Human Herpes Virus 6 and 7

I. Overview

 

• Although both typically cause dermatological infections and both can be a factor in transplant rejection, both have also been found in the bladder and vagina.

 

• Both HHV-6 and -7 can exist in three different states in the human body:

– As an active infection

– As a latent infection

– As DNA incorporated into the human nuclear genome

 

• HHV-6 and -7, much like other herpesviruses, can exist as a latent infection for decades without manifest illness.

 

• Both latent infection and chromosomally incorporated DNA can become activated and form an active infection.

 

• Several antiviral agents have been approved for treatment of both HHV-6 and -7.

 

II. Introduction

 

HHV-6 and -7 are T-lymphotropic beta-herpesviruses that commonly infect humans early in life. Seroprevalence of HHV-6 has been reported as being >80% in children >2yo. Prevalence of antibodies to HHV-7 is at least 75% in children 3 – 6yo, and likely to be 98% in adults.1 There can be significant issues with serological assays for HHV-6 and -7, including assay sensitivity, interpretation, cross-reactivity, and geographic variations. Nonetheless, the prevalence of both HHV-6 and -7 is estimated to be >95% in developed countries.2,3

 

Primary infection of HHV-6 and -7 can be asymptomatic or may manifest as febrile childhood illnesses such as exanthem subitem (roseola, or sixth disease), or as illnesses that mimic measles and rubella. HHV-7 has been reported in some cases of inflammatory skin diseases, such as psoriasis, and in some forms of Kaposi’s sarcoma.4

 

HHV-6 and -7 are much like other herpesviruses in their ability to establish latent infection. Each herpesvirus tends to establish latency in specific types of host cells; in the case of HHV-6 and -7, although a wide range of tissues can be infected, latent infection is established in T-cells.2,5 At the same time, HHV-6 and -7 are unique in that their reproductive life cycle is long, measured in days. As a result, HHV-6 and -7 are both difficult and slow to grow in cell culture systems.5

 

III. Clinical relevance

 

Both HHV-6 and -7 are ubiquitous during childhood. Both HHV-6 and -7 can cause roseola and transplant rejection. In addition, HHV-6 has been reported to cause fulminant hepatitis, otitis media, and infections of the central nervous system.1,5 However, few acute HHV-7 infections have been reported. Further, it remains unknown whether HHV-7 viremia suggests primary infection, such as it does with HHV-6, or reactivation. Even more, it is not clear whether primary infection with HHV-7 differs clinically from reactivation.6

 

Latent HHV-6 and -7 can be reactivated and become replicative at any time. The process by which this occurs is not well understood.5 Latency appears to occur both as a genuine latent state (in which there is no production of infectious virus) and as a low level of chronic replication. Superinfection with HHV-7 can cause reactivation of HHV-6.2

 

HHV-6 has been shown to interact with other viruses. It has been proposed as a cofactor with HIV in AIDS, as an activator of Epstein-Barr virus (EBV), as an enhancer of human papillomavirus (HPV) mRNA expression, and as a participant with adeno-associated virus (AAV) in cell transformation.2 HHV-6 has also been implicated in the pathogenesis of autoimmune diseases, and specifically autoimmune diseases of connective tissue, such as scleroderma.3,7

 

One of the mechanisms by which these interactions may occur is through modulation of the host immune system by HHV-6. Infection of peripheral blood mononuclear cells (PBMCs) with HHV-6 induced upregulation of both tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). HHV-6 can cause impaired antigen capture and/or processing by dendritic cells through changes in synthesis of human leukocyte antigen (HLA) class I and II.2

 

IV. