Human Herpesvirus 6 (HHV-6) comprises two closely related betaherpesviruses (genus Betaherpesvirus) called HHV-6A and HHV-6B. Like other herpesviruses, HHV-6 establishes persistent, chronic infections. Infection is usually latent, but reactivation can sometimes occur and may lead to disease symptoms.

HHV6-related images

Human herpesviruses. Left to right: (i) Paired chromosomes, with telomeric regions indicated in green: uniquely among human herpesviruses, HHV-6A and HHV-6B can establish life-long latency via integration into the subtelomeric regions of human chromosomes; (ii) Cryo-EM structure of a human herpesvirus capsid (HHV2); (iii) Histological slide showing HHV6 infected cells, with inclusion bodies in both the nucleus and the cytoplasm. (iv) HHV-6 reactivation is relatively common during pregnancy, and in approximately 1% of pregnancies HHV-6 may be transferred to the fetus.

HHV6 was first identified in 1986. Many aspects of its biology and its impact on human health remain to be understood. Remarkably, around 1-2% of people carry HHV6-derived sequences in their chomosomal DNA as alleles. These 'chromosomally-integrated HHV6 (ciHHV6)' sequences derive from HHV6 infections that led to viral genomes becoming integrated into the germline of ancestral humans. Recent studies show that chromosomally integrated HHV-6 can excise from chromosomes and activate under certain circumstances (e.g. immune deficiency, following transplantation).

"Except in acute or initial infections, the viral DNA can typically be found only by biopsy, as it does not circulate in peripheral blood. There is an urgent need for new technologies to detect these occult infections that are not apparent by standard quantitative PCR DNA testing methods, in order to prove or disprove the important disease associations that have been suggested." -- HHV6 Foundation

What is a GLUE project?

GLUE is an open, integrated software toolkit that provides functionality for storage and interpretation of sequence data.

GLUE supports the development of “projects” containing the data items required for comparative genomic analysis (e.g. sequences, multiple sequence alignments, genome feature annotations, and other sequence-associated data).

Projects are loaded into the GLUE "engine", creating a relational database that represents the semantic relationships between data items. This provides a robust foundation for the implementation of systematic comparative analyses and the development of sequence-based resources.

The core schema of this database can be extended to accommodate the idiosyncrasies of different projects, and GLUE provides a scripting layer (based on JavaScript) for developing custom analysis tools.

Hosting of GLUE projects in an online version control system (e.g. GitHub) provides a mechanism for their stable, collaborative development.

Some examples of 'sequence-based resources' built for viruses using GLUE include:

What does building the HHV6-GLUE project offer?

HHV6-GLUE offers a number of advantages for performing comparative sequence analysis of HHV6A and HHV6B:

  1. Reproducibility. For many reasons, bioinformatics analyses are notoriously difficult to reproduce. The GLUE framework supports the implementation of fully reproducible comparative genomics through the introduction of data standards and the use of a relational database to capture the semantic links between data items.

  2. Reusable data objects and analysis logic. For many - if not most - comparative genomic analyses, data preparation is nine tenths of the battle. The GLUE framework has been designed to ensure that work spent preparing high-value data items such as multiple sequence alignments need only be performed once. Hosting of GLUE projects in an online version control system such as GitHub allows for collaborative management of important data items and community testing of hypotheses.

  3. Validation. Building GLUE projects entails mapping the semantic links between data items (e.g. sequences, tabular data, multiple sequence alignments). This process provides an opportunity for cross-validation, and thereby enforces a high level of data integrity.

  4. Standardisation of the genomic co-ordinate space. GLUE projects allow all sequences to utilise the coordinate space of a chosen reference sequence. Contingencies associated with insertions and deletions (indels) are handled in a systematic way.

  5. Predefined, fully annotated reference sequences: This project includes fully-annotated reference sequences for major lineages within the Hepadnaviridae family.

  6. Alignment trees: GLUE allows linking of alignments constructed at distinct taxonomic levels via an ""alignment tree" data structure. In the alignment tree, each alignment is constrained to a standard reference sequence, thus all multiple sequence alignments are linked to one another via a standardised coordinate system.

Related Publications

Aswad A, Aimola G, Wight D, Roychoudhury P, Zimmermann C, Hill J, Lassner D, Xie H, Huang ML, Parrish NF, Schultheiss HP, Venturini C, Lager S, Smith GCS, Charnock-Jones DS, Breuer J, Greninger AL, and BB Kaufer. (2021)
Evolutionary History of Endogenous Human Herpesvirus 6 Reflects Human Migration out of Africa.
BMC Mol Biol Evol. [view]

Liu X, Kosugi S, Koide R, Kawamura Y, Ito J, Miura H, Matoba N, Matsuzaki M, Fujita M, Kamada AJ, Nakagawa H, Tamiya G, Matsuda K, Murakami Y, Kubo M, Aswad A, Sato K, Momozawa Y, Ohashi J, Terao C, Yoshikawa T, Parrish NF, and Y Kamatani. (2020)
Endogenization and excision of human herpesvirus 6 in human genomes.
PLoS Genet. [view]

Singer JB, Thomson EC, McLauchlan J, Hughes J, and RJ Gifford (2018)
GLUE: A flexible software system for virus sequence data.
BMC Bioinformatics [view]

Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S, DiLuca D, Flamand L, Frenkel N, Gallo R, Gompels UA, Höllsberg P, Jacobson S, Luppi M, Lusso P, Malnati M, Medveczky P, Mori Y, Pellett PE, Pritchett JC, Yamanishi K, and T Yoshikawa. (2014)
Classification of HHV-6A and HHV-6B as distinct viruses.
Arch Virol. [view]

Katzourakis A. and RJ. Gifford (2010)
Endogenous viral elements in animal genomes.
PLoS Genetics [view]


Robert J. Gifford (


This project is licensed under the GNU Affero General Public License v. 3.0.