Garber Lab Publications

UMMS Affiliation

Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology; Department of Pathology; Garber Lab; Program in Bioinformatics and Integrative Biology

Publication Date

2018-01-02

Document Type

Article

Disciplines

Bioinformatics | Computational Biology | Genomics | Hemic and Lymphatic Diseases | Immunology of Infectious Disease | Integrative Biology | Molecular Biology | Virology | Virus Diseases | Viruses

Abstract

Over 90% of the world's population is persistently infected with Epstein-Barr virus. While EBV does not cause disease in most individuals, it is the common cause of acute infectious mononucleosis (AIM) and has been associated with several cancers and autoimmune diseases, highlighting a need for a preventive vaccine. At present, very few primary, circulating EBV genomes have been sequenced directly from infected individuals. While low levels of diversity and low viral evolution rates have been predicted for double-stranded DNA (dsDNA) viruses, recent studies have demonstrated appreciable diversity in common dsDNA pathogens (e.g., cytomegalovirus). Here, we report 40 full-length EBV genome sequences obtained from matched oral wash and B cell fractions from a cohort of 10 AIM patients. Both intra- and interpatient diversity were observed across the length of the entire viral genome. Diversity was most pronounced in viral genes required for establishing latent infection and persistence, with appreciable levels of diversity also detected in structural genes, including envelope glycoproteins. Interestingly, intrapatient diversity declined significantly over time (P < 0.01), and this was particularly evident on comparison of viral genomes sequenced from B cell fractions in early primary infection and convalescence (P < 0.001). B cell-associated viral genomes were observed to converge, becoming nearly identical to the B95.8 reference genome over time (Spearman rank-order correlation test; r = -0.5589, P = 0.0264). The reduction in diversity was most marked in the EBV latency genes. In summary, our data suggest independent convergence of diverse viral genome sequences toward a reference-like strain within a relatively short period following primary EBV infection.

IMPORTANCE Identification of viral proteins with low variability and high immunogenicity is important for the development of a protective vaccine. Knowledge of genome diversity within circulating viral populations is a key step in this process, as is the expansion of intrahost genomic variation during infection. We report full-length EBV genomes sequenced from the blood and oral wash of 10 individuals early in primary infection and during convalescence. Our data demonstrate considerable diversity within the pool of circulating EBV strains, as well as within individual patients. Overall viral diversity decreased from early to persistent infection, particularly in latently infected B cells, which serve as the viral reservoir. Reduction in B cell-associated viral genome diversity coincided with a convergence toward a reference-like EBV genotype. Greater convergence positively correlated with time after infection, suggesting that the reference-like genome is the result of selection.

Keywords

DNA sequencing, EBV, Epstein-Barr virus, genome analysis, phylogenetic analysis, viral diversity

Rights and Permissions

Copyright © 2018, American Society for Microbiology. Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.

DOI of Published Version

10.1128/JVI.01466-17

Source

J Virol. 2018 Jan 2;92(2). pii: e01466-17. doi: 10.1128/JVI.01466-17. Print 2018 Jan 15. Link to article on publisher's site

Journal/Book/Conference Title

Journal of virology

Related Resources

Link to Article in PubMed

PubMed ID

29093087

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