Symptomatic Epstein-Barr Virus Infection Research Articles

Epstein-Barr virus as a leading cause of multiple sclerosis: mechanisms and implications.

Epidemiological studies have provided compelling evidence that multiple sclerosis (MS) is a rare complication of infection with the Epstein-Barr virus (EBV), a herpesvirus that infects more than 90% of the global population. This link was long suspected because the risk of MS increases markedly after infectious mononucleosis (symptomatic primary EBV infection) and with high titres of antibodies to specific EBV antigens. However, it was not until 2022 that a longitudinal study demonstrated that MS risk is minimal in individuals who are not infected with EBV and that it increases over 30-fold following EBV infection. Over the past few years, a number of studies have provided clues on the underlying mechanisms, which might help us to develop more targeted treatments for MS. In this Review, we discuss the evidence linking EBV to the development of MS and the mechanisms by which the virus is thought to cause the disease. Furthermore, we discuss implications for the treatment and prevention of MS, including the use of antivirals and vaccines.

Valganciclovir is not associated with decreased EBV infection rate in pediatric kidney transplantation.

Primary infection or reactivation of Epstein-Barr Virus (EBV) is a significant cause of morbidity and mortality in pediatric kidney transplantation. Valganciclovir (VGC) treatment is recommended for prophylaxis of cytomegalovirus infection, but its role for the prevention of EBV infection remains controversial. All pediatric kidney transplant recipients aged <18 years old were considered for inclusion in this retrospective study. EBV negative recipients with an EBV positive donor (a group at risk of primary infection) or EBV positive recipients (a group at risk of reactivation) were included. Severe infection was defined by post-transplant lymphoproliferative disorder (PTLD), symptomatic EBV infection or by asymptomatic EBV infection with a viral load >4.5 log/ml. Outcomes were compared between patients receiving VGC prophylaxis (group P+) and those not receiving VGC prophylaxis (group P-). A total of 79 patients were included, 57 (72%) in the P+ group and 22 (28%) in the P- group; 25 (31%) were at risk of primary infection and 54 (69%) at risk of reactivation. During the first year post-transplant, the occurrence of severe EBV infection was not different between the P+ group (n = 13, 22.8%) and the P- group (n = 5, 22.7%) (p = 0.99). Among patients at risk of primary infection, the rate of severe EBV infection was not different between the two groups (42.1% in P+ vs. 33.3% in P-). A higher frequency of neutropenia was found in the P+ group (66.6%) than in the P- group (33.4%) (p < 0.01). Our observational study suggests no effect of VGC for the prevention of EBV infection in pediatric kidney transplant recipients, irrespective of their EBV status. Adverse effects revealed an increased risk of neutropenia.

Altered Immune Response to the Epstein-Barr Virus as a Prerequisite for Multiple Sclerosis.

Strong epidemiologic evidence links Epstein–Barr virus (EBV) infection and its altered immune control to multiple sclerosis (MS) development. Clinical MS onset occurs years after primary EBV infection and the mechanisms linking them remain largely unclear. This review summarizes the epidemiological evidence for this association and how the EBV specific immune control is altered in MS patients. The two main possibilities of mechanisms for this association are further discussed. Firstly, immune responses that are induced during a symptomatic primary EBV infection, namely infectious mononucleosis, might be amplified during the following years to finally cause central nervous system (CNS) inflammation and demyelination. Secondly, genetic predisposition and environmental factors might not allow for an efficient immune control of the EBV-infected B cells that might drive autoimmune T cell stimulation or CNS inflammation. These two main hypotheses for explaining the association of the EBV with MS would implicate opposite therapeutic interventions, namely either dampening CNS inflammatory EBV-reactive immune responses or strengthening them to eliminate the autoimmunity stimulating EBV-infected B cell compartment. Nevertheless, recent findings suggest that EBV is an important puzzle piece in the pathogenesis of MS, and understanding its contribution could open new treatment possibilities for this autoimmune disease.

