| “Chromosomally integrated HHV-6” (CIHHV-6) is an inherited condition in which the complete HHV-6 virus is integrated into the telomere of every chromosome. The condition affects around 1% of the population in the US and UK, and about .2% of the population in Japan[i] [ii]. Integrated HHV-6 can be inherited from either parent, so families with one carrier (father or mother) have a 50% chance of passing the condition on to each child. The condition can also be transmitted to transplant recipients undergoing transplantation from a CIHHV-6+ donor. CIHHV-6 individuals will always have a very high viral load—generally over 1 million copies per ml on whole blood samples—because the virus is integrated within the chromosomes of every nucleated cell. This high viral load can sometimes be mistaken for an active HHV-6 infection, and therefore can result in the unnecessary administration of potentially toxic antivirals to patients not actually suffering from a viral infection. |
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HHV-6 DNA levels are generally quite low in the blood, so it is easy to differentiate a CIHHV-6 patient from one who has an active infection through the use of a whole blood PCR DNA test.[iii] Only transplant patients that have developed graft vs host disease (GVHD) and patients with drug-induced hypersensitivity syndrome (DIHS) have been reported to have DNA loads comparable to those found in patients with CIHHV-6—as stated before, this reported number is generally greater than 1 viral copy per white blood cell of the blood sample being tested, or approximately 1 million copies per ml of blood. CIHHV-6 individuals will always test positive in a PCR DNA test of the serum and whole blood, but can test negative for HHV-6 DNA in plasma or spinal fluid (which is generally cell free) depending on the level of sensitivity of the assay.
CIHHV-6 individuals are usually asymptomatic, and the integrated virus is assumed to be latent in most cases. However, a recent study demonstrated that the integrated HHV-6 virus can replicate when exposed to certain drugs in vitro[iv], so it is possible that the integrated virus can reactivate and cause symptoms in these individuals under certain conditions. Another clue that CIHHV-6 virus does replicate came from a study that demonstrated the ability of CIHHV-6+ mothers to infect their non-CIHHV-6 children through the placenta.[v]
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.[vi] 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)[vii], 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.)
Physicians must use clinical judgment to decide whether symptomatic CIHHV-6 patients should be treated with antivirals. 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.
