scholarly journals Examining the dynamics of Epstein-Barr virus shedding in the tonsils and the impact of HIV-1 coinfection on daily saliva viral loads

2021 ◽  
Vol 17 (6) ◽  
pp. e1009072
Author(s):  
Catherine M. Byrne ◽  
Christine Johnston ◽  
Jackson Orem ◽  
Fred Okuku ◽  
Meei-Li Huang ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Immune Response ◽  
Epstein Barr Virus ◽  
Model Parameters ◽  
People Living With Hiv ◽  
Viral Loads ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Hiv 1

Epstein-Barr virus (EBV) is transmitted by saliva and is a major cause of cancer, particularly in people living with HIV/AIDS. Here, we describe the frequency and quantity of EBV detection in the saliva of Ugandan adults with and without HIV-1 infection and use these data to develop a novel mathematical model of EBV infection in the tonsils. Eligible cohort participants were not taking antiviral medications, and those with HIV-1 infection had a CD4 count >200 cells/mm3. Over a 4-week period, participants provided daily oral swabs that we analysed for the presence and quantity of EBV. Compared with HIV-1 uninfected participants, HIV-1 coinfected participants had an increased risk of EBV detection in their saliva (IRR = 1.27, 95% CI = 1.10–1.47) and higher viral loads in positive samples. We used these data to develop a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and immune response within the tonsillar epithelium to analyse potential factors that may cause EBV infection to be more severe in HIV-1 coinfected participants. The model, fit using Approximate Bayesian Computation, showed high fidelity to daily oral shedding data and matched key summary statistics. When evaluating how model parameters differed among participants with and without HIV-1 coinfection, results suggest HIV-1 coinfected individuals have higher rates of B cell reactivation, which can seed new infection in the tonsils and lower rates of an EBV-specific immune response. Subsequently, both these traits may explain higher and more frequent EBV detection in the saliva of HIV-1 coinfected individuals.

scholarly journals Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

2017 ◽  
Vol 9 (6) ◽  
pp. 574-586 ◽  
Author(s):  
Yuanjun Lu ◽  
Zailong Qin ◽  
Jia Wang ◽  
Xiang Zheng ◽  
Jianhong Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Epstein Barr Virus ◽  
Type I ◽  
Receptor Signaling ◽  
Viral Pathogen ◽  
Infection Period ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3′UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.

scholarly journals Rituximab in the Treatment of Epstein-Barr Virus Infection after hematopoietic stem cell Transplantation in Children

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5892-5892
Author(s):  
Zhiyong Peng ◽  
Chunfu Li ◽  
Yuelin He
Keyword(s):  
Stem Cell ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
Hematopoietic Stem ◽  
Viral Loads ◽  
Barr Virus ◽  
Ebv Infection ◽  
Infection Disease ◽  
Epstein Barr ◽  
Barr Virus Infection

Abstract OBJECTIVE: To investigate the efficacy and safety of Rituximab on Epstein-Barr virus infection disease after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in children. METHODS: A retrospective analysis was performed based on clinical data of 25 children with median age of 6 years, (3~14 years) diagnosed as EBV infection and received Rituximab from Jan. 2012 to Jun. 2014 in our center. Of them, 3 patients were diagnosed as post-transplant lymphoproliferative disorders (PTLD). All patients received Rituximab at dose of 375 mg/m2 once a week for 4 sequence weeks or discontinued therapy when EBV viral loads was <500 copies/mL two times consecutively. The complete remission (CR) was defined as EBV viral loads <500 copies/mL consecutively at least two time and without any related clinical symptoms. Side effects during infusion were evaluated by Common Terminology Criteria for Adverse Events. RESULTS: The median EBV-infection time was on day 70 (18~200) after HSCT. Each of patients received a median of 2 (1~4) infusions. There were no severe side effects during the infusion of Rituximab. The cumulative complete remission (CR) rate were 88% in total. The CR rate was 56.0±9.9 %, 80.0±8.0%, 84.0±7.3%, and 88.0±6.5%, respectively, in 1st, 2nd, 3rd, and 4th week. Two patients died, one due to infections and the other died of hepatitis while receiving therapy. The CR rate was 100% in patients with PTLD (3/3). CONCLUSIONS: These data suggest Rituximab is safe and effective when treating children with EBV infection disease after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Differential Methylation of Epstein-Barr Virus Latency Promoters Facilitates Viral Persistence in Healthy Seropositive Individuals

