Reactivation Of Latent Epstein-Barr Virus Research Articles

Epstein-Barr Virus DNA Exacerbates Arthritis in a Mouse Model via Toll-like Receptor 9.

Epstein-Barr virus (EBV) DNA is known to be shed upon reactivation of latent EBV. Based on our previous findings linking Toll-like receptor-9 (TLR9) to an EBV DNA-driven surge in IL-17A production, we aimed to examine the therapeutic potential of TLR9 inhibition in EBV DNA-exacerbated arthritis in a collagen-induced arthritis (CIA) mouse model. C57BL/6J mice were administered either collagen, EBV DNA + collagen, EBV DNA + collagen + TLR9 inhibitor, or only the TLR9 inhibitor. After 70 days, paw thicknesses, clinical scores, and gripping strength were recorded. Moreover, affected joints, footpads, and colons were histologically scored. Furthermore, the number of cells co-expressing IL-17A, IFN-γ, and FOXP3 in joint sections was determined by immunofluorescence assays. Significantly decreased paw thicknesses, clinical scores, and histological scores with a significantly increased gripping strength were observed in the group receiving EBV DNA + collagen + TLR9 inhibitor, compared to those receiving EBV DNA + collagen. Similarly, this group showed decreased IL-17A+ IFN-γ+, IL-17A+ FOXP3+, and IL-17A+ IFN-γ+ FOXP3+ foci counts in joints. We show that inhibiting TLR9 limits the exacerbation of arthritis induced by EBV DNA in a CIA mouse model, suggesting that TLR9 could be a potential therapeutic target for rheumatoid arthritis management in EBV-infected individuals.

Pulmonary Infection Due to Reactivation of Latent Epstein-Barr Virus in a Patient With Crohn's Disease Treated With Infliximab.

Pulmonary Infection Due to Reactivation of Latent Epstein-Barr Virus in a Patient With Crohn's Disease Treated With Infliximab.

Relationship satisfaction determines the association between Epstein-Barr virus latency and somatic symptoms after the loss of a spouse.

The loss of a spouse is associated with a host of negative health outcomes. While bereaved individuals commonly report somatic symptoms, no investigations exist of the association between reactivation of latent Epstein-Barr virus (EBV) and somatic symptoms among this population. Further, how an individual perceives the quality of their lost relationship in retrospect may impact loss outcomes. Among 99 bereaved spouses, elevated EBV antibody titers were associated with somatic symptoms for those who retrospectively reported high or mean levels of relationship satisfaction (RS), but not among those less satisfied. Further, higher RS was associated with greater grief symptoms. This study identifies higher retrospective RS as a possible risk factor for negative physical and mental health outcomes during bereavement.

Reactivation of Latent Epstein-Barr Virus: A Comparison after Exposure to Gamma, Proton, Carbon, and Iron Radiation.

Among the many stressors astronauts are exposed to during spaceflight, cosmic radiation may lead to various serious health effects. Specifically, space radiation may contribute to decreased immunity, which has been documented in astronauts during short- and long-duration missions, as evidenced by several changes in cellular immunity and plasma cytokine levels. Reactivation of latent herpes viruses, either directly from radiation of latently infected cells and/or from perturbation of the immune system, may result in disease in astronauts. Epstein‒Barr virus (EBV) is one of the eight human herpes viruses known to infect more than 90% of human adults and persists for the life of the host without normally causing adverse effects. Reactivation of several latent viruses in astronauts is well documented, although the mechanism of reactivation is not well understood. We studied the effect of four different types of radiation, (1) 137Cs gamma rays, (2) 150-MeV protons, (3) 600 MeV/n carbon ions, and (4) 600 MeV/n iron ions on the activation of lytic gene transcription and of reactivation of EBV in a latently infected cell line (Akata) at doses of 0.1, 0.5, 1.0, and 2.0 Gy. The data showed that for all doses used in this study, lytic gene transcription was induced and median viral loads were significantly higher for all types of radiation than in corresponding control samples, with the increases detected as early as four days post-exposure and generally tapering off at later time points. The viability and size of EBV-infected Akata cells were highly variable and exhibited approximately the same trend in time for all radiation types at 0.1, 0.5, 1.0, and 2.0 Gy. This work shows that reactivation of viruses can occur due to the effect of different types of radiation on latently infected cells in the absence of changes or cytokines produced in the immune system. In general, gamma rays are more effective than protons, carbon ions, and iron ions in inducing latent virus reactivation, though these high-energy particles did induce more sustained and later reactivation of EBV lytic gene transcription. These findings also challenge the common relative biological effectiveness concept that is often used in radiobiology for other end points.

