High frequency of co-infection by Epstein–Barr virus types 1 and 2 in patients with multiple sclerosis

Santón, Almudena; Cristóbal, Eva; Aparicio, Marta; Royuela, Ana; Villar, Luisa M.; Álvarez‐Cermeño, José C.

doi:10.1177/1352458511411063

Cited by 24 publications

(18 citation statements)

References 34 publications

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“…In all cases, the consensus sequence deriving from deep sequencing coincided with the one determined by Sanger sequencing, confirming the cosegregation of newly identified variants with the known EBNA2 alleles. We also found one or more variable positions in all HDs (1-17) and individuals with MS (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). For all couples of variants lying on the same read (coverage $50), the hypothesis of independent segregation, indicative of random sequencing errors, was rejected through a x 2 test (p , 0.05), thus supporting the coexistence of different genotypes.…”

Section: Resultsmentioning

confidence: 91%

“…7 To disclose possible MS-related EBV strains, various groups have followed a candidate-gene approach. [8][9][10][11][12][13][14] Along the same line, we chose to investigate EBV variability in MS by studying Epstein-Barr nuclear antigen 2 (EBNA2). EBNA2 is, in principle, the best candidate for this kind of study because it is the most polymorphic among all EBV genes: 5 major alleles of the EBV type 1 strain, the most frequent strain in the general Caucasian population, 15 have been identified based on nucleotide variations within the most variable region of EBNA2, which is also involved in the interaction with host proteins.…”

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confidence: 99%

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Epstein-Barr virus genetic variants are associated with multiple sclerosis

et al. 2015

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Objective: We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in persons with multiple sclerosis (MS) and control subjects to verify whether virus genetic variants are involved in disease development. 84-14.32; p 5 0.016) and underrepresentation of 1.3B allele (OR 5 0.23; 95% CI 0.08-0.51; p 5 0.0006). We identified new genetic variants, mostly 1.2 allele-and MS-associated (especially amino acid variation at position 245; OR 5 9.4; 95% CI 1.19-78.72; p 5 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and patients with MS (range 1-17 and 3-19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features. MethodsConclusions: Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development. Despite converging evidence supporting an etiologic role for Epstein-Barr virus (EBV) in multiple sclerosis (MS), we still do not know through which mechanisms the virus may contribute to disease development. 1 The potential pathogenic role of EBV genetic variants in MS may be in keeping with epidemiologic observations, in particular the geographic gradient of MS and the change in MS risk in migrants, 2 and with the reported association between virus genetic variants and EBV-related malignancies with different geographic distribution.3-5 Also, the discrepancy between the global diffusion of EBV infection and the low prevalence of MS could be at least in part explained by EBV genomic diversity that differently affects MS development.Major methodologic difficulties hinder the study of EBV variants through sequencing of the whole viral genome. To date, only 8 complete genome sequences have been described: 5 from patients with EBV-related diseases and 3 from healthy individuals.6 This is mainly attributable

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Section: Resultsmentioning

confidence: 91%

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confidence: 99%

Epstein-Barr virus genetic variants are associated with multiple sclerosis

et al. 2015

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“…Regarding only the two major EBV types, rates of coinfection of EBV type 1 and type 2 range from 0% to 53% (Kunimoto et al 1992; Srivastava et al 2000; Walling et al 2003). High frequency of coinfection with both type 1 and type 2 EBV has been reported in MS patients (Santón et al 2011). Given that we do not find evidence of coinfection by different natural EBV types, it is worth noting that we might have underestimated intraindividual EBV diversity if our variants came only from a dominant isolate or the LCLs that were sequenced within the 1kG Project were the result of a selection bias toward transformation-competent EBV isolates (Tierney et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis of Wild-Type Epstein–Barr Virus Genomes Derived from Healthy Individuals of the 1000 Genomes Project

