HHV-6 Belongs to the Herpesvirus Superfamily
Herpesviruses are a large family of DNA viruses with 107 species identified. Nine herpesviruses are known to infect humans, such as the herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), associated with orolabial herpes and genital herpes; the varicella zoster virus, associated with chickenpox and shingles; and the Epstein–Barr virus (EBV), associated with mononucleosis and some cancers.1,2 HHV-6 belongs to this virus superfamily and is closely related to CMV (HHV-5).3
The Three Faces of HHV-6 and Their Clinical Relevance
Much like other herpesviruses, HHP-6 infection can exist in three interchangeable states, active infection, latent infection, and DNA incorporated.3
HHV-6 commonly infects humans early in life. Its prevalence is estimated to be >95% in developed countries.4–6
Primary infection of HHV-6 can be asymptomatic or may manifest as febrile childhood illnesses such as exanthem subitem (roseola). In rare cases, HHV-6 can cause febrile seizures, encephalitis, or intractable seizures, after which the virus becomes latent. Its latent infection is established in T-cells although a wide range of tissues can be infected.5,7 Latency appears to occur both as a genuine latent state (no production of infectious virus) and as a low level of chronic replication. Latent HHV-6 can be reactivated. The process by which this occurs is not well understood.7
In addition, HHV-6 has been reported to cause transplant rejection, fulminant hepatitis, otitis media, infections of the central nervous system, and other autoimmune diseases.4,6-8 HHV-6 has also been found to be present in the bladder and vagina,9 in salivary and bronchial glands,10 and in lung tissue.11 Recent studies have shown HHV-6 as one of the dominant pathogens in patients with idiopathic pneumonia syndrome (IPS).12,13 These patients were associated with a compromised immune system as a result of immunosuppressive therapies and/or transplantation procedures.11-13
Interactions of HHV-6 with other viruses, potentially through modulation of the host immune system, have also been observed.5 It has been proposed as a cofactor with HIV, an activator of EBV, an enhancer of human papillomavirus (HPV) mRNA expression, and a participant in adeno-associated virus (AAV)-induced cell transformation.5
Molecular Detection of HHV-6
Although isolation of a virus in cell culture can unambiguously demonstrate the presence of the virus in a sample, it is not clinically feasible for HHV-6 due to its fastidious nature and long reproductive life cycle (measured in days) 7.
Serological assays are less useful due to their poor sensitivity for primary infections, inability to identify reactivations, and the cross-reaction with other herpesviruses.6
Polymerase chain reaction (PCR) is a powerful tool to detect HHV-6. The detection has been reported in cerebrospinal fluid using PCR.6 In the case of HHV–6 infection in the bladder, the minimum PCR detection levels are sensitive enough to detect replicating viral particles.
Clinical Treatment Options
No drug has yet been approved exclusively for the treatment of HHV-6. Clinicians most often utilize the anti-CMV agents, ganciclovir (Cytovene® IV), cidofovir (Vistide® IV), and foscarnet (Foscavir® IV, deep vein) for the clinical treatment of HHV-6. These drugs are nucleoside analogues and target and inhibit viral DNA polymerase. 3,6,14,15
Although no internationally approved guidelines currently exist for the clinical treatment of HHV-6, the International Herpesvirus Management Forum and American Society of Transplantation Infectious Disease Community of Practice have recommended foscarnet as the preferential treatment option for HHV-6 encephalitis in patients with anemia, as ganciclovir poses an additional risk of dose-limiting hematological toxicity. Risks associated with foscarnet include renal toxicity, complications from catheter-related deep vein thrombosis, and infection. Of the three compounds, an oral prodrug is currently only available for ganciclovir (Valcyte® ORAL).3
- Mettenleiter; et al. Molecular Biology of Animal Herpesviruses. Animal Viruses: Molecular Biology. www.horizonpress.com. Caister Academic Press. ISBN 978-1-904455-22-6 (2008).
- Virus Taxonomy: 2019 Release. talk.ictvonline.org. International Committee on Taxonomy of Viruses. Retrieved 9 May 2020.
- HHV-6 Foundation | HHV-6 Disease Information for Patients, Clinicians, and Researchers | Available at: https://hhv-6foundation.org/clinicians/hhv-6-treatment. Retrieved 16th June 2020.
- Ansari, A., Li, S., Abzug, M. J. & Weinberg, A. Human Herpesviruses 6 and 7 and Central Nervous System Infection in Children. Emerging Infectious Diseases 10, 1450–1454 (2004).
- De Bolle, L., Naesens, L. & De Clercq, E. Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy. Clin Microbiol Rev 18, 217–245 (2005).
- Agut, H., Bonnafous, P. & Gautheret-Dejean, A. Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections. Clin. Microbiol. Rev. 28, 313–335 (2015).
- Whitley, R. J. Herpesviruses. in Medical Microbiology (University of Texas Medical Branch at Galveston) (1996).
- Broccolo, F. et al. Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases. J. Clin. Virol. 46, 43–46 (2009).
- Chen T, Hudnall SD. Anatomical mapping of human herpesvirus reservoirs of infection. Mod Pathol. 19(5):726-737 (2006).
- Krueger GR, Wassermann K, De Clerck LS, Stevens WJ, Bourgeois N, Ablashi DV, Josephs SF, Balachandran N. Latent herpesvirus-6 in salivary and bronchial glands. Lancet 336:1255-1256 (1990).
- Carrigan DR, Drobyski WR, Russler SK, Tapper MA, Knox KK, Ash RC. Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Lancet. 338(8760):147-149 (1991).
- Jouneau S, Poineuf JS, Minjolle S, et al. Which patients should be tested for viruses on bronchoalveolar lavage fluid?. Eur J Clin Microbiol Infect Dis. 32(5):671-677 (2013).
- Seo S, Renaud C, Kuypers JM, et al. Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies. Blood. 125(24):3789-3797 (2015).
- Overview of Herpesvirus Infections – Infectious Diseases. Merck Manuals Professional Edition https://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/overview-of-herpesvirus-infections. Retrieved 16th June 2020.
- De Clercq, E. et al. Antiviral agents active against human herpesviruses HHV-6, HHV-7, and HHV-8. Rev. Med. Virol. 11, 381–395 (2001).