Chromosomally integrated HHV-6 individuals are usually asymptomatic, and the integrated virus is assumed to be latent in most cases. However, Chromosomally integrated virus can replicate when exposed to certain drugs in vitro (Arbuckle 2010). Although less than 1% of the population carries this integrated virus, the condition is far more prevalent among patients (2%) and a prevalence of 3.3% was reported in children suspected of encephalitis (Pellett 2011). Several case reports have shown that ciHHV-6 patients with encephalitis respond to antivirals (Troy 2007, Wittekindt 2009, Kobayashi 2011) and two ciHHV-6 siblings with cognitive dysfunction were successfully treated with antiviral therapy (Montoya 2012). It is not known if the integrated virus is activating in these cases or if ciHHV-6 individuals are unable to control replication of other strains — or both. One indication that the integrated genome does activate and create infectious virus comes from a study that demonstrated the ability of ciHHV-6+ mothers to infect their non-ciHHV-6 children through the placenta (Hall 2010, Gravel 2013).
Marek’s Disease Virus, a herpesvirus associated with lymphoma and immunosuppression in chickens, is also known to undergo integration into the chromosomes, and has been shown to reactivate from its integrated state via unknown mechanisms (Delecluse 1993). It is also possible that chromosomally-integrated virus could cause pathological problems without replication, due to cytokines produced in response to abortive infection (an infection in which some viral components are synthesized and present in the body, but no fully infective virus is actually produced and actively replicating). The site of integration within the chromosomal telomeres may also influence pathology.
Drugs used to reactivate ciHHV-6 in vitro included an HDAC inhibitor called Trichostatin A, and hydrocortisone. HHV-6 reactivates in most cases of drug induced hypersensitivity syndrome (DIHS) (Tohyama 2007), so ciHHV-6 patients may want to exercise caution in using HDAC inhibitors or drugs known to reactivate HHV-6. Drugs commonly associated with HHV-6 reactivation in DIHS include allopurinol, carbamazepine, sulfasalazine, phenytoin and minocycline. (See HHV-6 & DIHS/DRESS for more details.)
Although there are specialized tests (such as HHV-6 messenger RNA testing) that can differentiate active from inactive HHV-6 infections in ciHHV-6 patients, these assays are not available in most commercial laboratories so physicians must use clinical judgment to decide whether symptomatic ciHHV-6 patients should be treated with antivirals. In the USA Coppe Labs now has a mRNA test for HHV-6 that can be used by physicians to determine if their ciHHV-6 patients have active virus. In Europe, IDKT in Germany has offers a mRNA test for HHV-6. Coppe also offers hair follicle testing to confirm suspected ciHHV-6 status.
Alternate causes of symptoms consistent with active HHV-6 infection must first be ruled out to ensure that a ciHHV-6 individual is not unnecessarily treated with the potentially toxic antivirals generally administered to treat active HHV-6 infection. If reactivated ciHHV-6 is determined, the same drugs that effectively treat active HHV-6 infection should also be effective in treating HHV-6 symptoms caused by the reactivation of ciHHV-6. Visit the CIHHV-6 Testing page to learn more.