Inherited Chromosomally Integrated HHV-6: Diagnosis and Clinical Features

Background: Human herpesvirus 6 (HHV-6) can integrate its genome into host chromosomes, including germline cells, resulting in inherited chromosomally integrated HHV-6 (iciHHV-6). Affecting approximately 0.4%-2.9% of the population, individuals with iciHHV-6 carry the viral genome in every nucleated cell, often leading to diagnostic confusion. Methods: This review summarizes current findings on the epidemiology, integration mechanisms, clinical features, diagnostic strategies, and potential reactivation of iciHHV-6, based on recent clinical and molecular research. Results: HHV-6 integrates into telomeric regions through homologous recombination, involving both viral and host telomeric repeats. iciHHV-6 is frequently identified incidentally via polymerase chain reaction-based testing during the evaluation of central nervous system infections or transplant monitoring. High HHV-6 DNA loads in blood or cerebrospinal fluid may mimic active infection, potentially leading to unnecessary antiviral therapy. Although iciHHV-6 is often asymptomatic, emerging evidence indicates possible viral gene expression and rare reactivation, especially in immunocompromised individuals. Additionally, iciHHV-6 may be associated with clinical conditions such as angina, preeclampsia and reproductive disorders. Conclusions: Distinguishing iciHHV-6 from active infection is essential to avoid misdiagnosis and inappropriate treatment. Awareness of its clinical implications, integration patterns and diagnostic markers is crucial. Further research is needed to clarify the pathogenic potential of iciHHV-6 and guide clinical management.