What Is HHV-6? What is Chromosomally Integrated HHV-6

What is Chromosomally Integrated HHV-6

“Chromosomally integrated HHV-6” (CIHHV-6) is an inherited condition in which the complete HHV-6 genome is integrated into the telomere of every chromosome. The condition affects around 0.8% of the population in the US and UK, but appears to affect a greater percentage of patients and may be overly represented in patients with encephalitis and other conditions (Pellett 2011), and some CIHHV-6 individuals may have difficulty defending themselves against community acquired strains of HHV-6, resulting in persistent infection, cognitive dysfunction and fatigue (Pantry 2013, Montoya 2012). 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. CIHHV-6 individuals will always have a very high viral load—generally over 1 million copies per ml on whole blood samples, and over 3,000 copies/ml in serum. 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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Click here to download a comprehensive Q&A on CIHHV-6 published by experts in the field.

CIHHV-6 individuals are usually asymptomatic, and the integrated virus is assumed to be latent in most cases.  However, the integrated HHV-6 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 CIHHV6 patients with encephalitis respond to antivirals (Troy 2007, Wittekindt 2009, Kobayashi 2011) and two CIHHV6 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 CIHHV6 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 CIHHV6 patients, these assays are not available in commercial laboratories so 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. Visit the CIHHV-6 Testing page to learn more.

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. Only transplant patients with encephalitis or graft vs host disease (GVHD) or patients with drug-induced hypersensitivity syndrome (DIHS) have been reported to have DNA loads comparable to those found in patients with CIHHV-6, or over 1 million copies per ml in whole 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. An asymptomatic or mildly ill CIHHV-6 patient might have a viral load of 200 to 3000 copies/ml in plasma, depending on the amount of time that passes between the blood draw and  processing.

If your physician suspects that you have CIHHV-6, and you have had the following laboratory results on more than one occasion, you can register here to participate in research studies pertaining to CIHHV-6. Then email us your test results after registering.

  • A whole blood quantitative PCR test > 500,000 copies per mL
  • A serum blood test of over 3,000 copies per mL
  • A plasma blood test of over 1000 copies per mL


If you are a physician interested in participating in research studies pertaining to CIHHV-6, please register here.

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