EBV infected B cells may represent a site of HHV-6 latency.
A team from Stanford University analyzed whole genome sequencing (WGS) results from over 4500 individuals in over 1000 families affected by autism, known as the iHART dataset. The majority of samples came from EBV-immortalized lymphoblastoid cell lines (LCLs). The WGS had been performed primarily to evaluate human genes, but this Stanford study looked for sequences from exogenous DNA viruses as well as viral sequences integrated into the host genome—non-human sequences that may not have been recognized when the WGS studies were first conducted.
The investigators report finding iciHHV-6 in about 0.6% of the individuals studied, a population prevalence similar to the prevalence of 0.8 to 1% reported in the US and Europe (Peddu 2019). They found no instance of iciHHV-7 although one family has been previously reported (Prusty 2017). No examples were identified of the extremely rare cases of iciHHV-6 at two integration sites (e.g., one inherited from each parent). The team also confirmed previous reports indicating that the full viral genome, rather than fragments of the genome, is integrated into the host genome in most instances of iciHHV-6.
They also found extremely high viral loads of exogenous (not inherited) HHV-6A and HHV-6B sequences in some LCL samples. The authors propose that the process of immortalizing these cell lines (typically by Epstein-Barr virus infection) may have made the telomeres more conducive to viral integration.
The authors infected immortalized LCLs with HHV-6A, HHV-6B and HHV-7. The cells were easily infected. Previous studies have shown that HHV-6A/B can integrate into most cell lines, including both telomerase positive (HeLA, MCF-7, HCT-116) and telomerase negative cell lines (Gravel 2017). HHV-6A/B integrated into the host telomere, and did not reactivate frequently.
In contrast, when the authors infected LCLs with HHV-7, the viral genome integrated into the host telomere, and then reactivated. The authors speculate that, despite temporarily integrating into the host telomere, that HHV-7 achieves latency by forming an episome, as commonly occurs with other herpesviruses.
Finally, although HHV-6A/B preferentially infects CD4+ T cells in vitro, the authors raise the possibility that B cells may be one site of latency for HHV-6A/B, based on their studies of lymphoblastoid cell lines. While interesting, the main question about the analysis of in vitro studies on lymphoblastoid cell lines is whether they apply to what occurs in vivo.
Read full article: Chrisman 2022