Co-Stimulatory Molecules during Immune Control of Epstein Barr Virus Infection

The Epstein Barr virus (EBV) is one of the prominent human tumor viruses, and it is efficiently immune-controlled in most virus carriers. Cytotoxic lymphocytes strongly expand during symptomatic primary EBV infection and in preclinical in vivo models of this tumor virus infection. In these models and patients with primary immunodeficiencies, antibody blockade or deficiencies in certain molecular pathways lead to EBV-associated pathologies. In addition to T, NK, and NKT cell development, as well as their cytotoxic machinery, a set of co-stimulatory and co-inhibitory molecules was found to be required for EBV-specific immune control. The role of CD27/CD70, 4-1BB, SLAMs, NKG2D, CD16A/CD2, CTLA-4, and PD-1 will be discussed in this review. Some of these have just been recently identified as crucial for EBV-specific immune control, and for others, their important functions during protection were characterized in in vivo models of EBV infection and its immune control. These insights into the phenotype of cytotoxic lymphocytes that mediate the near-perfect immune control of EBV-associated malignancies might also guide immunotherapies against other tumors in the future.

Epstein-Barr Virus Prevalence at Diagnosis and Seroconversion during Follow-Up in Pediatric Inflammatory Bowel Disease.

Primary Epstein–Barr virus infection in pediatric patients with inflammatory bowel disease during immunomodulation with thiopurines has been associated with increased risk for malignancies or hemophagocytic lymphohistiocytosis. We determined Epstein–Barr virus (EBV) seroprevalence at inflammatory bowel disease (IBD) diagnosis and seroconversion during follow-up in a large single center cohort of children with IBD. EBV serology results and patient characteristics were retrospectively retrieved from the hospital documentation system. EBV seronegative patients at IBD diagnosis were prospectively retested. We report on IBD patients with symptomatic active EBV infection and a complicated disease course, and those diagnosed with malignancy with respect to EBV status and drug exposure. Of 402 patients, 194 (48%) had available EBV serology results at time of IBD diagnosis at a median of 12 years (IQR 9–14 years). Thereof, 102 (53%) were EBV-positive. Of 92 EBV-negative patients, 66 were retested and 17% showed a seroconversion at a mean follow-up time of 4.3 years (SD 3 years). Three children treated with azathioprine experienced acute clinically relevant EBV infection 2, 2.5, and 4 years after IBD diagnosis, two developed signs of hemophagocytic lymphohistiocytosis. Three cases of malignancy occurred in the cohort, though none seemed to be triggered by EBV. In conclusion, almost 50% of pediatric IBD patients were EBV-naïve following diagnosis and may be at increased risk to develop severe EBV infection during immunosuppressive therapy, potentially associated with complications such as hemophagocytic lymphohistiocytosis or malignancy.

Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) for which both genetic and environmental risk factors have been identified. The strongest synergy among them exists between the MHC class II haplotype and infection with the Epstein Barr virus (EBV), especially symptomatic primary EBV infection (infectious mononucleosis) and elevated EBV-specific antibodies. In this review, we will summarize the epidemiological evidence that EBV infection is a prerequisite for MS development, describe altered EBV specific immune responses in MS patients, and speculate about possible pathogenic mechanisms for the synergy between EBV infection and the MS-associated MHC class II haplotype. We will also discuss how at least one of these mechanisms might explain the recent success of B cell-depleting therapies for MS. While a better mechanistic understanding of the role of EBV infection and its immune control during MS pathogenesis is required and calls for the development of innovative experimental systems to test the proposed mechanisms, therapies targeting EBV-infected B cells are already starting to be explored in MS patients.

Kissing genetic MS risk loci to life.