Pain in the elderly and its association with latent Epstein-Barr virus reactivation

Background Stress promotes immune dysregulation, including reactivation of latent viral infections and inflammation. Immune dysregulation can have severe health consequences, including delayed wound healing, impaired responses to vaccination, development and progression of cancer, and onset of mood disorders. Little is known about how pain is associated with reactivation of herpesviruses. Objective To evaluate the effects of pain on reactivation of latent Epstein-Barr virus (EBV), c-reactive protein (CRP), and interleukin-6 (IL-6) after controlling for age, gender, body mass index (BMI), race and income. Methods 51 bereaved and 64 controls were examined for pain (SF-36_Pain_Subscale) and immune dysregulation (EBV antibody titers, CRP, and IL-6). Linear regression models, adjusted for age, gender, BMI, race, and income were used to examine the association between pain and immune dysregulation. Results Results showed that greater pain was associated with higher reactivation of EBV ( β = −0.30; p β = −0.22; p β = −0.14; p = 0.16). Moreover, being older was associated with reactivation of EBV ( β = 0.32; p β = 0.27; p β = 0.34; p Conclusion Our results add to growing evidence of how pain can promote immune dysregulation. To our knowledge, this study is the first to demonstrate an association between pain and reactivation of a latent herpesvirus, which provides important implications for health outcomes.

Childhood chronic inflammatory demyelinating polyneuropathy secondary to reactivation of Epstein-Barr virus

A case of childhood chronic inflammatory demyelinating polyneuropathy (CIDP) due to Epstein-Barr virus (EBV) infection is reported. A 15-year-old male presented with CIDP, which initially mimicked Guillain-Barre syndrome. He subsequently developed major relapses at four and five months after initial presentation. He recovered six weeks after the last relapse. Serological studies showed positive Epstein-Barr nuclear antigen IgG and negative EBV viral capsid antigen IgM. However, EBV deoxyribonucleic acid was detected by polymerase chain reaction from cerebrospinal fluid, measuring up to 1000 copies/mL. His CIDP, which ran a relapsing course, could be explained by reactivation of latent EBV, triggered by other viral illness. Given patient's full recovery, the mechanism of injury is likely due to EBV-associated immune-mediated process, rather than from a direct viral infiltration of the peripheral nerve. This is the first report of a CIDP with documented EBV infection in cerebrospinal fluid.

Chlorpyrifos Induces the Expression of the Epstein-Barr Virus Lytic Cycle Activator BZLF-1 via Reactive Oxygen Species

Organophosphate pesticides (OPs) are among the most widely used synthetic chemicals for the control of a wide variety of pests, and reactive oxygen species (ROS) caused by OPs may be involved in the toxicity of various pesticides. Previous studies have demonstrated that a reactivation of latent Epstein-Barr virus (EBV) could be induced by oxidative stress. In this study, we investigated whether OPs could reactivate EBV through ROS accumulation. The Raji cells were treated with chlorpyrifos (CPF), one of the most commonly used OPs. Oxidative stress indicators and the expression of the EBV immediate-early gene BZLF-1 were determined after CPF treatment. Our results show that CPF induces oxidative stress as evidenced by decreased malondialdehyde (MDA) level, accompanied by an increase in ROS production, DNA damage, glutathione (GSH) level, and superoxide dismutase (SOD) and catalase (CAT) activity. Moreover, CPF treatment significantly enhances the expression of BZLF-1, and the increased BZLF-1 expression was ameliorated by N-acetylcysteine (NAC) incubation. These results suggest that OPs could contribute to the reactivation of the EBV lytic cycle through ROS induction, a process that may play an important role in the development of EBV-associated diseases.

