In analyzing 8 individuals and two parents with inherited chromosomally integrated HHV-6 (iciHHV-6), a team in Japan has taken steps to determine the origin of viral integration. All of the individuals were found to have HHV-6A (6 patients) or HHV-6B (2 patients) integrated into the telomeric region of chromosome 22, a common site of integration. By DNA profiling using microsatellite markers and telomeric repeat sequences, the investigators concluded that an early integration event likely occurred in a common ancestor.
The 8 Japanese patients in the study were recruited for genotypic evaluation after iciHHV-6 status was confirmed. HHV-6 was first detected in these patients following evaluation for causative agents in a variety of clinical diseases. While much remains unknown about the clinical manifestations of iciHHV-6 reactivation, reactivation has been reported in iciHHV-6 patients with encephalitis (Wittekindt 2009, Troy 2008), cognitive dysfunction, and fatigue (Montoya 2012), and iciHHV-6 positivity has been associated with cardiac complications (Kühl 2014, Gravel 2015) as well as an increased risk of GVHD in transplant patients. Notably, iciHHV-6A has traditionally been more strongly linked to malignancy and inflammatory diseases, while iciHHV-6B has been tied to heart problems (Tweedy 2015). The integrated virus has also been shown to reactivate in response to immunosuppression, certain drugs, and during pregnancy (Gravel 2013).
In the Japanese cohort, six cases were iciHHV-6A+ while 2 were iciHHV-6B+, but the virus was integrated into chromosome 22 in all cases, as confirmed by FISH. The investigators focused on 5 specific microsatellite markers on chromosome 22q13.33 and telomeric repeat sequences in the viral genome. As microsatellites are repetitive DNA sequences with a high mutation rate, observing similarity in these sequences can indicate a “founder effect,” which occurs when loss of genetic variation arises in the descendants of a very small number of individuals. Two patients, one with iciHHV-6A, the other with iciHHV-6B, each had a parent available for testing. The team began by confirming, in both cases, that the parent and child had identical microsatellite haplotypes on one allele, as well as the same number of viral telomeric repeat sequences.
Upon analysis of the two iciHHV-6B+ patients in the cohort, the authors found that the telomeric repeat sequences and the PCR product sizes of the microsatellites differed. In light of this, it was unclear whether the founder effect was at play. IciHHV-6A+ patients, however, painted a different picture; 4 individuals- plus the single iciHHV-6A+ parent- had the same 5 microsatellite haplotypes on one allele, and the other two individuals shared 3-4 microsatellite haplotypes with the others. Two pairs of patients had the same number of HHV-6A telomeric repeats- 14 and 16- and the remaining two individuals had unmatched numbers. The investigators concluded that the data supports the existence of a founder effect for iciHHV-6A on chromosome 22. Prior work from Tweedy et al. indicated that there is likely also a common ancestral origin and founder effect in a cohort of central Europeans with iciHHV-6A integration on the chromosome 17 subtelomere (Tweedy 2016).
In order to further clarify the origins of inherited ciHHV-6, the authors propose an international collaboration for a more expansive analysis.
Read the full paper here: Kawamura 2017.