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NPJ Genom Med. 2018 Sep 5;3:25. doi: 10.1038/s41525-018-0064-5. eCollection 2018.

HHV-6 encoded small non-coding RNAs define an intermediate and early stage in viral reactivation.

Author information

1Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany.
Present Address: Institute for Virology and Immunobiology, Versbacher Str. 7, 97078 Würzburg, Germany.
2CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
3Microsynth AG, Balgach, Switzerland.
4Department of Dermatology, Bichat Hospital, APHP, Paris 7 University, Paris, France.
Helmholtz Institute for RNA-based Infection Research (HIRI), Würzburg, Germany.


Human herpesvirus 6A and 6B frequently acquires latency. HHV-6 activation has been associated with various human diseases. Germ line inheritance of chromosomally integrated HHV-6 makes viral DNA-based analysis difficult for determination of early stages of viral activation. We characterized early stages of HHV-6 activation using high throughput transcriptomics studies and applied the results to understand virus activation under clinical conditions. Using a latent HHV-6A cell culture model in U2OS cells, we identified an early stage of viral reactivation, which we define as transactivation that is marked by transcription of several viral small non-coding RNAs (sncRNAs) in the absence of detectable increase in viral replication and proteome. Using deep sequencing approaches, we detected previously known as well as a new viral sncRNAs that characterized viral transactivation and differentiated it from latency. Here we show changes in human transcriptome upon viral transactivation that reflect multiple alterations in mitochondria-associated pathways, which was supported by observation of increased mitochondrial fragmentation in virus reactivated cells. Furthermore, we present here a unique clinical case of DIHS/DRESS associated death where HHV-6 sncRNA-U14 was abundantly detected throughout the body of the patient in the presence of low viral DNA. In this study, we have identified a unique and early stage of viral activation that is characterized by abundant transcription of viral sncRNAs, which can serve as an ideal biomarker under clinical conditions.

Conflict of interest statement

The authors declare no competing interests.

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