Large scale sequencing effort of HHV-6B defines global diversity, finds new genes, and identifies changes due to viral culture

A gigantic sequencing effort by investigators at University of Washington has provided a wealth of new information about the HHV-6B genome, including important flaws of the reference strains currently in use.

Alexander Greninger, MD, PhD, of University of Washington, Department of Laboratory Medicine

Until recently, only two HHV-6B genome sequences of circulating viruses were available. The UW team led by Alexander Greninger and Keith Jerome sequenced an astonishing 125 isolates including 64 inherited chromosomally integrated strains and 61 community isolates from New York, Japan and Africa. They also reannotated more than 10% of the genome using comparative genomics, transcriptomics, and proteomics, providing valuable data for future studies of molecular mechanisms and viral pathogenesis.

The authors conclude from their analysis that the origin of the inherited chromosomally integrated strains are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection, with a large “founder effect”. The study was published in BMC Genomics: “Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6”.

In a second publication, Greninger and colleagues analyzed cultured reference strains for both HHV-6A and HHV-6B and found that these adapted strains have developed genomic alterations, most likely due to the culture process.  The team found large, heterogeneous tandem repeats associated with the origin of replication present in HHV-6A strains that were originally found in HHV-6B Z29 by Philip Pellett and colleagues in 1995. Other reference strains had regions with large tandem duplications and deletions, whereas isolates from labs with fewer passages did not contain these inconsistencies.

The UW team also reported the first interspecies recombination between HHV-6A and HHV-6B, something not previously seen in a betaherpesvirus. Their second paper was published in Journal of Virology: “Copy number heterogeneity, large origin tandem repeats, and interspecies recombination in HHV-6A and HHV-6B reference strains”.