Abstract
Approximately, 1% of human population possesses a copy of human herpesvirus 6A and 6B (HHV-6A/B) in the genome. This viral element is referred to as inherited chromosomally integrated HHV-6A/B (iciHHV-6A/B) and is encoded in all of their cells. A recent study revealed that iciHHV-6A/B potentially increases the immune responses against HHV-6. However, it remains unclear whether iciHHV-6A/B affects human gene expression. Here, we perform global transcriptome analysis using the datasets obtained from various human tissues. We detected two and four individuals positive for iciHHV-6A and iciHHV-6B, respectively, and revealed that the transcriptional expression of iciHHV-6A/B was sporadic in the human body. Transcriptome analysis identified the human genes differentially expressed between iciHHV-6A/B-positive and -negative individuals. Particularly, the expression of some genes encoding immunoglobulins decreased in sigmoid colon of iciHHV-6A/B-positive individuals. Our findings suggest that iciHHV-6A/B may be associated with human health maintenance.
References
Daibata M, Taguchi T, Sawada T, Taguchi H, Miyoshi I (1998) Chromosomal transmission of human herpesvirus 6 DNA in acute lymphoblastic leukaemia. Lancet 352:543–544
Liu S, Huang S, Chen F, Zhao L, Yuan Y, Francis SS et al (2018) Genomic analyses from non-invasive prenatal testing reveal genetic associations, patterns of viral infections, and Chinese population history. Cell 175(347–359):e314
Peddu V, Dubuc I, Gravel A, Xie H, Huang ML, Tenenbaum D et al (2019) Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expression in vivo that correlates with increased antibody immune response. J Virol. https://doi.org/10.1128/JVI.01418-19
Yamanishi K, Mori Y, Pellett PE (2013) Human herpesviruses 6 and 7. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams & Wilkins, Philadelphia, pp 2058–2079
Sharon E, Volchek L, Frenkel N (2014) Human herpesvirus 6 (HHV-6) alters E2F1/Rb pathways and utilizes the E2F1 transcription factor to express viral genes. Proc Natl Acad Sci USA 111:451–456
Tomoiu A, Gravel A, Flamand L (2006) Mapping of human herpesvirus 6 immediate-early 2 protein transactivation domains. Virology 354:91–102
Doniger J, Muralidhar S, Rosenthal LJ (1999) Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate. Clin Microbiol Rev 12:367–382
GTEx Consortium (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580–585
Camacho C, Coulouris G, Avagyan V, Ma N, Papadopoulos J, Bealer K et al (2009) BLAST+: architecture and applications. BMC Bioinform 10:421
Moustafa A, Xie C, Kirkness E, Biggs W, Wong E, Turpaz Y et al (2017) The blood DNA virome in 8,000 humans. PLoS Pathog 13:e1006292
Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21
Frankish A, Diekhans M, Ferreira AM, Johnson R, Jungreis I, Loveland J et al (2019) GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res 47:D766–D773
Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550
Dagna L, Pritchett JC, Lusso P (2013) Immunomodulation and immunosuppression by human herpesvirus 6A and 6B. Future Virol 8:273–287
Lusso P (2006) HHV-6 and the immune system: mechanisms of immunomodulation and viral escape. J Clin Virol 37(Suppl 1):S4–10
Kano Y, Inaoka M, Shiohara T (2004) Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia. Arch Dermatol 140:183–188
Nikolaou K, Varinou L, Inoue N, Arsenakis M (2003) Identification and characterization of gene products of ORF U90/89 of human herpesvirus 6. Acta Virol 47:17–26
Acknowledgments
We would like to thank Mai Suganami (Division of Systems Virology, Institute of Medical Science, the University of Tokyo, Japan) for technical support. The super-computing resource, SHIROKANE, was provided by Human Genome Center, The Institute of Medical Science, the University of Tokyo, Japan. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.
Funding
This study was supported in part by JST CREST (to KS) including AIP challenge program (to RK); AMED J-PRIDE JP19fm0208006 (to KS); AMED Research Program on HIV/AIDS JP19fk0410014 (to KS) and JP19fk0410019 (to KS); JSPS Scientific Research B JP18H02662 (to KS), Scientific Research on Innovative Areas JP16H06429 (to KS), JP16K21723 (to KS), JP17H05813 (to KS), and JP19H04826 (to KS), Fund for the Promotion of Joint International Research (Fostering Joint International Research) JP18KK0447 (to KS); JSPS Research Fellow PD JP19J01713 (to JI); Ichiro Kanehara Foundation (to KS); Lotte Foundation (to KS); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to KS); Sumitomo Foundation (to KS).
Author information
Authors and Affiliations
Contributions
All authors conceived and designed the study, and wrote the paper. RK and JI performed bioinformatic analysis.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The utilization of the GTEx dataset was authorized through the Database of Genotypes and Phenotypes (dbGaP; https://dbgap.ncbi.nlm.nih.gov) for the following project: “Screening of subclinical viral infections in healthy human tissues (#19481)”.
Additional information
Edited by Hartmut Hengel.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Kumata, R., Ito, J. & Sato, K. Inherited chromosomally integrated HHV-6 possibly modulates human gene expression. Virus Genes 56, 386–389 (2020). https://doi.org/10.1007/s11262-020-01745-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11262-020-01745-5