active in Burkitt’s lymphoma. EBNA1 and LMP1/2 are expressed in the type II latency program, which is observed in Hodgkin’s lymphoma. LMP1 and LMP2 expression activate proliferation program in the cell. The type III latency program, in which all of the latency gene products are expressed, is often detected during acute infectious mononucleosis or in virus infected B cell line and in inimmunocompromised individuals after tissue transplantation. Immunodeficiency-related B-cell posttransplant lymphoproliferative disorders (PTLDs) are caused directly by EBV. Chronic active EBV (CAEBV) infection develops due to the inappropriate viral load. This disease is characterized by chronic infectious mononucleosis-like symptoms with illness lasting for 6-24 months and in the course of the disease lymphoproliferative disorders like T or NK cell lymphomas may arise. The determined pattern of latent gene expression during CAEBV is latency type II. In this review we sum up the existing data linking EBV with rheumatoid arthritis and systemic erythematous lupus. SLE patients have abnormally high expression of several viral mRNAs coding for BZLF1, gp350, viral IL10, LMP1, LMP2 and EBNA1. So during this pathology EBV persists in litic and in latent phases.  Also it has been demonstrated the humoral response to both latent and lytic EBV antigens in both sera and synovial fluids from patients with rheumatoid arthritis. Chronic Fatigue Syndrome (CFS) is characterized by severe fatigue with typical, cognitive dysfunctions and flu-like symptoms. Numerous studies find evidence for an association of CFS with EBV. In a subset of patients CFS begins with infectious mononucleosis. Elevated antibodies against EBV dUTPase and DNA polymerase has been found in CFS patients but not in controls Consistent with these data, elevated titers antibodies to ZEBRA detected in CFS patients. These data suggest that during CFS virus reactivate and enter in lytic replication. But according to other reports EBV virus in CFS patients replicates only latently. So, in the articles we summarized the data which reveal the connection between the disease development, phase of persistence and the program of gene expression.