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease of the central nervous system (CNS) [1]. Its debilitating effects on sensory, motor, autonomic, and neurocognitive functions affect primarily young adults, especially women (two to three times more frequent than in men), and is most frequent in northern countries, affecting more than 150 individuals of every 100,000 inhabitants e.g. in Canada and the Scandinavian countries. The development of this often initially relapsing/remitting and later progressive disease is associated with genetic and environmental risk factors [1, 3]. The major histocompatibility complex (MHC) class II gene locus is by far the most prominent genetic risk factor, and altered immune responses to the Epstein Barr virus (EBV), the causative infectious agent of most cases of infectious mononucleosis or “kissing disease”, have in recent years emerged as the most prominent environment induced risk factors for MS [1]. Interestingly, particularly infectious mononucleosis as symptomatic primary EBV infection, caused by a lymphocytosis of mainly lytic EBV antigen specific CD8+ T cells, and elevated antibody responses against EBV have been found to synergize with the MS associated MHC class II molecule HLA-DRB1*1501 to increase MS risk seven- to fifteen-fold, respectively [1]. Moreover, EBV infection seems to precede MS onset by several years in nearly all patients. Thus, EBV infection currently appears as a prerequisite for MS development that increases the risk for this autoimmune disease in genetically susceptible individuals.

Investigation of IL-2 and IFN-γ to EBV Peptides in Stimulated Whole Blood among Multiple Sclerosis Patients and Healthy Individuals

Introduction: Epstein-Barr virus (EBV), a double-stranded DNA virus, has 2 phases of lytic and latent infection in host cells. After infecting B lymphocytes, EBV becomes persistent in these cells. In healthy individuals, T lymphocytes play a key role in killing EBV-infected B cells. Statistical studies have shown that symptomatic EBV infection increases the risk of MS. Methods: This study intended to measure the immune system’s response against the different components of EBV, focusing particularly on T lymphocytes’ reaction. Consequently, the mRNA level of IL-2 and IFN-γ, liable for impressing autoimmune diseases and as indicators of T-cell function, was compared in EBNA1- and BRLF1-treated whole blood (WB) cultures of 10 healthy individuals and 10 MS patients using real-time RT-PCR. Results: The analysis of the results demonstrated a significant increased level of IL-2 in MS patients than healthy subjects after exposure to both peptides. Also, the mRNA level of IFN-γ increased in MS patients in EBNA1-treated WB culture. Conclusion: According to the study’s results, EBV peptides can reactivate immune cells, especially T lymphocytes, and may indirectly induce inflammation and develop MS; however, it seems that long-time exposure to these peptides has reducing effect on T-cell function and faces the control of infected B lymphocytes with difficulties.

S2582 Acute Hepatitis Secondary to Asymptomatic Epstein-Barr Virus (EBV) Infection

INTRODUCTION: Symptomatic EBV infection usually presents with fever, sore throat, lymphadenopathy, termed as infectious mononucleosis syndrome. Marginal elevation of liver enzymes may be seen however, acute symptomatic hepatitis without mononucleosis syndrome is rare. We present a case of a female with acute cholestatic hepatitis with laboratory-confirmed EBV infection without mononucleosis syndrome. CASE DESCRIPTION/METHODS: A 36-year-old female, underweight, with past history of alcohol use (sober for 60+ days), seizure disorder, sub-clinical hypothyroidism presented with intermittent nausea followed by non-bloody, non-bilious vomiting for 5 days without melena or blood in the stool. She didn’t report any fever, chills, night sweats, sick contacts, recent travel history. On clinical exam, her vital signs were blood pressure 112/78 mm Hg, pulse 104/min, oral temperature of 36.7 deg C and breathing comfortably on room air. Inspection notable scleral icterus without periorbital skin involvement, no buccal mucosa changes, enlarged tonsil, no spider nevi, or scratch mark on inspection, no lymphadenopathy on palpation. The abdomen was soft and protuberant on the exam with liver just palpable below costal margin but non-tender to palpation. Her home medicine includes oral vitamin B12, folic acid, zonisamide (no changes to regimen in 2 years). Initial laboratory evaluation revealed a normal white cell count with an elevated liver enzymes, bilirubin, and alkaline phosphatase (R factor: 1.2). An ultrasonography of abdomen showed a common bile duct diameter of 3 mm without any dilation of extra or intrahepatic ducts, visualized portion of the portal vein was patent and showed hepatopetal flow. Unremarkable pancreas with cholelithiasis without cholecystitis. To rule in/out additional causes of cholestatic jaundice, viral, and antibody panel were sent which were positive for EBV infection. Additionally, ANA was positive reflecting cross-reactivity between EBV proteins and autoantigens. Her symptoms improved with conservative management which included hydration and low-fat diet. DISCUSSION: EBV is an important cause of cholestatic hepatitis resulting in elevated liver enzymes and bilirubin, however, the presentation is usually associated with mononucleosis syndrome. EBV hepatitis as a differential in patients with cholestatic hepatitis but without demonstrable biliary obstruction, prompt identification would avoid costly and/or invasive diagnostic procedures. No effective treatment is available for EBV hepatitis.Table 1.: Laboratory profile on admission and 8 weeks later

