Importance of chromosomally integrated HHV-6A and -6B in the diagnosis of active HHV-6 infection

Abstract

Human herpesvirus-6 (HHV-6) exists as two closely related variants: A and B. Whereas no disease has been firmly associated with HHV-6A, variant B causes febrile illness in young children and is pathogenic in immunosuppressed transplant recipients. Chromosomally integrated HHV-6 (with either variant A or B) occurs in a minority of people. This phenomenon has the potential to confound the diagnosis of active HHV-6 infection, since chromosomally integrated HHV-6 DNA sequences are inherited through the germline. Therefore, viral DNA is in every nucleated cell in the body and can be found in a range of body fluids including whole blood, serum, plasma and cerebrospinal fluid. There are characteristically very high viral loads in whole blood (> 6 log10 HHV-6 genomes/ml) and serum (5 log10 HHV-6 genomes/ml); these can be used to differentiate individuals with viral chromosomal integration from those with active HHV-6 infection, where viral loads are significantly lower. Increasingly, the polymerase chain reaction (to detect viral nucleic acid) is used for diagnosis; therefore, it is important to exclude HHV-6 chromosomal integration before concluding that there is evidence of active HHV-6 infection.