Slightly less than 1% of the population is born with inherited HHV-6A or HHV-6B genomes integrated into their chromosomes in every nucleated cell. These individuals will always have positive results on HHV-6 PCR DNA tests with viral loads in the millions when cells are tested (whole blood) and loads of several hundred to several thousand in the plasma. Prevalence varies by country with slightly lower prevalence in Japan and Canada and higher prevalence in Scotland. Children hospitalized for seizures or encephalitis may have a higher prevalence of ciHHV-6, reported to be 2.9-3.3% (Leong 2007).
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).
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 copy of the genome in every nucleated cell, they will have detectable levels of HHV-6 DNA in the plasma or serum, simply as a result of normal cell death. When the cells die, the viral DNA from the lysed cells can be found in the plasma at detectable levels.
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 past reports suggested that the integrated HHV-6 virus might not capable of replicating, it is now understood that chromosomally integrated genomes can be excised from the chromosome and produce infectious virus. Hall demonstrated that ciHHV-6+ mothers infect their non-ciHHV-6 children transplacentally (Hall 2010) (Gravel 2013). Also, researchers at the University of South Florida showed that the integrated HHV-6 can be activated in vitro by stimulating the cells with steroids and a pan-HDAC inhibitor (Arbuckle 2010).
An infant born with both ciHHV6A and a severe immune deficiency activated with his own inherited virus (Endo 2014). A transplant patient given an HDAC inhibitor also showed signs of activation (Politikos 2018). It is also possible that this integrated virus could cause inflammation due to gene expression in the absence of replication.
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).