Co-infection of Cytomegalovirus and Epstein-Barr Virus Diminishes the Frequency of CD56dimNKG2A+KIR- NK Cells and Contributes to Suboptimal Control of EBV in Immunosuppressed Children With Post-transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but potentially life-threatening complication, frequently associated with Epstein-Barr virus (EBV), which develops after solid organ or stem cell transplantation. Immunosuppression received by transplant recipients has a significant impact on the development of PTLD by suppressing the function of T cells. The preferential proliferation of NKG2A-positive natural killer (NK) cells during primary symptomatic EBV infection known as infectious mononucleosis (IM) and their reactivity toward EBV-infected B cells point to a role of NK cell in the immune control of EBV. However, NK cell-mediated immune response to EBV in immunosuppressed transplant recipients who develop PTLD remains unclear. In this study, we longitudinally analyzed the phenotype and function of different NK cell subsets in a cohort of pediatric liver transplant patients who develop PTLD and compared them to those of children with IM. We found persistently elevated plasma EBV DNA levels in the PTLD patients indicating suboptimal anti-viral immune control. PTLD patients had markedly decreased frequency of CD56dimNKG2A+Killer Immunoglobulin-like receptor (KIR)− NK cells from the time of diagnosis through remission compared to those of IM patients. Whilst the proliferation of CD56dimNKG2A+KIR− NK cells was diminished in PTLD patients, this NK cell subset maintained its ability to potently degranulate against EBV-infected B cells. Compared to cytomegalovirus (CMV)-seropositive and -negative IM patients, PTLD patients co-infected with CMV and EBV had significantly higher levels of a CMV-associated CD56dimNKG2ChiCD57+NKG2A−KIR+ NK cell subset accumulating at the expense of NKG2A+KIR− NK cells. Taken together, our data indicate that co-infection of CMV and EBV diminishes the frequency of CD56dimNKG2A+KIR− NK cells and contributes to suboptimal control of EBV in immunosuppressed children with PTLD.

Epstein-Barr virus infection with acute acalculous cholecystitis in previously healthy children.

Acute acalculous cholecystitis (AAC), an inflammatory process of the gallbladder (GB) in the absence of gallstones, typically occurs in seriously ill patients. AAC can complicate primary Epstein-Barr virus (EBV) infection, but it is an atypical clinical presentation. The aim of our study was to analyse AAC occurrence in children with primary symptomatic EBV infection who had been admitted to the hospital. We retrospectively evaluated the medical documentation of 181 children with EBV infection who were diagnosed based on the presence of viral capsid antigen IgM antibodies. All EBV-positive patients underwent transabdominal ultrasonography of the liver in the supine and right anterior oblique positions. Fifteen children who presented with AAC symptoms, including abdominal pain and a positive Murphy's sign, were analysed as a subsample and re-evaluated after 2-3months. The incidence of AAC in children hospitalised with infectious mononucleosis (IM) was estimated at 8.3%. Analysis of the laboratory results confirmed that the C-reactive protein (CRP) concentration was the only parameter which was higher in children who presented with AAC symptoms. The mean number of leucocytes and monocytes and liver enzyme activities were not significantly higher. The radiological findings of AAC were evident: increased GB wall thickness, non-shadowing echogenic sludge and pericholecystic fluid collection. AAC during primary EBV infection appears to be a more common pathology than previously suspected. Its relatively mild nature and the lack of laboratory abnormalities mean that ultrasonographic examination is required for diagnosis. This might explain why the prevalence in children is underestimated.