High Incidence of Late, Sustained and Clinically Inconsequential Epstein Barr Virus (EBV) Reactivation Following Combined Unrelated Cord Blood and Haploidentical CD34+ Cell Transplantation

Introduction: Unrelated cord blood (UCB) transplantation is a useful alternative for patients (pts) with malignant or non-malignant hematological disorders who lack an HLA matched donor. However, because UCB is devoid of memory T-cells, viral infections are more problematic following this transplant approach. EBV is a latent γ-herpesvirus that infects more than 90% of the world’s population. Following UCB transplantation, early (<100 days) reactivation of latent EBV is common and is associated with a high risk of post-transplant lymphoproliferative disorder (PTLD). The likelihood of PTLD following late EBV reactivation (>100 days) is less well characterized. We investigated EBV reactivation and PTLD development in early vs late post-transplant periods in severe aplastic anemia (SAA) pts undergoing combined UCB and haploidentical CD34+ cell transplantation.Methods: Pts with SAA and life-threatening neutropenia (ANC <500/uL) refractory to ≥2 immunosuppressive agents were eligible for treatment if they lacked an HLA-matched donor. Conditioning consisted of cyclophosphamide (120 mg/kg), fludarabine (125 mg/m2), equine ATG (160 mg/kg) and a single dose of 200 cGy of total body irradiation. Graft-vs-host disease (GVHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil. Pts received a single ³4/6 HLA antigen matched UCB unit co-infused with a G-CSF mobilized, T-cell depleted CD34+ selected (Miltenyi CliniMacs system) allograft collected by apheresis of a haploidentical relative. EBV copy numbers were measured weekly for the first six months post-transplant and thereafter as clinically warranted.Results: 18 pts with treatment refractory SAA (median age 18 years; range 4-30), including 4 with SAA evolved to myelodysplastic syndrome (MDS) were transplanted. All pts were platelet and RBC transfusion-dependent. 11 pts received a ≥4/6 HLA matched UCB unit and 7 received a 5/6 HLA-matched unit. UCB units contained a median 2.8 x 107 TNCs/kg (range 1.7- 5.2) and 2.1 x 105CD34+cells/kg (range 0.5- 4.7) and haploidentical peripheral blood grafts contained a median 3.2 x106 CD34+cells/kg (range 3- 4.1) and 2.3 x 103 CD3+cells/kg (range 0.8- 5). All 18 pts were EBV IgG seropositive pretransplant. With a median follow-up of 689 days (range 160-2022), 16 pts survive, all disease free and transfusion independent. 16/18 (89%) pts developed EBV reactivation (EBV copy number >1000 copies/ml of whole blood or >150 genome equivalents/million PBMC) at a median 42 days post-transplant (range 2-1165). 12 pts (67%) had EBV reactivation before transplant day 100 (defined as early reactivation). Among those with early reactivation, 10/12 (83%) were treated preemptively with rituximab while 2/12 (17%) did not receive treatment and cleared the EBV viremia without intervention. Late EBV reactivation (defined as reactivation occurring after day 100) occurred in 15/18 (83%) pts. Among those with late reactivation, 12/15 (80%) were not treated while 3/15 (20%) received rituximab, which was given preemptively for PTLD in 2 pts and used to treat biopsy-confirmed PTLD on day 343 in one pt. The median time to first rituximab use was 37 days (range 8-343). Among the 12 pts with late EBV reactivation not given treatment, 9 (50% of those transplanted) had sustained viremia of >1000 copies lasting >30 days (defined as late and sustained EBV reactivation). All pts with late and sustained EBV reactivation remained asymptomatic despite high viral copy numbers, including 4 who had peak EBV copy numbers >30,000 copies/ml (Figure). There was no statistically significant difference in immune reconstitution, as determined by quantitative serum IgG levels and absolute numbers of CD4+ and CD8+ T-cells on day 100, 6 months, 1 year and > 1 year post-transplant in those with vs without late and sustained EBV reactivation.Conclusion: We observed that late and sustained EBV reactivation occurs commonly following combined UCB/haploidentical selected CD34+ cell transplantation, even in pts off immunosuppressive therapy and without CD4 and/or CD8 lymphopenia. In most cases, it was clinically inconsequential, and did not require rituximab treatment. The factors contributing to late sustained EBV reactivation including potential defects in viral-specific immunity remain under investigation.Figure: [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Thalidomide, Lenalidomide and Pomalidomide Disrupt Epstein-Barr Virus (EBV) Latency: Clinical Implications

