Chronic active Epstein-Barr virus infection

The ubiquitous Epstein-Barr virus (EBV), which establishes latency after primary infection, does not cause any symptomatic diseases as long as cellular immunity is intact. In apparently immunocompetent individuals, a chronic infection can develop, and this has been called as chronic active EBV infection (CAEBV). CAEBV is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and, hepatosplenomegaly. This disease is rare but severe with high morbidity and mortality. Recently, its pathophysiology is not an infection but a clonal expansion of EBV-infected T or natural killer NK cells. In this review, I discuss our current understanding of the pathogenesis of CAEBV and summarize its clinical features, therapies, and prognosis.     

Laboratory diagnosis of Epstein-Barr virus infection

Laboratory confirmation of EBV infection requires proper methods and schema of investigation adequate to aim of diagnostic procedure. In paper the results of routine diagnostic tests of EBV infection performed in Department of Virology NIH in 2005-2006 years was included and also, evaluation of usefulness of different laboratory methods was done. Based on results of ELISA tests 10,7% routine investigated subjects was classified as primary EBV infection, 20,1% was seronegative, 7,4% was classified as reactivation of latent infection and serological markers in 45,6% subjects pointed past EBV infection. Positive result of PCR method was obtain in 11,2% samples subjected of routine laboratory investigation. Comparison of specific and non-specific serological methods results (ELISA versus tests of heterophile antibodies) showed the high percentage of false negative results in children tested by non-specific tests. PCR results in serum samples from patients with primary infection (confirmed by serological tests) were positive in 15% cases only. Based on analyzed results it could be stated that reliable confirmation of infectious mononucleosis, as primary EBV infection, is detection of specific IgM antibodies and in case of heterophile antibodies tests the possibility of false negative results, mainly in children, must be taken into account. The most proper samples for PCR method are whole blood, sections of tissue or cells from swabs.     

The immunology of the infection caused by the human immunodeficiency virus

In this work the data contained in the literature and obtained by the author are presented. These data may change the traditional concepts of the immunopathology of AIDS. The analysis of these data indicates that the explanation of disturbances in the immune system, attributing their cause to the cytocidal action of HIV, is simplified. HIV may infect cells containing no antigen CD4. Perhaps, the fusion of gp41 with the membrane of the target cells is necessary for the penetration of HIV into the cells. Macrophages serve as the main reservoir of HIV and may carry the virus to different organs. The prolonged latent period may be ascribed to cytotoxic lymphocytes specifically active against HIV and suppressing its replication. The progress of the disease is due to viral and cellular factors and depends on the functional changes in T-cells, B-cells, macrophages, the formation of immune complexes, the presence of stimulating antibodies and autoimmune phenomena.     

Simulating Epstein-Barr virus infection with C-ImmSim

MOTIVATION: Epstein-Barr virus (EBV) infects greater than 90% of humans benignly for life but can be associated with tumors. It is a uniquely human pathogen that is amenable to quantitative analysis; however, there is no applicable animal model. Computer models may provide a virtual environment to perform experiments not possible in human volunteers. RESULTS: We report the application of a relatively simple stochastic cellular automaton (C-ImmSim) to the modeling of EBV infection. Infected B-cell dynamics in the acute and chronic phases of infection correspond well to clinical data including the establishment of a long term persistent infection (up to 10 years) that is absolutely dependent on access of latently infected B cells to the peripheral pool where they are not subject to immunosurveillance. In the absence of this compartment the infection is cleared. AVAILABILITY: The latest version 6 of C-ImmSim is available under the GNU General Public License and is downloadable from www.iac.cnr.it/~filippo/cimmsim.html     

Activated lymphocytes during acute Epstein-Barr virus infection

Activated lymphocytes, as identified by HLA-DR expression, associated with acute Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM) were shown to be a heterogeneous population containing significantly elevated cytotoxic/suppressor (CD8) T cells, natural killer (CD16) cells and helper (CD4) T cells. CD8 T cells were the primary activated population representing 24.5% of the total lymphocyte population. The activated CD4 T cells and natural killer cells accounted for 6.7% and 3.5% of the total lymphocyte population, respectively. Analysis of serum soluble interleukin 2 receptors (IL-2R) demonstrated significantly (p less than 0.001) elevated levels in the serum of acute IM patients compared with normal controls. Elevated levels of serum IL-2R were correlated (r = 0.67) with increased percentages of Leu 2a+/HLA-DR+T cells (i.e., activated CD8 T cells). Patients with X-linked lymphoproliferative syndrome and virus-associated hemophagocytic syndrome, two syndromes associated with severe acute EBV infections, demonstrated the most dramatic increase in serum IL-2R levels. These data demonstrate that EBV is associated with intense immune stimulation and that during acute IM activated lymphocytes, other than the CD8 T cells, may contribute to the immune response to EBV.     

