Investigators led by Nicola Royle, PhD of the University of Leicester, used molecular dating methods to determine that most strains of inherited chromosomally integrated HHV-6 (iciHHV-6) come from a small number of human ancestors. These ancient strains vary considerably from modern, non-inherited strains, vary by region, and appear just as likely to activate as their more modern cousins, creating important considerations for immunocompromised patients.
While smaller studies have recently reported common ancestry in iciHHV-6 strains from distinct geographical regions such as Japan (Kawamura 2017) and central Europe (Tweedy 2016), the present study provides full-sequence analysis of 28 distinct iciHHV-6 genomes. Approximately 1% of the worldwide population (~70 million people) has inherited ciHHV-6.
While the present study demonstrates that iciHHV-6 genomes are significantly divergent from modern HHV-6 genomes obtained from non-iciHHV-6 individuals, the study also shows ciHHV-6B genomes in Europeans are more closely related to each other than to iciHHV-6B genomes from China and Pakistan, suggesting regional variation. At least one group of European iciHHV-6B carriers appears to have inherited the same iciHHV-6B genome, integrated in the same telomeric allele, from a common ancestor estimated by the study’s authors to have existed 24,500 ±10,600 years ago.
The authors report that despite the antiquity of these strains, the majority of iciHHV-6B (95%) and ciHHV-6A (72%) genomes were found to contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation. This is consistent with past studies which have demonstrated evidence of both in-vitro and in-vivo lytic viral reactivation (Arbuckle 2010, Endo 2014) and gene transcription (Arbuckle 2010, Strenger 2014) from the iciHHV-6A/B reservoir.
Virus reactivation in iciHHV-6 individuals (and subsequent clinical sequelae) is an emerging field with many recent papers helping to clarify the clinical implications of iciHHV-6 status.
The presence of iciHHV-6 in either recipient or donor presents unique challenges in correctly differentiating clinically significant HHV-6 reactivation from baseline iciHHV-6 in the transplant setting. One recent study of over 4,000 HCT donor-recipient pairs demonstrated that acute graft-versus-host disease (GVHD) was significantly more frequent when recipient or donor had iciHHV-6, while CMV viremia was more frequent when recipients – but not donors – were iciHHV-6 positive (Hill 2017).
Another recent case, in which recurrent HHV-6 myocarditis was described in an immunocompromised iciHHV-6 patient, has reiterated the possibility of end-organ disease in iciHHV-6 individuals who may become immunocompromised (Nguyen 2017). In this instance, reverse transcription PCR was utilized to identify viral mRNA in tissues in order to clearly distinguish localized areas of active HHV-6 infection from underlying iciHHV-6. These cases highlight the analytical complexity inherent in the diagnosis of HHV-6 disease in individuals with iciHHV-6.
Read the full paper: Zhang 2017