Chromosomally Integrated HHV-6

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. EBV can also integrate into the chromosomes of B-cells in cases of chronic reactivation (Hurley et al, 1991). 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 .2% but two smaller studies from the UK suggest it may be between 1 and 2% (Clark 2007). Ward found that 1.6% of children suspected of viral encephalitis had chromosomal integration in the spinal fluid.

Viral sequences have been identified by FISH analysis on the telomeric ends of chromosomes 1, 17, and 22 (Clark 2006). Although one study suggested that these integrated sequences may be inherited through the germline (from parent to child) (Tanaka-Taya 2004), others have reported that the virus is not integrated into every cell but only in certain types of cells, e.g. T cells and monocytes. This finding would rule out vertical transmission. (Luppi et al, 2006). Another possibility is that this condition may result from an inherited specific immune defect similar to X-linked lymphoproliferative syndrome.

Patients with CIHHV-6 generally have several million copies per ml in the whole blood and are therefore easy to identify with Q PCR. Patients with primary infection or reactivation from immunosuppression following a transplant generally have viral loads that are in the tens of thousands, not millions. Patients with low level chronic reactivation typically have very low levels of DNA in the whole blood, at levels of less than 500 copies per ml, which falls below the level of detection at most commercial labs. CIHHV-6 patients also have replicating virus in the hair follicle, so a qualitative PCR test in a hair follicle may suggest that the patient has chromosomal integration.

A person with CIHHV-6 will never be negative in whole blood or serum. Significant viral loads are also always present in the CSF of patients with CIHHV-6. The DNA found in the serum and whole blood is not considered “free virus” from active infection, but rather comes from lysed or dead cells that release DNA into the serum or spinal fluid. 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.

While some individuals with chromosomally integrated HHV-6 are asymptomatic, the condition may be associated with an increased risk of lymphoproliferative disease or encephalitis/encephalopathy. An assay that can differentiate episomal (or replicating) virus from integrated virus would help answer the question of whether a CIHHV-6 patient would benefit from antiviral treatment.

A method to differentiate episomal and integrated EBV  has been described by scientists in Austria. (Reisinger 2006) and a kit was recently introduced in the US to differentiate HHV-6, EBV and HHV-7 integrated from episomal virus. (Bioworld Consulting Laboratories)