IntroductionThalidomide (THAL), and the IMiDs® immunomodulatory agents lenalidomide (LEN), and pomalidomide (POM) are all approved for use in multiple myeloma (MM) either as single agents, or in combination with dexamethasone (DEX). Despite the enhanced efficacy of these novel agents, concern has arisen as to the increased incidence of secondary primary malignancies (SPM). For example, the IFM 2005-002 trial reported cases of lymphoblastic leukemia and Hodgkin's disease (HD) following LEN use (Attal, Lauwers-Cances et al. 2012) in MM patients on maintenance therapy. Also, a recent case report described a MM patient who developed HD who had been treated with salvage therapy containing THAL(Chim, Choi et al. 2013), and two publications reported EBV reactivation in MM patients treated with LEN (Kneppers, van der Holt et al. 2011; Kroger, Zabelina et al. 2013). As HD is causally linked to EBV, this raises the question as to whether the IMiDs reactivate latent EBV infection in normal memory B-cells, and thereby increase the risk of EBV-related malignancies. To this end, we have investigated the ability of the IMiD's to induce reactivation of latently infected B-cell lines. MethodsA panel of latently infected EBV-positive B-cell lines including Burkitt's lymphoma (BL) cells and lymphoblastoid cell lines (LCL) were treated with either LEN, THAL or POM, and the status of the EBV lytic cycle was evaluated using in vitro and in vivo models. ResultsTreatment of BL and LCL cell lines with physiological concentrations of IMiDs (1-5 μM) induced the immediate early gene BZLF1 and the early gene BMRF1. Interestingly, the ability to induce EBV reactivation was in their potency order (i.e. POM>LEN>THAL). The IMiD's also induced lytic cell death, as an LCL carrying a BZLF1-deleted EBV, which is incapable of undergoing a lytic cycle, showed no change in cell viability, compared to wild-type cells which had increased cell death. The addition of the nucleoside analogue ganciclovir (GCV) enhanced the cytotoxic effect of LEN and POM alone in BL cells lines. An in vivo xenograft model of BL demonstrated that the combination of LEN and GCV was highly efficacious at suppressing tumor cell growth, thus confirming the ability of LEN to stimulate the EBV-lytic life cycle. The ability to induce EBV reactivation was directly related to the stimulation of phosphatidylinositol-3 kinase (PI3K) signaling, which was completely blockaded by the PI3K-δ inhibitor, CAL101. The combination of LEN with either, DEX or rituximab, induced increased BMRF1 compared to the LEN alone. ConclusionsThe IMiD class of drugs has a potent ability to reactivate the lytic cycle in B-cells latently infected with EBV. We hypothesize that the IMiD's reactivate latently infected resting memory B cells through enhancing PI3K signaling. This reactivation may be further potentiated when the IMiDs are used in combination with rituximab or DEX, which may simultaneously enhance the EBV lytic cycle and suppress the host immune response. These findings suggest the possibility that immunocompromised patients who receive IMiDs should be monitored for evidence of EBV reactivation. Also, this may suggest a mechanism by which patients may develop EBV-associated SPM, an effect which is similar to the methotrexate induced EBV-positive lymphomas seen in rheumatoid arthritis patients (Feng, Cohen et al. 2004).ReferencesAttal, M., V. Lauwers-Cances, et al. (2012). “Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.” The New England journal of medicine 366(19): 1782-1791.Chim, C. S., P. T. Choi, et al. (2013). “Hodgkin's lymphoma as a second cancer in multiple myeloma never exposed to lenalidomide.” Annals of hematology 92(6): 855-857.Feng, W. H., J. I. Cohen, et al. (2004). “Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas.” Journal of the National Cancer Institute 96(22): 1691-1702.Kneppers, E., B. van der Holt, et al. (2011). “Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial.” Blood 118(9): 2413-2419.Kroger, N., T. Zabelina, et al. (2013). “Toxicity-reduced, myeloablative allograft followed by lenalidomide maintenance as salvage therapy for refractory/relapsed myeloma patients.” Bone marrow transplantation 48(3): 403-407. Disclosures:Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees.