Heterologous prime-boost vaccination protects against EBV antigen-expressing lymphomas.

The Epstein-Barr virus (EBV) is one of the predominant tumor viruses in humans, but so far no therapeutic or prophylactic vaccination against this transforming pathogen is available. We demonstrated that heterologous prime-boost vaccination with the nuclear antigen 1 of EBV (EBNA1), either targeted to the DEC205 receptor on DCs or expressed from a recombinant modified vaccinia virus Ankara (MVA) vector, improved priming of antigen-specific CD4+ T cell help. This help supported the expansion and maintenance of EBNA1-specific CD8+ T cells that are most efficiently primed by recombinant adenoviruses that encode EBNA1. These combined CD4+ and CD8+ T cell responses protected against EBNA1-expressing T and B cell lymphomas, including lymphoproliferations that emerged spontaneously after EBNA1 expression. In particular, the heterologous EBNA1-expressing adenovirus, boosted by EBNA1-encoding MVA vaccination, demonstrated protection as a prophylactic and therapeutic treatment for the respective lymphoma challenges. Our study shows that such heterologous prime-boost vaccinations against EBV-associated malignancies as well as symptomatic primary EBV infection should be further explored for clinical development.

Emergence of CD4+ and CD8+ Polyfunctional T Cell Responses Against Immunodominant Lytic and Latent EBV Antigens in Children With Primary EBV Infection

Long term carriers were shown to generate robust polyfunctional T cell (PFC) responses against lytic and latent antigens of Epstein-Barr virus (EBV). However, the time of emergence of PFC responses against EBV antigens, pattern of immunodominance and difference between CD4+ and CD8+ T cell responses during various stages of EBV infection are not clearly understood. A longitudinal study was performed to assess the development of antigen-specific PFC responses in children diagnosed to have primary symptomatic (infectious mononucleosis [IM]) and asymptomatic (AS) EBV infection. Evaluation of IFN-γ secreting CD8+ T cell responses upon stimulation by HLA class I-specific peptides of EBV lytic and latent proteins by ELISPOT assay followed by assessment of CD4+ and CD8+ PFC responses upon stimulation by a panel of overlapping EBV peptides for co-expression of IFN-γ, TNF-α, IL-2, perforin and CD107a by flow cytometry were performed. Cytotoxicity of T cells against autologous lymphoblastoid cell lines (LCLs) as well as EBV loads in PBMC and plasma were also determined. Both IM and AS patients had elevated PBMC and plasma viral loads which declined steadily during a 12-month period from the time of diagnosis whilst decrease in the magnitude of CD8+ T cell responses toward EBV lytic peptides in contrast to increase toward latent peptides was shown with no significant difference between those of IM and AS patients. Both lytic and latent antigen-specific CD4+ and CD8+ T cells demonstrated polyfunctionality (defined as greater or equal to three functions) concurrent with enhanced cytotoxicity against autologous LCLs and steady decrease in plasma and PBMC viral loads over time. Immunodominant peptides derived from BZLF1, BRLF1, BMLF1 and EBNA3A-C proteins induced the highest proportion of CD8+ as well as CD4+ PFC responses. Diverse functional subtypes of both CD4+ and CD8+ PFCs were shown to emerge at 6–12 months. In conclusion, EBV antigen-specific CD4+ and CD8+ PFC responses emerge during the first year of primary EBV infection, with greatest responses toward immunodominant epitopes in both lytic and latent proteins, correlating to steady decline in PBMC and plasma viral loads.