1999 ◽  
Vol 73 (12) ◽  
pp. 9959-9968 ◽  
Author(s):  
Emily J. Paulson ◽  
Samuel H. Speck
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Viral Genome ◽  
Epstein Barr Virus ◽  
Critical Role ◽  
Viral Gene ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) establishes a life-long infection in humans, with distinct viral latency programs predominating during acute and chronic phases of infection. Only a subset of the EBV latency-associated antigens present during the acute phase of EBV infection are expressed in the latently infected memory B cells that serve as the long-term EBV reservoir. Since the EBV immortalization program elicits a potent cellular immune response, downregulation of viral gene expression in the long-term latency reservoir is likely to facilitate evasion of the immune response and persistence of EBV in the immunocompetent host. Tissue culture and tumor models of restricted EBV latency have consistently demonstrated a critical role for methylation of the viral genome in maintaining the restricted pattern of latency-associated gene expression. Here we extend these observations to demonstrate that the EBV genomes in the memory B-cell reservoir are also heavily and discretely methylated. This analysis reveals that methylation of the viral genome is a normal aspect of EBV infection in healthy immunocompetent individuals and is not restricted to the development of EBV-associated tumors. In addition, the pattern of methylation very likely accounts for the observed inhibition of the EBV immortalization program and the establishment and maintenance of a restricted latency program. Thus, EBV appears to be the first example of a parasite that usurps the host cell-directed methylation system to regulate pathogen gene expression and thereby establish a chronic infection.

scholarly journals Association between Antibody Responses to Epstein-Barr Virus Glycoproteins, Neutralization of Infectivity, and the Risk of Nasopharyngeal Carcinoma

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Qian-Ying Zhu ◽  
Xiang-Wei Kong ◽  
Cong Sun ◽  
Shang-Hang Xie ◽  
Allan Hildesheim ◽  
...  
Keyword(s):  
Immune Response ◽  
Nasopharyngeal Carcinoma ◽  
Humoral Immune Response ◽  
Epstein Barr Virus ◽  
Healthy Controls ◽  
Humoral Immune ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Antibody Levels

ABSTRACT While Epstein-Barr virus (EBV) is the major cause of nasopharyngeal carcinoma (NPC), the value of the humoral immune response to EBV glycoproteins and NPC development remains unclear. Correlation between antiglycoprotein antibody levels, neutralization of EBV infectivity, and the risk of NPC requires systematic study. Here, we applied a cytometry-based method and enzyme-linked immunosorbent assay to measure neutralization of infectivity and antibody response to EBV glycoproteins (gH/gL, gB, gp350, and gp42) of plasma samples from 20 NPC cases and 20 high-risk and 20 low-risk healthy controls nested within a screening cohort in Sihui, southern China. We found that NPC cases have similar plasma neutralizing activity in both B cells and epithelial cells and EBV glycoprotein-specific IgA and IgG antibody levels compared with those of healthy controls. Significant correlations were observed between gH/gL IgG and gB IgG and the neutralizing ability against EBV infection of epithelial cells and B cells. These results indicate that a high level of glycoprotein antibodies may favor protection against primary EBV infection, instead of being low-risk biomarkers for NPC in long-term EBV-infected adults. In conclusion, this study provides novel insights into the humoral immune response to EBV infection and NPC development, providing valuable leads for future research that is important for prevention and treatment of EBV-related diseases. IMPORTANCE Epstein-Barr virus (EBV) is a human oncogenic gammaherpesvirus that infects over 90% of humans in the world and is causally associated with a spectrum of epithelial and B-cell malignancies such as nasopharyngeal carcinoma (NPC). A prophylactic vaccine against EBV is called for, but no approved vaccine is available yet. Therefore, EBV remains a major public health concern. To facilitate novel vaccines and therapeutics for NPC, it is of great importance to explore the impact of humoral immune response to EBV glycoproteins before the development of NPC. Therefore, in this study, we systematically assessed the correlation between antiglycoprotein antibody levels, neutralization of EBV infectivity, and the risk of NPC development. These results provide valuable information that will contribute to designing effective prevention and treatment strategies for EBV-related diseases such as NPC.

scholarly journals Epidemiological risk factors associated with primary infection by Epstein–Barr virus in HIV-1-positive subjects in the Brazilian Amazon region

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Leonn Mendes Soares Pereira ◽  
Eliane dos Santos França ◽  
Iran Barros Costa ◽  
Igor Tenório Lima ◽  
Amaury Bentes Cunha Freire ◽  
...  
Keyword(s):  
Risk Factors ◽  
Epstein Barr Virus ◽  
Illicit Drug ◽  
Symptom Development ◽  
Viral Loads ◽  
Barr Virus ◽  
Brazilian Amazon Region ◽  
Epstein Barr ◽  
Associated Risk Factors ◽  
Hiv 1

