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Aims Human herpesvirus 6 (HHV‐6) A and B are two betaherpesviruses that are associated with many conditions including roseola, drug‐induced hypersensitivity syndrome, limbic encephalitis, and myocarditis. HHV‐6 is integrated in the germline [chromosomically integrated HHV‐6 (ciHHV‐6)] in ∼0.8% of the human population. To date, the prevalence, species distribution, and treatment responses of ciHHV‐6 are unknown for cardiac patients. Methods and results We determined the prevalence of HHV‐6 and ciHHV‐6 genotypes in 1656 endomyocardial biopsies of patients with persisting unexplained symptoms of heart failure. Infection of cardiac tissue was identified by nested PCR, electron microscopy, and immunohistochemistry. Virus load and mRNA levels were followed in ciHHV‐6 patients treated with ganciclovir. HHV‐6 was detected in 273 of 1656 cardiac tissues (16.5%; HHV‐6B, 98.2%, HHV‐6A, 1.8%) by PCR. Nineteen of the 1656 patients (1.1%) presented with persistently high HHV‐6 copy numbers indicative of ciHHV‐6. Sequencing confirmed ciHHV‐6A in seven patients (36.8%) which was considerably higher than detected in non‐ciHHV‐6 patients. Inheritance was demonstrated in three selected families, confirming ciHHV‐6 chromosomal integration by PCR and fluorescence in situ hybridization. HHV‐6 reactivation and chromosomal integration were confirmed in peripheral blood mononuclear cells and heart tissue. Virus particles were identified in degenerating myocytes and interstitial cells. Antiviral treatment abolished viral mRNA and ameliorated cardiac symptoms. Conclusion Virus replication in cardiac tissue of ciHHV‐6 heart failure patients suggests that ciHHV‐6 reactivation causes persistence of unexplained heart failure symptoms. We demonstrated that antiviral treatment, effective in decreasing viral transcripts and clinical complaints of cardiomyopathies, is a new therapeutic option for ciHHV‐6‐associated diseases.

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Early-life infections and associated neuroinflammation is incriminated in the pathogenesis of various mood disorders. Infection with human roseoloviruses, HHV-6A and HHV-6B, allows viral latency in the central nervous system and other tissues, which can later be activated causing cognitive and behavioral disturbances. Hence, this study was designed to evaluate possible association of HHV-6A and HHV-6B activation with three different groups of psychiatric patients. DNA qPCR, immunofluorescence and FISH studies were carried out in post-mortem posterior cerebellum from 50 cases each of bipolar disorder (BPD), schizophrenia, 15 major depressive disorder (MDD) and 50 appropriate control samples obtained from two well-known brain collections (Stanley Medical Research Institute). HHV-6A and HHV-6B late proteins (indicating active infection) and viral DNA were detected more frequently (p < 0.001 for each virus) in human cerebellum in MDD and BPD relative to controls. These roseolovirus proteins and DNA were found less frequently in schizophrenia cases. Active HHV-6A and HHV-6B infection in cerebellar Purkinje cells were detected frequently in BPD and MDD cases. Furthermore, we found a significant association of HHV-6A infection with reduced Purkinje cell size, suggesting virus-mediated abnormal Purkinje cell function in these disorders. Finally, gene expression analysis of cerebellar tissue revealed changes in pathways reflecting an inflammatory response possibly to HHV-6A infection. Our results provide molecular evidence to support a role for active HHV-6A and HHV-6B infection in BPD and MDD.

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