Epstein-Barr Virus-Specific Immune Control by Innate Lymphocytes.

Epstein–Barr virus (EBV) is a potent B cell transforming pathogen in humans. In most persistently EBV-infected individuals, potent cytotoxic lymphocyte responses prevent EBV-associated pathologies. In addition to comprehensive adaptive T cell responses, several innate lymphocyte populations seem to target different stages of EBV infection and are compromised in primary immunodeficiencies that render individuals susceptible to symptomatic EBV infection. In this mini-review, I will highlight the functions of natural killer, γδ T cells, and natural killer T cells during innate immune responses to EBV. These innate lymphocyte populations seem to restrict both lytic replication and transforming latent EBV antigen expression. The mechanisms underlying the recognition of these different EBV infection programs by the respective innate lymphocytes are just starting to become unraveled, but will provide immunotherapeutic strategies to target pathologies that are associated with the different EBV infection programs.

NK Cell Influence on the Outcome of Primary Epstein-Barr Virus Infection.

The herpesvirus Epstein–Barr virus (EBV) was discovered as the first human candidate tumor virus in Burkitt’s lymphoma more than 50 years ago. Despite its strong growth transforming capacity, more than 90% of the human adult population carries this virus asymptomatically under near perfect immune control. The mode of primary EBV infection is in part responsible for EBV-associated diseases, including Hodgkin’s lymphoma. It is, therefore, important to understand which circumstances lead to symptomatic primary EBV infection, called infectious mononucleosis (IM). Innate immune control of lytic viral replication by early-differentiated natural killer (NK) cells was found to attenuate IM symptoms and continuous loss of the respective NK cell subset during the first decade of life might predispose for IM during adolescence. In this review, we discuss the evidence that NK cells are involved in the immune control of EBV, mechanisms by which they might detect and control lytic EBV replication, and compare NK cell subpopulations that expand during different human herpesvirus infections.

Active CMV and EBV infections in renal transplant recipients with unexplained fever and elevated serum creatinine

Proper identification of active cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections are helpful for monitoring antiviral treatment in transplant recipients. Qualitative and quantitative CMV, EBV DNA PCR techniques in the context of serological tests are performed for early detection and differentiation of active and latent CMV and EBV infections in renal transplantation. Basically, 129 renal transplanted recipients monitored carefully and hospitalized for unexplained elevated creatinine levels or high fever and 21 of their donors were studied. CMV DNA was detected in 63.5% of the febrile episodes following transplantation and in 46.42% of readmitted patients using qualitative PCR method. In the first group, 15% of the patients and in the second group 42.85% of the patients had copy numbers more than cutoff point (900 copies/mL). Cutoff point had 100% sensitivity and 82.5% specificity for active and symptomatic CMV infection. Only 15.5% of the subjects were positive for EBV infection by qualitative PCR method. Among them 5% had >2000 copies/mL and were symptomatic. One subject with a history of three times hospitalization had higher EBV viral load and developed post-transplant lymphoproliferative disorder. CMV load was significantly correlated with elevated creatinine levels (OR = 3.1, p = 0.006), abnormal heart sounds (OR = 4.7; p = 0.02) and hypertension (OR = 3.6; p = 0.03). Only qRT-PCR could differentiate between latent and active infections and might be clinically useful for monitoring symptomatic CMV and EBV infections and initiation of the antiviral therapy. Elevated creatinine levels, hypertension, and abnormal heart sounds could be considered as main manifestations of HCMV infection in kidney recipients.

