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  1. eLife

    Evaluation Summary:

    Human Herpesvirus 6A (HHV6A) and 6B are common herpesviruses that establish lifelong infection in latent form and can cause severe disease upon reactivation. They are spread by acquired infection of free virus and by germ-line transmission of inherited chromosomally-integrated HHV-6A/6B in telomeres. The authors develop an approach to analyse a hypervariable region of the HHV-6B genome and exploit it to investigate the relationship between acquired and inherited virus, presenting evidence that HHV-6B can readily transition between telomere-integrated and free virus forms.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  2. eLife

    Reviewer #1 (Public Review):

    In this manuscript, the authors used a very innovative approach to address crucial questions in HHV-6 biology. The hypervariable regions within the DR shed light on exciting aspects including virus transmission, phylogeny and the prediction of integration sites in iciHHV-6 individuals. The authors provide a tremendous amount of data and carefully interpreted these in the context of HHV-6 biology. Their analysis was done on a pretty sizeable data set, which included a large number of families and provided important insights, including the observation that a mother with iciHHV-6 can horizontally transmit her inherited virus to her non-iciHHV-6 son. The sequence analyses are complemented with several state-of-the-art STELA assays that demonstrated that a single DR as well as a complete DR-U genome can be excises from the telomere integrated state. In addition, another STELA approach allowed the identification of integrated virus genomes in non-iciHHV-6 genomes that should be also used in follow up studies. Overall, this manuscript is very well written (despite the huge amount of complex data), the conclusions are justified and it addressed critical question in the field. Only minor changes should be made prior to publication as outlined below.

  3. eLife

    Reviewer #2 (Public Review):

    Wood et al. use amplicon sequencing of a highly variable (DRR-pvT1) regions in the HHV-6A/6B genome to track transmission chains of inherited and acquired HHV-6. The authors sequenced the DRR-pvT1 regions from 102 cases and demonstrate the variability of the HHV-6B DRR-pvT1 between unrelated cases and within related groups. Based on similarity between sequenced iciHHV-6B DRR-pvT1 regions to those of genomes with a previously determined integration site, they predicted the integration sites of iciHHV-6B genomes, and some were confirmed by subtelomere-iciHHV-6B junction sequencing. Variability in DRR-pvT1 is also used to discuss within family inheritance patterns, and demonstrate passing of a reactivated ici-HHV6B genome from mother to son as an acquired infection.

    In addition, using PCR based methods, the authors estimate the rate of telomere integration in-vivo (saliva and kidney samples). Next, they study the phenomenon of partial iciHHV-6B excision and telomere truncation that occurs through strand invasion of the telomer 3' overhang into the DR region forming a t-loop that can is excised out. Using PCR with specific primers, the authors estimate the rate of excision and subsequent telomere lengthening in different samples.

  4. eLife

    Reviewer #3 (Public Review):

    Overall, this is an impressive, tour-de-force study on HHV6 genetics, telomere integration, reactivation, and transmission. There are some minor concerns with the PCR methods of detection and the limited functional analysis with respect to viral latency, reactivation, and transmission.

  5. Version 1 published on bioRxiv