109. Marital status is related to Epstein-Barr virus latency in individuals undergoing cancer diagnostic procedures

Married individuals reap many health benefits, including higher 5-year relative survival rates from cancer than unmarried individuals. We investigated whether cellular immune function differed by marital status (married vs. single vs. divorced, separated, or widowed) during the stress of cancer diagnosis. Immune dysfunction was indexed by reactivation of latent Epstein-Barr virus (EBV), and was measured using EBV viral capsid antigen (VCA) IgG antibody titers. In 393 men and women awaiting or shortly following diagnosis for breast or colorectal cancer, EBV antibody titers differed significantly by marital status, p < 0.05. This effect remained significant after controlling for covariates such as cancer status, cancer type, cancer stage, age, BMI, and comorbidities. Planned contrasts revealed that individuals who were separated, divorced, or widowed ( n = 94) had significantly higher EBV antibody titers compared to married individuals, p < 0.05. Higher EBV antibody titers indicate increased viral reactivation; these findings suggest that separated, divorced, and widowed individuals had diminished cellular immunity. Single individuals ( n = 50) had intermediate EBV antibody titer levels, which did not differ significantly from the other two groups. Consistent with other literature, EBV antibody titers did not differ significantly between benign controls and those diagnosed with cancer. These findings help to better characterize the immune effects of marital status during a stressful life event, and may help researchers identify those at risk for immune dysregulation during cancer survivorship.

Human Solid Tumor Xenografts in Immunodeficient Mice Are Vulnerable to Lymphomagenesis Associated with Epstein-Barr Virus

Xenografting primary human solid tumor tissue into immunodeficient mice is a widely used tool in studies of human cancer biology; however, care must be taken to prove that the tumors obtained recapitulate parent tissue. We xenografted primary human hepatocellular carcinoma (HCC) tumor fragments or bulk tumor cell suspensions into immunodeficient mice. We unexpectedly observed that 11 of 21 xenografts generated from 16 independent patient samples resembled lymphoid neoplasms rather than HCC. Immunohistochemistry and flow cytometry analyses revealed that the lymphoid neoplasms were comprised of cells expressing human CD45 and CD19/20, consistent with human B lymphocytes. In situ hybridization was strongly positive for Epstein-Barr virus (EBV) encoded RNA. Genomic analysis revealed unique monoclonal or oligoclonal immunoglobulin heavy chain gene rearrangements in each B-cell neoplasm. These data demonstrate that the lymphoid neoplasms were EBV-associated human B-cell lymphomas. Analogous to EBV-associated lymphoproliferative disorders in immunocompromised humans, the human lymphomas in these HCC xenografts likely developed from reactivation of latent EBV in intratumoral passenger B lymphocytes following their xenotransplantation into immunodeficient recipient mice. Given the high prevalence of latent EBV infection in humans and the universal presence of B lymphocytes in solid tumors, this potentially confounding process represents an important pitfall of human solid tumor xenografting. This phenomenon can be recognized and avoided by routine phenotyping of primary tumors and xenografts with human leukocyte markers, and provides a compelling biological rationale for exclusion of these cells from human solid tumor xenotransplantation assays.

