In rare cases, HHV-6 is found to be integrated into human chromosomes in high copy numbers producing unusually high viral loads in the whole blood and serum. Both HHV-6A and B have been found integrated into the chromosomes of immunocompetent patients at persistently high levels of viral DNA in blood, sera, and hair follicles (Ward 2006). A large study in Japan showed that the incidence is 0.2% but two smaller studies from the UK suggest it may be approximately 0.8 and 1.5%. Children hospitalized for seizures or encephalitis have higher rates of ciHHV-6, reported to be 2.9-3.3% (Leong 2007).
Viral sequences have been identified by FISH analysis on the telomeric ends of chromosomes (Clark 2006). Luppi et al were the first to show that these integrated sequences may be inherited through the germline (from parent to child) and subsequently, several studies have demonstrated confirmed that the virus can be transmitted vertically (Tanaka-Taya 2004).
A person with ciHHV-6 will never be negative by PCR for HHV-6 in whole blood or serum although it is possible for a ciHHV-6 individual to test negative for HHV-6 DNA in plasma or CSF. The DNA found in the serum and whole blood of a person with ciHHV-6 does not indicate active infection as it would in a person without this form of HHV-6. Since patients with integrated HHV-6 have a large number of DNA copies integrated into cells, they will have detectable levels of integrated DNA found in the serum as a result of normal cell death.
It is possible to determine whether an individual has ciHHV-6 with a quantitative PCR test as these patients will have over 1 million copies per ml of whole blood. Patients with primary infection or reactivation from immunosuppression following a transplant generally have viral loads that are in the tens of thousands, not millions.
While most individuals with ciHHV-6 are asymptomatic, individuals with ciHHV-6 may be overly represented in certain patient populations such as encephalitis and chronic fatigue syndrome (Pantry 2013). Although several authors previously suggested that the integrated HHV-6 virus is not capable of replicating, two recent studies have demonstrated that chromosomally integrated virus can indeed produce infectious virions. Hall demonstrated that ciHHV-6+ mothers infect their non-ciHHV-6 children through the placenta (Hall 2010). Also, a group led by Peter Medveczky at the University of South Florida demonstrated that the ciHHV-6 virus can be made to activate by stimulating the integrated cells with chemicals (Arbuckle 2010).
Marek’s Disease Virus, a herpesvirus associated with lymphoma and immunosuppression in chickens, also integrates into the chromosome commonly and has been shown to reactivate from its integrated state via unknown mechanisms (Delecluse 1993). It is also possible that this integrated virus could cause pathological problems without replication due to cytokines produced in response to abortive infection. The site of integration may also influence pathology.