Sequence Variation of Epstein-Barr Virus: Viral Types, Geography, Codon Usage, and Diseases

Correia, Samantha; Bridges, Ray; Wegner, Fanny; Venturini, Cristina; Palser, Anne L.; Middeldorp, Jaap M.; Cohen, Jeffrey I.; Lorenzetti, Mario Alejandro; Bassano, Irene; White, Rob; Kellam, Paul; Breuer, Judith; Farrell, Paul J.

doi:10.1128/jvi.01132-18

Cited by 81 publications

(116 citation statements)

References 35 publications

(53 reference statements)

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“…Whilst polymorphisms in EBER, EBNA1 (V‐Val), BZLF1 promoter (Zp‐V3), RPMS1 and LMP1 had been proposed to be associated with NPC and other EBV‐associated malignancies, these studies were based on data derived from pre‐selected candidate genes and are prone to detect spurious association due to failure to adjust for the effects of population stratification . To illustrate this point, we analysed the association of these polymorphisms with NPC by chi‐square test in our case–control dataset without considering the population structure.…”

Section: Resultsmentioning

confidence: 99%

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

Hui

Chan

Yang

et al. 2019

Intl Journal of Cancer

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Whether certain variants of Epstein–Barr virus (EBV) are linked to the pathogenesis of nasopharyngeal carcinoma (NPC), which shows a marked geographic restriction, remains an unresolved issue. We performed a case–control study comparing genomic sequences of EBV isolated from saliva samples of 142 population carriers with those from primary tumour biopsies derived from 62 patients with NPC of Hong Kong. Cluster analysis discovered five EBV subgroups 1A‐C and 2A‐B amongst the population carriers in contrast to the predominance of 1A and ‐B in the majority of NPC. Genome‐wide association study (GWAS) identified a panel of NPC‐associated single nucleotide polymorphisms (SNPs) and indels in the EBER locus. The most significant polymorphism, which can be found in 96.8% NPC cases and 40.1% population carriers of Hong Kong, is a four‐base‐deletion polymorphism downstream of EBER2 (EBER‐del) from coordinates 7188–7191 (p = 1.91 × 10−7). In addition, the predicted secondary structure of EBER2 is altered with likely functional consequence in nearly all NPC cases. Using the SNPs and indels associated with NPC, genetic risk score is assigned for each EBV variant. EBV variants with high genetic risk score are found to be much more prevalent in Hong Kong Chinese than individuals of other geographic regions and in NPC than other EBV‐associated cancers. We conclude that high risk EBV variants with polymorphisms in the EBER locus, designated as HKNPC‐EBERvar, are strongly associated with NPC. Further investigation of the biological function and potential clinical application of these newly identified polymorphisms in NPC and other EBV‐associated cancers is warranted.

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Section: Resultsmentioning

confidence: 99%

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

Hui

Chan

Yang

et al. 2019

Intl Journal of Cancer

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“…EBV strains are classified as T1 or T2 according to differences in their EBNA2 and EBNA 3A/B/C latency gene sequences, while there is very little variation in most other EBV genes [21,22]. However, there are consistent differences in some of the EBV lytic genes including gp350 and gp42 [23,24]. T1 EBV infection is thought to be much more common than T2 EBV infection in western countries, and most EBV experimentation has been performed using T1 EBV strains [21,22].…”

Section: Introductionmentioning

confidence: 99%

B cells infected with Type 2 Epstein-Barr virus (EBV) have increased NFATc1/NFATc2 activity and enhanced lytic gene expression in comparison to Type 1 EBV infection

et al. 2020

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Humans are infected with two distinct strains (Type 1 (T1) and Type 2 (T2)) of Epstein-Barr virus (EBV) that differ substantially in their EBNA2 and EBNA 3A/B/C latency genes and the ability to transform B cells in vitro. While most T1 EBV strains contain the "prototype" form of the BZLF1 immediate-early promoter ("Zp-P"), all T2 strains contain the "Zp-V3" variant, which contains an NFAT binding motif and is activated much more strongly by B-cell receptor signalling. Whether B cells infected with T2 EBV are more lytic than cells infected with T1 EBV is unknown. Here we show that B cells infected with T2 EBV strains (AG876 and BL5) have much more lytic protein expression compared to B cells infected with T1 EBV strains (M81, Akata, and Mutu) in both a cord blood-humanized (CBH) mouse model and EBVtransformed lymphoblastoid cell lines (LCLs). Although T2 LCLs grow more slowly than T1 LCLs, both EBV types induce B-cell lymphomas in CBH mice. T1 EBV strains (M81 and Akata) containing Zp-V3 are less lytic than T2 EBV strains, suggesting that Zp-V3 is not sufficient to confer a lytic phenotype. Instead, we find that T2 LCLs express much higher levels of activated NFATc1 and NFATc2, and that cyclosporine (an NFAT inhibitor) and knockdown of NFATc2 attenuate constitutive lytic infection in T2 LCLs. Both NFATc1 and NFATc2 induce lytic EBV gene expression when combined with activated CAMKIV (which is activated by calcium signaling and activates MEF2D) in Burkitt Akata cells. Together, these results suggest that B cells infected with T2 EBV are more lytic due to increased activity of the cellular NFATc1/c2 transcription factors in addition to the universal presence of the Zp-V3 form of BZLF1 promoter.

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“…Correia et al recently refined the sequence variations of EBNA‐1 by identifying major patterns of polymorphisms in the N‐terminal part of EBNA‐1 . They noted that there is linkage in variations of the N‐ and C‐terminal of EBNA‐1.…”

Section: Discussionmentioning

confidence: 99%

Epstein‐Barr virus latent gene EBNA‐1 genetic diversity among transplant patients compared with patients with infectious mononucleosis

Sullivan

Isabel

Khodai‐Booran

et al. 2019

Clinical Transplantation

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Introduction As a step toward evaluating the association between Epstein‐Barr virus genetic diversity and post‐transplant lymphoproliferative disorder (PTLD), we conducted a preliminary study to compare the genetic diversity of the EBNA‐1 gene among transplant patients and patients with infectious mononucleosis (IM). Methods We sequenced the EBNA‐1 gene in blood samples from study subjects using Sanger methodology. The sequences were aligned with a reference strain and compared with publicly available sequences. Results We analyzed 33 study samples and 25 publicly available sequences along with the reference strain B95‐8. The evaluable samples were from sixteen patients with IM (median age 14.0 years, range 2‐24) and 17 transplant patients. There were six children without PTLD (median age 1.93 years, range 0.79‐7.46) and 11 who developed PTLD (median age 5.67 years, range 0.96‐17.45). A predominant EBNA‐1 variant (P‐thr) was identified across the study groups. Differences were observed between the samples from the IM patients compared with the transplant samples. Conclusion The predominant EBNA‐1 strain is in contrast to reports of the predominant strain in North America. The results suggest differences between the EBNA‐1 strains among the study groups. Further studies will examine the relationship between EBNA‐1 strains and PTLD occurrence and outcomes.

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Sequence Variation of Epstein-Barr Virus: Viral Types, Geography, Codon Usage, and Diseases

Cited by 81 publications

References 35 publications

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

B cells infected with Type 2 Epstein-Barr virus (EBV) have increased NFATc1/NFATc2 activity and enhanced lytic gene expression in comparison to Type 1 EBV infection

Epstein‐Barr virus latent gene EBNA‐1 genetic diversity among transplant patients compared with patients with infectious mononucleosis

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