Inhibition of epstein‐barr virus reactivation in nasopharyngeal carcinoma cells by dietary sulforaphane

Epstein-Barr virus (EBV) has been associated with several human malignancies including nasopharyngeal carcinoma (NPC). Reactivation of latent EBV has been considered to contribute to the carcinogenesis of NPC. Blocking the EBV lytic cycle has been shown effective in the treatment of EBV-associated diseases. We have searched for natural dietary compounds inhibiting EBV reactivation in NPC cells. Among them, sulforaphane (SFN) was found to be effective in the inhibition of EBV reactivation in latent EBV-positive NPC cells, NA and HA. SFN is a histone deacetylase (HDAC) inhibitor and has been recognized as an antioxidant and antitumor compound for chemoprevention. However, its antiviral effect is less well elucidated. In this study, after determination of the cytotoxicity of SFN on various epithelial cells, we showed that SFN treatment inhibits EBV reactivation, rather than induction, by detection of EBV lytic gene expression in EBV-positive NPC cells. We also determined that the number of cells supporting the EBV lytic cycle is decreased using immunofluorescence and flow cytometric analysis. Moreover, we have found that this inhibitory effect decreases virus production. To elucidate the inhibitory mechanism of SFN on the EBV lytic cycle, luciferase reporter assays were carried out on the Zta and Rta promoters. The results show that SFN inhibits transactivation activity of the EBV immediate-early gene Rta but not Zta. Together, our results suggest that SFN has the capability to inhibit EBV lytic cycle and the potential to be taken as a dietary compound for prevention of EBV reactivation.

Herpes simplex virus type 1 infection activates the Epstein-Barr virus replicative cycle via a CREB-dependent mechanism

The reactivation of latent Epstein-Barr virus (EBV) to lytic replication is important in pathogenesis and requires virus-host cellular interactions. However, the mechanism underlying the reactivation of EBV is not yet fully understood. In the present study, herpes simplex virus type 1 (HSV-1) was shown to induce the reactivation of latent EBV by triggering BZLF1 expression. The BZLF1 promoter (Zp) was not activated by HSV-1 essential glycoprotein-induced membrane fusion. Nevertheless, Zp was activated within 6 h post HSV-1 infection in virus entry-dependent and replication-independent manners. Using a panel of Zp deletion mutants, HSV-1 was shown to promote Zp through a cyclic adenosine monophosphate (cAMP) response element (CRE) located in ZII. The phosphorylated cAMP response element-binding (phos-CREB) protein, the cellular transactivator that binds to CRE, also increased after HSV-1 infection. By transient transfection, cAMP-dependent protein kinase A and HSV-1 US3 protein were found to be capable of activating Zp in CREB- and CRE-dependent manners. The relationship between EBV activation and HSV-1 infection revealed a possible common mechanism that stimulated latent EBV into lytic cycles in vivo.

Effects of Reactivation of Latent Epstein-Barr Virus Using Polymerase Chain Reaction on Acute Hepatitis A in Children

