Investigating the Consequences of Herpesvirus Integration into Host Telomeres

The two species of human herpesvirus 6 (HHV-6A and HHV-6B) and chicken Marek's disease virus (MDV) include sequences homologous to (TTAGGG)n within their genomes and have the capacity to integrate into telomeres in their hosts. As a result of historic germline integrations into telomeres, approximately 1% of the human population carry an inherited, chromosomally integrated copy of HHV-6 in every cell (iciHHV-6). The iciHHV-6 genome can be partially or completely released from its integrated state and we have previously proposed that this is achieved via a t-loop mediated mechanism. Single TElomere Length Analysis (STELA) and long range PCRs were used to explore the relationship between these integrated viruses and the host telomere.

Here, it was shown that spontaneous truncation of the integrated HHV-6 genome leads to the formation of a novel telomere at one of two telomere repeat containing positions within the HHV-6 genome. The short novel telomere or the presence of telomere-like repeats in the novel telomere may have the potential to trigger a DNA damage response and cellular senescence. These events were detected in vivo and in vitro, therefore carriers of iciHHV-6 may experience greater genome instability than individuals without iciHHV-6. Detection of these truncation events in sperm suggest than genome instability in the germline explains of how iciHHV-6-DR-only carriers have arisen and work on the iciHHV-6 integration site provide strong evidence that this is exactly what has happened. HHV-6B contains a highly variable region (pvT1) that was revealed to be unique in 87% of HHV-6B carriers, rising to 100% in unrelated carriers of noninherited HHV-6B. pvT1 has been used to monitor transmission of HHV-6B within families, supporting the idea that non-inherited HHV-6 is usually transmitted within families. pvT1 was also used to ?nd evidence that iciHHV-6 can reactivate and be transmitted. The ?rst demonstration that de novo HHV-6 integrations occur in saliva from healthy donors who have non-inherited HHV-6. This is strong supporting evidence that HHV-6 becomes latent by integrating into telomeres.

In this study, the telomere associated with integrated MDV was shown to form in a speci?c region of telomere repeats in MDV. The relative orientations of the MDV genome regions were also investigated and it was discovered that the MDV genome consistently integrates in the same orientation. Finally, a model of MDV integration and release as a precursor to MDV reactivation was proposed.