Investigators in the UK led by geneticist Nicola Royle at University of Leicester have reported that individuals with inherited HHV-6 (slightly less than 1% of the population) may be at risk for viral reactivation from a virus they inherited from a parent. These individuals have a copy of the viral genome integrated into the chromosome of every cell. This phenomenon of integrated HHV-6 was first reported in 1993 (Luppi et al) but was not studied extensively until ten years ago. Initially believed to be a benign condition, recent reports have suggested that those with the condition may be more likely to reactivate with HHV-6, with adverse clinical consequences.
The British team showed that the telomere (part of the chromosome) with integrated virus tends to be unstable and often shorter than other telomeres in these individuals, increasing the likelihood of chromosomal instability. To their surprise, the team detected extra-chromosomal viral DNA and occasionally circular molecules of HHV-6 that appear to be fully functional, indicating that the viral genome had become excised from the telomere. This may represent the first step towards viral reactivation.
The authors point out that their research may have important implications for transplantations involving organs with the inherited form of HHV-6. Transplant patients undergo immunosuppression and are at greater risk for viral reactivation. Although larger studies are needed, a Mayo clinic study of seven ciHHV-6 liver transplant recipients found that they had a higher rate of allograft rejection and bacterial infection than 506 patients without ciHHV-6 (Lee 2011). Also, several case reports have suggested that immunocompetent ciHHV-6 individuals may have difficulty controlling HHV-6 reactivation (Troy 2008, Montoya 2012), perhaps due to tolerance (Pantry 2013).
Another unresolved question is whether the integrated virus in these individuals can be activated by HDAC inhibitors or by severe allergic reactions. HDACi drugs can reactivate latent virus HHV-6 (Arbuckle 2010) and HHV-6 viremia occurs in over 85% of severe hypersensitivity reactions (Pritchett 2013) for reasons that are not completely understood.
Currently, transplant centers do not routinely test for integrated or reactivated HHV-6, although the practice is becoming more common with cord blood transplant centers. A recent meta-analysis showed that approximately 8% of cord blood transplant patients develop HHV-6B limbic encephalitis following reactivation (Scheurer 2012).
The authors conclude that their data is consistent with the idea that telomeric integration may be a form of HHV-6 latency, as first suggested by University of South Florida’s Peter Medveczky (Arbuckle 2010). HHV-6A and HHV-6B appear to be the only human herpesviruses that may enter into latency by integrating into the telomere. Marek’s Disease virus, a herpesvirus that causes tumors in chickens, also integrates into the telomere.
The study was done at University of Leicester, which is well-known for important work in genetics. See the full text of the paper here. We asked Dr. Royle a few questions about her work, see the full conversation below.
Interview with Nicola Royle, PhD
Q: How did you become interested in integrated HHV-6?
A: My interest in ciHHV-6 arose from a chance conversation with Professor Martin Dyer, clinical oncologist at the University of Leicester, who had treated a patient who was also a ciHHV-6 carrier. The conversation immediately sparked my interest as I have always been fascinated by the important roles that telomeres play in stabilizing chromosomes and the genome and so our collaboration began. The basic biological questions that arose in my mind were: what is the virus doing in the telomere and does it affect how the telomere functions?
Q: What work do you plan in the future?
A: We have shown that the presence of the viral genome makes the telomere less stable and that the entire viral genome can escape from the chromosome in cell lines from ciHHV-6 carriers. We propose that the viral genome escapes from the telomere by using processes that are a normal part of telomere biology. We want to know how often the viral genome gets released from the telomere, what regulates this process for example, does telomere shortening due to age influence the frequency of HHV-6 release from the chromosome. In addition what effect does this release (of part or the entire viral genome) have on the cell? We also want to know whether HHV-6 integration occurs in non-ciHHV-6 carriers after primary infection.
Q: What is the significance of the findings for individuals with ciHHV-6?
A: This is a difficult question to answer at the moment and is mere speculation as it depends on how often the effects we have seen in cell lines from carriers occur in vivo. Clearly though, there are two possible routes that might impact on individuals who are ciHHV-6 carriers:
- Release of the viral genome in a circular form, with a single reconstituted direct repeat region, may facilitate occasional viral reactivation.
- In cell lines we have found that viral genome has a destabilizing effect on the telomere that carries it and this can result in the formation of a very short telomere. It is known that short telomeres signal DNA damage and that this can lead to the onset of cellular senescence. Senescent cells are no longer able to divide and accumulate in tissues as we age. If the telomere effects seen in ciHHV-6 cell lines are replicated in vivo then we could predict a long-term effect on tissue homeostasis that may be variable between tissues and individuals.