Purpose: We previously reported that concurrent reactivation of latent Epstein-Barr virus (EBV) in children with hepatitis A virus (HAV) infection is common and EBV reactivation with HAV infection adversely affects the clinical features of hepatitis. However, the incidence of concurrent reactivation was not accurate because the detection of EBV reactivation was based on serologic methods. Therefore, we studied the effects of polymerase chain reaction (PCR)-proven EBV reactivation, thus a more precise concurrence, on acute HAV infection in children. Methods: PCR were conducted in 34 patients, who had enrolled previous study and diagnosed with acute HAV infection between January 2008 and June 2010. Their medical records were reviewed. Results: Among 34 patients with acute HAV infection, 12 patients (35.3%) had EBV reactivation which was proven using serologic and molecular biologic techniques. There were significant differences in the peak levels of AST and ALT between the reactivated and non-reactivated groups (p=0.001 and p＜0.001, respectively). The duration of full recovery from hepatitis was more prolonged in the reactivated group (p＜0.001). Clinical parameters, such as serum protein (p＜0.001) and albumin concentrations (p＜0.001), atypical lymphocyte count (p=0.001), prothrombin time-international normalized ratio (PT-INR, p＜0.001), and splenomegaly (p＜0.001), showed significant differences. The clinical features in the reactivated sub-group ＞10 years of age revealed more liver dysfunction compared to the non-reactivated sub-group. A comparison with a previous study was performed. Conclusion: PCR-proven reactivation of latent EBV in children with HAV infection is common and EBV reactivation with HAV infection adversely affects the clinical features of hepatitis, especially in older children. (Korean J Pediatr Gastroenterol Nutr 2011; 14: 59∼66)

Evidence that Amphotericin B Mediates Reactivation of Latent Epstein-Barr Virus in Hodgkin's Lymphoma Allowing Cytotoxicity by Acyclovir

This brief communication focuses on aspects of a recent case report (Yonsei Med J 2005;46:425-30) on a full and sustained remission of Hodgkin's lymphoma (HL) after a single day of chemotherapy. A septic episode required stopping chemotherapy and starting amphotericin B and acyclovir. Remission evidence was seen within days of starting these. A review of research supporting the notion that amphotericin B can reactivate latent Epstein-Barr virus and thus allow acyclovir to kill infected HL cells is given. Experimental work is required to confirm or refute this possibility. If successful, amphotericin B and acyclovir treatment could be extended to other EBV-driven cancers such as Burkitt's lymphoma, nasopharyngeal carcinoma and the occasional EBV-related epithelial cancer of the breast, colon, prostate, and others.

Epstein–Barr virus-related plasmablastic lymphomas arising from long-standing sacrococcygeal cysts in immunosuppressed patients

Epstein–Barr virus-related plasmablastic lymphomas arising from long-standing sacrococcygeal cysts in immunosuppressed patients

Academic Stress—Influence on Epstein-Barr Virus and Cytomegalovirus Reactivation, Cortisol, and Prolactin

This study evaluated the effects of a common stressful event, academic examination, on (1) reactivation of latent Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and (2) levels of cortisol and prolactin in serum. Blood samples were drawn from 2 groups of female students at the beginning of the semester (baseline) and during final examination periods (stress samples) of summer and fall-winter semesters. During summer, fall-winter, and overall, examination stress resulted in significantly increased levels of cortisol at P = .037, .016 and .004, respectively, but not prolactin (P = .32, .09 and .1, respectively). Examination stress significantly increased EBV viral capsid antigen (VCA) IgG levels from baseline levels (P = .0028) in the summer group, but not in the fall-winter group. In addition, the difference in frequency of reactivation in EBV-seropositive subjects in the summer vs the fall-winter (64% vs 15%) was significant at P = .005. Furthermore, after the examination, the percent increase of EBV VCA IgG in the summer (56%) was significantly different (P = .002) from the percent increase (–2%) in the fall-winter. On the other hand, examination stress did not affect the frequency of CMV reactivation or CMV IgG levels in either group. These data suggest that academic stress can reactivate some of the latent herpesviruses to various degrees at different seasons, and that in vivo reactivation of specific latent viral genes might involve multiple neuroendocrine interactions.

The amino-terminal C/H1 domain of CREB binding protein mediates zta transcriptional activation of latent Epstein-Barr virus.