AbstractTo identify the prevalence and risk factors for primary Epstein–Barr virus (EBV) infection in human immunodeficiency virus (HIV)-1-positive adult treatment-naïve patients between January 2018 and December 2019 in a state of the Brazilian Amazon region. A total of 268 HIV-1 positive patients and 65 blood donors participated in the study. Epidemiological data were obtained from medical records and through a designed questionnaire. EBV infection was screened by the semiquantitative detection of anti-viral capsid antigen (VCA) EBV IgM and IgG, followed by molecular detection of the EBNA-3C gene. The plasma viral loads of HIV-1 and EBV were quantified using a commercial kit. The prevalence of primary coinfection was 7.12%. The associated risk factors were education level, family income, history of illicit drug use and sexually transmitted infections, homosexual contact and condom nonuse. Approximately 58.5% had late initiation of highly active antiretroviral therapy, which influenced the risk of HIV-EBV 1/2 multiple infection (odds ratio (OR): 4.76; 95% CI 1.51–15.04) and symptom development (p = 0.004). HIV viral load was associated with patient age (OR: 2.04; 95% CI 2.01–2.07; p = 0.026) and duration of illicit drug use (OR: 1.57; 95% CI 1.12–2.22; p = 0.0548). EBV viral load was associated with younger age (OR: 0.82; 95% CI 0.79–1.03; p = 0.0579). The replication of both viruses was associated with symptom development (HIV = OR: 2.06; 95% CI 1.22–3.50; p = 0.0073; EBV = OR: 8.81; 95% CI 1–10; p = 0.0447). The prevalence of HIV/EBV coinfection was lower than that observed in other studies, and social vulnerability and promiscuous sexual behavior were associated risk factors. A long time of HIV-1 infection, without therapy, influenced the risk of coinfection and disease progression. The viral loads of both viruses may be associated with some epidemiological aspects of the population.

scholarly journals Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Rachel J. Abbott ◽  
Annette Pachnio ◽  
Isabela Pedroza-Pacheco ◽  
Alison M. Leese ◽  
Jusnara Begum ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Acute Phase ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Febrile Illness ◽  
Viral Loads ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR− natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8+ T cells, but overall CD8+ T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control. IMPORTANCE Epstein-Barr virus (EBV) is transmitted orally, replicates in the throat, and then invades the B lymphocyte pool through a growth-transforming latent infection. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8+ T cells and natural killer (NK) cells. Here we show that in five cases of asymptomatic infection, viral loads in the blood were as high as those in patients during the acute phase of IM, whereas the cell-mediated responses, even when they resembled those in patients during the acute phase of IM in timing and quality, were never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se but of the hyperactivated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between the viral load and the response kinetics, emphasizing how much there is still to learn about primary EBV infection.

scholarly journals The CD8+ T-Cell Response to an Epstein-Barr Virus-Related Gammaherpesvirus Infecting Rhesus Macaques Provides Evidence for Immune Evasion by the EBNA-1 Homologue

2005 ◽  
Vol 79 (20) ◽  
pp. 12681-12691 ◽  
Author(s):  
Mark H. Fogg ◽  
Amitinder Kaur ◽  
Young-Gyu Cho ◽  
Fred Wang
Keyword(s):  
Immune Response ◽  
Immune Evasion ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Rhesus Macaques ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Ctl Activity

ABSTRACT Epstein-Barr virus (EBV) infection persists for life in humans, similar to other gammaherpesviruses in the same lymphocryptovirus (LCV) genus that naturally infect Old World nonhuman primates. The specific immune elements required for control of EBV infection and potential immune evasion strategies essential for persistent EBV infection are not well defined. We evaluated the cellular immune response to latent infection proteins in rhesus macaques with naturally and experimentally acquired rhesus LCV (rhLCV) infection. RhLCV EBNA-1 (rhEBNA-1) was the most frequently targeted latent infection protein and induced the most robust responses by peripheral blood mononuclear cells tested ex vivo using the gamma interferon ELISPOT assay. In contrast, although in vitro stimulation and expansion of rhLCV-specific T lymphocytes demonstrated cytotoxic T-lymphocyte (CTL) activity against autologous rhLCV-infected B cells, rhEBNA-1-specific CTL activity could not be detected. rhEBNA-1 CTL epitopes were identified and demonstrated that rhEBNA-1-specific CTL were stimulated and expanded in vitro but did not lyse targets expressing rhEBNA-1. Similarly, rhEBNA-1-specific CTL clones were able to lyse targets pulsed with rhEBNA-1 peptides or expressing rhEBNA-1 deleted for the glycine-alanine repeat (GAR) but not full-length rhEBNA-1 or rhLCV-infected B cells. These studies show that the rhLCV-specific immune response to latent infection proteins is similar to the EBV response in humans, and a potential immune evasion mechanism for EBNA-1 has been conserved in rhLCV. Thus, the rhLCV animal model can be used to analyze the immune responses important for control of persistent LCV infection and the role of the EBNA-1 GAR for immune evasion in vivo.

Epstein–Barr virus, latitude and multiple sclerosis

2012 ◽  
Vol 19 (3) ◽  
pp. 362-365 ◽  
Author(s):  
Giulio Disanto ◽  
Julia Pakpoor ◽  
Julia M Morahan ◽  
Carolina Hall ◽  
Ute C Meier ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Odds Ratio ◽  
Epstein Barr Virus ◽  
Serological Markers ◽  
Related Factors ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Lines Of Evidence

Several lines of evidence support a role for Epstein–Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02–1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.

scholarly journals Increased oral Epstein-Barr virus shedding with HIV-1 co-infection is due to a combination of B cell activation and impaired cellular immune control

2019 ◽  
Author(s):  
Catherine M. Byrne ◽  
Christine Johnston ◽  
Jackson Orem ◽  
Fred Okuku ◽  
Meei-Li Huang ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
B Cell Activation ◽  
Barr Virus ◽  
Ebv Infection ◽  
Infected Cells ◽  
Epstein Barr ◽  
Cellular Immune ◽  
Hiv 1

AbstractEpstein-Barr virus (EBV) infection is transmitted by saliva and is a major cause of cancer in people living with HIV/AIDS as well as in the general population. To better understand the determinants of oral EBV shedding we evaluated the frequency and quantity of detectable EBV in the saliva in a prospective cohort study of 85 adults in Uganda, half of whom were co-infected with HIV-1. Participants were not receiving antiviral medications, and those with HIV-1 co-infection had a CD4+ T cell count >200 cells/mm3. Daily, self-collected oral swabs were collected over a 4-week period. Compared with HIV-1 uninfected participants, co-infected participants had an increased frequency of oral EBV shedding (IRR=1.27, 95% CI=1.10-1.47). To explain why EBV oral shedding is greater in HIV-1 co-infected participants, we developed a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and antiviral cellular immune responses within the tonsillar epithelium, and examined parameter-specific differences between individuals of different HIV-1 infection statuses. We fit the model to our observational data using Approximate Bayesian Computation. After fitting, model simulations showed high fidelity to daily oral shedding time-courses and matched key summary statistics. Examination of the model revealed that higher EBV loads in saliva are driven by B cell activation causing EBV lytic replication in the tonsils, in combination with a less effective EBV-specific cellular immune response. Thus, both these factors contribute to higher and more frequent EBV shedding in HIV-1 co-infected individuals compared to HIV-1 uninfected individuals. These conclusions were further validated by modelling daily oral EBV shedding in a 26-participant North American cohort. Our results provide insights into the determinants of EBV shedding and implicate B cell activation to be a potential therapeutic target to reduce EBV replication in HIV-1 co-infected individuals at high risk for EBV-related malignancies.Author summaryEpstein-Barr virus (EBV) is a ubiquitous infection worldwide. Infection with EBV is associated with the development of several kinds of cancer, including B cell lymphoma and nasopharyngeal carcinoma. Rates of EBV replication and disease are higher in individuals who are also infected with HIV-1. HIV-1 infection is associated with increased B cell activation, which is known to induce EBV reactivation, as well as immunodeficiency resulting from loss of T cells. However, whether these factors contribute to higher rates of EBV replication during co-infection, and by how much, was unknown. We analysed oral EBV shedding data in a cohort of adults from Uganda that were chronically infected with EBV. We found that participants that were HIV-1 infected were much more likely to have detectable quantities of EBV in their saliva. Also, when detected, the quantity of EBV present in the saliva was usually higher in HIV-1 infected participants. To better understand these findings, we developed a mathematical model to describe the dynamics of EBV, EBV-infected cells, and the cellular immune response within the tonsils. By rigorously matching our model to our participant data, we determined that high EBV loads in saliva are caused by high rates of infected B cell activation, as well as worse cellular immune control of EBV infection. These results provide an explanation of the impact of HIV-1 on EBV infection. Further, they suggest that strategies that suppress B cell activation may prevent EBV-related malignancy in people who are also infected with HIV-1.

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