Antibody producing B lineage cells invade the central nervous system predominantly at the time of and triggered by acute Epstein–Barr virus infection: A hypothesis on the origin of intrathecal immunoglobulin synthesis in multiple sclerosis

Patients with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), typically have an intrathecal synthesis of immunoglobulin (Ig)G. Intrathecal IgG is produced by B lineage cells that entered the CNS, but why and when these cells invade the CNS of patients with MS is unknown. The intrathecal IgG response in patients with MS is polyspecific and part of it is directed against different common viruses (e.g. measles virus, rubella virus, varicella zoster virus). Strong and consistent evidence suggests an association of MS and Epstein–Barr virus (EBV) infection and EBV seroprevalence in patients with MS is practically 100%. However, intriguingly, despite of the universal EBV seroprevalence, the frequency of intrathecally produced IgG to EBV in patients with MS is much lower than that of intrathecally produced IgG to other common viruses. The acute phase of primary EBV infection is characterized by a strong polyclonal B cell activation. As typical for humoral immune responses against viruses, EBV specific IgG is produced only with a temporal delay after acute EBV infection. Aiming to put the above facts into a logical structure, we here propose the hypothesis that in individuals going on to develop MS antibody producing B lineage cells invade the CNS predominantly at the time of and triggered by acute primary EBV infection. Because at the time of acute EBV infection EBV IgG producing B lineage cells have not yet occurred, the hypothesis could explain the universal EBV seroprevalence and the low frequency of intrathecally produced IgG to EBV in patients with MS. Evidence supporting the hypothesis could be provided by large prospective follow-up studies of individuals with symptomatic primary EBV infection (infectious mononucleosis). Furthermore, the clarification of the molecular mechanism underlying an EBV induced invasion of B lineage cells into the CNS of individuals going on to develop MS could corroborate it, too. If true, our hypothesis would link EBV infection, the most important environmental risk factor for MS, with intrathecal IgG synthesis, the most characteristic laboratory feature of MS. Besides explaining the origin of intrathecal IgG synthesis in patients with MS, the hypothesis could thus also provide a conceptual framework for clarifying the mechanism through which EBV contributes to the development of MS.

Epstein-Barr Virus—Associated Posttransplantation Lymphoproliferative Disorder With Tacrolimus Metabolism Deterioration in Infants After Living-Donor Liver Transplantation

Posttransplantation lymphoproliferative disorder (PTLD) in infants after liver transplantation is strongly associated with tacrolimus (Tac) administration and primary Epstein-Barr virus (EBV) transmission. From 1991 to 2012, 32 survivors younger than 2 years who had undergone living-donor liver transplantation using Tac for primary immunosuppression were retrospectively investigated for changes in Tac trough levels before and at the onset of posttransplantation viral infection episodes. Twenty-one recipients experienced 33 viral infection episodes associated with EBV-related PTLD (n = 5), symptomatic EBV infection without development of PTLD (n = 8), and other viral infections (n = 20). Although the average Tac trough levels during the 2 months before the onset of viral infection episodes were similar among the 33 episodes (9.0 ± 2.8 ng/mL), the Tac trough levels at the onset were significantly higher in the episodes with PTLD than in those with EBV infection without the development of PTLD and with other viral infections (19.2 ± 9.0 ng/mL vs. 9.3 ± 5.2 ng/mL and 10.6 ± 5.1 ng/mL, respectively) (P<0.05). Tacrolimus trough levels at the onset of PTLD were significantly higher during the 2 months before the onset (median, 1.83 times higher than average) compared with EBV infection (1.14 times higher) and other viral infections (1.06 times higher) (P<0.05). The Tac blood concentration-to-dose ratio at the onset of PTLD was more than twice as high as the average value during the 2 months before the onset. Deteriorated Tac metabolism accompanied by a positive change in the blood EBV DNA load may enable us to predict the development of PTLD in liver-transplanted infants with viral infection.