Latent Epstein-Barr virus (EBV) is maintained as a nucleosome-covered episome that can be transcriptionally activated by overexpression of the viral immediate-early protein, Zta. We show here that reactivation of latent EBV by Zta can be significantly enhanced by coexpression of the cellular coactivators CREB binding protein (CBP) and p300. A stable complex containing both Zta and CBP could be isolated from lytically stimulated, but not latently infected RAJI nuclear extracts. Zta-mediated viral reactivation and transcriptional activation were both significantly inhibited by coexpression of the E1A 12S protein but not by an N-terminal deletion mutation of E1A (E1ADelta2-36), which fails to bind CBP. Zta bound directly to two related cysteine- and histidine-rich domains of CBP, referred to as C/H1 and C/H3. These domains both interacted specifically with the transcriptional activation domain of Zta in an electrophoretic mobility shift assay. Interestingly, we found that the C/H3 domain was a potent dominant negative inhibitor of Zta transcriptional activation function. In contrast, an amino-terminal fragment containing the C/H1 domain was sufficient for coactivation of Zta transcription and viral reactivation function. Thus, CBP can stimulate the transcription of latent EBV in a histone acetyltransferase-independent manner mediated by the CBP amino-terminal C/H1-containing domain. We propose that CBP may regulate aspects of EBV latency and reactivation by integrating cellular signals mediated by competitive interactions between C/H1, C/H3, and the Zta activation domain.

Aggressive B-cell lymphoma induced by Epstein-Barr virus infection in erythrodermic cutaneous T-cell lymphoma

The coexistence of two cutaneous non-Hodgkin's lymphomas of different lineage is rare. We report a patient with an indolent erythrodermic cutaneous T-cell lymphoma followed by an aggressive B-cell lymphoma. To our best knowledge, this is the first report describing Epstein-Barr virus-associated B-cell lymphoma in a patient with cutaneous T-cell lymphoma. We suggest that the long-standing cutaneous T-cell lymphoma, as well as the long-term chemotherapy, suppressed host immunity and caused reactivation of latent Epstein-Barr virus.

Human immunodeficiency virus-associated Hodgkin's disease contains latent, not replicative, Epstein-Barr virus

Severe immunodeficiency is associated with reactivation of latent Epstein-Barr virus (EBV) that is manifested by virus replication. It is unknown whether EBV replication also occurs in the Hodgkin's disease (HD) tissue of patients infected with the human immunodeficiency virus (HIV). Therefore, we studied paraffin-embedded lymph nodes from 13 cases of HIV-associated HD to determine the latent or replicative state of EBV infection. All patients were seropositive HIV-infected men; additional clinical information was available for 12 patients. The risk factor(s) for HIV infection were homosexuality ( n = 7), intravenous drug abuse ( n = 2), homosexuality and intravenous drug abuse ( n = 1), sexual promiscuity ( n = 1), or hemophilia ( n = 1). Advanced clinical stage and B symptoms were common at the time of initial diagnosis of HD. The histological subtype of Hodgkin's disease was universally mixed cellularity, except for a single case classified as nodular sclerosis. Seven cases exhibited foci of relative lymphoid depletion. Five cases contained foci of necrosis. ReedSternberg (RS) cells and RS cell variants were positive for CD30/ BerH2 and negative for CD45/LCA, CD45RO/UCHL1, and CD20/ L26 in all cases. Tumor cells were positive for CD15/LeuMl in seven cases. In all 13 cases, RS cells and RS cell variants were infected by latent EBV as shown by in situ hybridization to EBV-encoded ribonucleic acid (EBER1). In 12 of 13 cases neoplastic cells coexpressed EBV latent membrane protein 1 (LMP1). EBV replication was examined by two different methods: immunohistochemistry to identify EBV-encoded BZLF1 protein and in situ hybridization to detect EBV BHLF1 transcripts. No positivity in RS or RS cell variants was detected with either assay of EBV replication (95% confidence interval [ci]= 0% to 23%). The findings confirm that EBV is detected more frequently in HIV-associated HD when compared with immunocompetent patients with HD. The findings also suggest that EBV is tightly latent within RS and RS cell variants of HIV-associated HD. It appears that factors other than host immune status are important in maintaining EBV latency in HIV-associated HD.