Chromosomally integrated human herpesvirus 6 in heart failure: prevalence and treatment

Abstract

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.

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

“…Consequently, patients with ciHHV-6 have very high DNAemia (>10 5 genomes per milliliter) if measured in whole blood. The clinical significance of ciHHV-6 in transplant recipients has not yet been defined, and it is not known whether ciHHV-6 may reactivate and produce an active infection in patients with enhanced immunosuppression (87). One study found that liver transplant recipients with ciHHV-6 had a trend toward higher rates of acute allograft rejection compared with patients with low-level or without HHV-6 replication (83).…”

Viral heart disease — treatment

“…Ganciclovir/valganciclovir Most of the patients with HHV-6-induced VHD are infected with HHV-6B (which infects endothelial progenitor cells) rather than with HHV-6A (which infects neural cells) [15,16]. It is highly probable that HHV-6 enhances pathogenicity of other viruses [15].…”

“…In some patients, HHV-6 virus is chromosomally integrated (ciHHV-6 -identification by repeated measurement of viral loads above 10 4 DNA copies per µg of isolated DNA in tissue or blood cells) [3,15,16]. ci-HHV-6A is probably associated with an increased risk of MC [3,15,16]. HHV-6 is not cleared by IFN or ganciclovir (herpesvirus-specific inhibitor of replication) [16].…”

“…ci-HHV-6A is probably associated with an increased risk of MC [3,15,16]. HHV-6 is not cleared by IFN or ganciclovir (herpesvirus-specific inhibitor of replication) [16]. Intravenously administered ganciclovir for 10 days followed by oral valganciclovir for six months in MC, viral CM, and ciHHV-6 HF patients improved the clinical condition and echocardiographic parameters (Table 1) [16].…”

“…HHV-6 is not cleared by IFN or ganciclovir (herpesvirus-specific inhibitor of replication) [16]. Intravenously administered ganciclovir for 10 days followed by oral valganciclovir for six months in MC, viral CM, and ciHHV-6 HF patients improved the clinical condition and echocardiographic parameters (Table 1) [16]. Patients reported a rapid improvement of symptoms after two weeks of treatment [16], which is probably due to the elimination of DNA replication and RNA synthesis [16].…”