Immune activation suppresses initiation of lytic Epstein-Barr virus infection

Primary infection with Epstein-Barr virus (EBV) is asymptomatic in children with immature immune systems but may manifest as infectious mononucleosis, a vigorous immune activation, in adolescents or adults with mature immune systems. Infectious mononucleosis and chronic immune activation are linked to increased risk for EBV-associated lymphoma. Here we show that EBV initiates progressive lytic infection by expression of BZLF-1 and the late lytic genes gp85 and gp350/220 in cord blood mononuclear cells (CBMC) but not in peripheral blood mononuclear cells (PBMC) from EBV-naive adults after EBV infection ex vivo. Lower levels of proinflammatory cytokines in CBMC, used to model a state of minimal immune activation and immature immunity, than in PBMC were associated with lytic EBV infection. Triggering the innate immunity specifically via Toll-like receptor-9 of B cells substantially suppressed BZLF-1 mRNA expression in acute EBV infection ex vivo and in anti-IgG-stimulated chronically latently EBV-infected Akata Burkitt lymphoma cells. This was mediated in part by IL-12 and IFN-gamma. These results identify immune activation as critical factor for the suppression of initiation of lytic EBV infection. We hypothesize that immune activation contributes to EBV-associated lymphomagenesis by suppressing lytic EBV and in turn promotes latent EBV with transformation potential.     

A case of Lemierre's syndrome following Epstein-Barr virus infection

Lemierre's syndrome, or necrobacillosis, is a life-threatening septic thrombophlebitis of the internal jugular vein. The causative organism is Fusobacterium necrophorum. Here we report a case of Lemierre's syndrome in a young male and describe the clinical presentations and treatment. Epstein-Barr virus (EBV) was a suspected predisposing factor in this case.     

Host factors associated with the kinetics of Epstein-Barr virus DNA load in patients with primary Epstein-Barr virus infection

The aims of this study were to elucidate the kinetics of Epstein-Barr virus (EBV) DNA load in serially collected peripheral blood mononuclear cells of patients with primary EBV infection, and to determine the correlated host factors. Blood samples were collected from 24 patients with primary EBV infection. EBV DNA copy numbers were measured using real-time polymerase chain reaction. Based on the kinetics of EBV DNA load, the 24 patients were divided into two groups: rapid regression and slow regression. Eighteen of the 24 patients (75%) were included in the slow regression and 6 (25%) in the rapid regression group. No statistically significant differences were observed between the two groups in clinical features and laboratory findings. However, acute phase (3 to 10 days after the onset of the illness) serum samples from six children in the slow regression and four in the rapid regression group revealed significantly higher serum interleukin (IL)-1β (P= 0.018), IL-12 (P= 0.009), tumor necrosis factor-α (P= 0.019), interferon-inducible protein 10, and monokine induced by interferon γ concentrations in the rapid regression than the slow regression group. On the other hand, sera from six children in the slow regression and four in the rapid regression group in the convalescent phase (14 to 21 days after the onset of the illness) showed no statistically significant differences between the two groups in these biomarker concentrations. Based on this, it was concluded that the kinetics of EBV DNA load can be divided to two different patterns after primary EBV infection, and immune response might be associated with viral clearance.     

The suppression of Epstein-Barr virus infection in vitro occurs after infection but before transformation of the cell

It has been demonstrated that T cells from humans can suppress the transformation of EBV-infected B cells in vitro. In this paper, studies are presented on the mechanism of the suppression. The T cells do not act against the virus itself nor the infection process. They appear to suppress the outgrowth of B cells after they are infected but before they are transformed. The T cells are much less effective in suppressing the outgrowth of the B cells once the latter have transformed (24th post-infection). The significance of these observations to EBV infection and other forms of T cell-mediated anti-EBV immunity is discussed.     

Epstein-Barr virus infection of polarized tongue and nasopharyngeal epithelial cells

Epstein-Barr virus (EBV) initially enters the body through the oropharyngeal mucosa and subsequently infects B lymphocytes through their CD21 (CR2) complement receptor. Mechanisms of EBV entry into and release from epithelial cells are poorly understood. To study EBV infection in mucosal oropharyngeal epithelial cells, we established human polarized tongue and pharyngeal epithelial cells in culture. We show that EBV enters these cells through three CD21-independent pathways: (i) by direct cell-to-cell contact of apical cell membranes with EBV-infected lymphocytes; (ii) by entry of cell-free virions through basolateral membranes, mediated in part through an interaction between beta1 or alpha5beta1 integrins and the EBV BMRF-2 protein; and (iii) after initial infection, by virus spread directly across lateral membranes to adjacent epithelial cells. Release of progeny virions from polarized cells occurs from both their apical and basolateral membranes. These data indicate that multiple approaches to prevention of epithelial infection with EBV will be necessary.     

A virtual look at Epstein-Barr virus infection: simulation mechanism

Epstein-Barr virus (EBV) is an important human pathogen that establishes a life-long persistent infection and for which no precise animal model exists. In this paper, we describe in detail an agent-based model and computer simulation of EBV infection. Agents representing EBV and sets of B and T lymphocytes move and interact on a three-dimensional grid approximating Waldeyer's ring, together with abstract compartments for lymph and blood. The simulation allows us to explore the development and resolution of virtual infections in a manner not possible in actual human experiments. Specifically, we identify parameters capable of inducing clearance, persistent infection, or death.     

T-cell memory: lessons from Epstein-Barr virus infection in man

Epstein-Barr virus offers an ideal opportunity to follow the human T-cell response to a virus infection over time from its acute primary phase, as seen in infectious mononucleosis patients, into the memory phase that accompanies life-long virus persistence. Here we review recent evidence on the development and maturation of cytotoxic T-cell memory using this viral system.