Santpere

Darré

Blanco

et al. 2014

Genome Biology and Evolution

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Most people in the world (∼90%) are infected by the Epstein–Barr virus (EBV), which establishes itself permanently in B cells. Infection by EBV is related to a number of diseases including infectious mononucleosis, multiple sclerosis, and different types of cancer. So far, only seven complete EBV strains have been described, all of them coming from donors presenting EBV-related diseases. To perform a detailed comparative genomic analysis of EBV including, for the first time, EBV strains derived from healthy individuals, we reconstructed EBV sequences infecting lymphoblastoid cell lines (LCLs) from the 1000 Genomes Project. As strain B95-8 was used to transform B cells to obtain LCLs, it is always present, but a specific deletion in its genome sets it apart from natural EBV strains. After studying hundreds of individuals, we determined the presence of natural EBV in at least 10 of them and obtained a set of variants specific to wild-type EBV. By mapping the natural EBV reads into the EBV reference genome (NC007605), we constructed nearly complete wild-type viral genomes from three individuals. Adding them to the five disease-derived EBV genomic sequences available in the literature, we performed an in-depth comparative genomic analysis. We found that latency genes harbor more nucleotide diversity than lytic genes and that six out of nine latency-related genes, as well as other genes involved in viral attachment and entry into host cells, packaging, and the capsid, present the molecular signature of accelerated protein evolution rates, suggesting rapid host–parasite coevolution.

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“…According to Levin et al [7], the elevation of antibody titres to EBNA-1, seen in future MS patients during their early 20s, suggests a more severe or more recent primary infection or reactivation of a preexisting infection, accompanied by a vigorous cellular immune response. Very recently, Santon et al [34] detected dual infection by both types (1 and 2) of EBV in 63 patients (90%) and 46 controls (37·4%). Logistic regression models showed a significant (P < 0·001) association between MS and dual-type infection.…”

Section: Discussionmentioning

confidence: 99%

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

Csuka

Simon

Hóbor

et al. 2013

Clinical and Experimental Immunology

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SummarySeveral studies suggest that infection by Epstein-Barr virus (EBV) might be one of the environmental factors which facilitates the development of autoimmune disorders in genetically susceptible individuals. Recent data indicate that high anti-Epstein-Barr nuclear antigen 1 (EBNA)-1 immunoglobulin (Ig)G titre is a strong risk factor for multiple sclerosis (MS) in patients both with and without the main genetic predisposing trait, human leucocyte antigen (HLA)-DRB1*15:01. Because no similar studies have been published in systemic lupus erythematosus (SLE) patients, we determined the HLA-DRB1*15:01 carrier state and the serum titres against the whole EBNA-1 and its small fragments aa35-58 and aa398-404 in 301 SLE patients, 135 MS patients and in 345 healthy controls. The carrier state of the HLA-DRB1*15:01 allele was deduced from genotyping of a tagSNP (rs3135388) by applying a Taqman-based assay. The serum concentrations of antibodies to EBNA-1 and its aa35-58 or aa398-404 fragments were determined using a commercial assay (ETI-EBNA-G) and home-made enzyme-linked immunosorbent assays, respectively. The serum concentration of anti-EBNA-1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA-DRB1*15:01 carriers and non-carriers. Furthermore, titres of antibodies against the aa35-58 EBNA-1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398-404 EBNA-1 antibodies were elevated significantly only in the SLE patients. These findings indicate that high anti-EBNA-1 IgG titres are HLA-DRB1*15:01-independent risk factors not only for MS, but also for SLE, while high antibody titres against the aa398-404 fragment are characteristic for SLE.

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High frequency of co-infection by Epstein–Barr virus types 1 and 2 in patients with multiple sclerosis

Abstract: This study provides molecular evidence associating co-infection of type 1 and 2 EBV with MS.

Cited by 24 publications

References 34 publications

Epstein-Barr virus genetic variants are associated with multiple sclerosis

Epstein-Barr virus genetic variants are associated with multiple sclerosis

Genome-Wide Analysis of Wild-Type Epstein–Barr Virus Genomes Derived from Healthy Individuals of the 1000 Genomes Project

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

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