Editorial Commentary: Genetics and Infectious Mononucleosis

(See the Major Article by Rostgaard et al on pages 1684–9.) The epidemiology of primary Epstein-Barr virus (EBV) infection is not completely understood. We know that kissing is the major route of transmission of primary EBV infection among teenagers and young adults [1], but we do not know the mechanism(s) of transmission among preadolescent children. In addition, we do not know why the majority of primary EBV infections in young children go unrecognized [2], whereas those in adolescents and young adults usually result in infectious mononucleosis (IM) [1]. We also do not know whether it is better to get infected by EBV early in life or later on. Evidently, much remains to be learned about the enigmatic epidemiology of EBV, but we now have some compelling information that genes are involved. In this issue of Clinical Infectious Diseases, Rostgaard and colleagues tracked familial clustering of hospitalized cases of IM [3]. Using very large Danish national databases, these investigators reported that same-sex twins had a rate ratio of 9.3 for mono, compared with 2.3 for first-degree relatives (opposite-sex twins, siblings, and parents), 1.4 for second-degree relatives (half-siblings, grandparents, uncles, and aunts), and 1.0 for third-degree relatives (first cousins). The 95% confidence intervals for those 4 classes of relationships did not overlap, supporting the conclusion that degree of relatedness increased the likelihood of contracting mono. Hwang et al, utilizing the California Twin Program registry, reported that concordance for IM in monozygotic twins was twice that of dizygotic twins [4]. They interpreted their results as consistent with a genetic contribution to susceptibility to mono. Twins certainly share the same environment and likely have similar behavior, which cannot be ruled out as risk factors. However, the significantly greater number of cases in monozygotic or same-sex twins vs dizygotic or opposite-sex twins in both the California and the Danish studies is compelling evidence that susceptibility to IM has a genetic component. A strength of both studies was the large size of the cohort investigated. A limitation of the Danish study was that only relatively severe IM was captured (85% of the cases were inpatient admissions), and therefore the results may not be applicable to typical outpatient cases of mono. Shortcomings of both studies include the lack of laboratory confirmation of EBV infection, and few data on racial groups other than whites. Rostgaard and colleagues suggest that genome-wide association studies might uncover EBV susceptibility loci that not only confer a risk for IM but also for development of EBV-associated cancer or autoimmune disease. Including diverse racial/ethnic groups in such investigations could broaden our ability to discover important genetic variants associated with acquisition, severity, and sequelae of EBV infection. In support of this, 2 separate cross-sectional surveys of US children found that early acquisition of EBV infection, as evidenced by having antibodies against EBV viral capsid antigen, was a racial disparity that could not be satisfactorily explained by socioeconomic factors alone [5, 6]. The enormous difference in overall age- and sex-adjusted EBV antibody prevalence between non-Hispanic white (32%) and non-Hispanic black children (62%) in the study by Condon et al [6] is consistent with a genetic basis for the racial clustering of EBV infection in younger children. A history of IM predisposes to Hodgkin lymphoma [7] and multiple sclerosis [8]. Why? A plausible explanation is that more severe primary EBV infection reflects dysregulated immune control of the virus (probably due to the host's genetic makeup), which persists during viral latency, eventually leading to EBV-associated malignancy or autoimmune disease. Rostgaard and colleagues have told us that susceptibility to symptomatic EBV infection is genetically influenced. Our challenge now is to find a candidate genetic marker that identifies individuals in jeopardy for serious EBV disease so that we can recognize them and potentially intervene before they get sick. These individuals would greatly benefit from a prophylactic EBV vaccine, and such vaccines are now in development [9].

Human Natural Killer Cells Prevent Infectious Mononucleosis Features by Targeting Lytic Epstein-Barr Virus Infection

Primary infection with the human oncogenic Epstein-Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion that predisposes for the development of distinct EBV-associated lymphomas. Why some individuals experience this symptomatic primary EBV infection, whereas the majority acquires the virus asymptomatically, remains unclear. Using a mouse model with reconstituted human immune system components, we show that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis mainly because of a loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies.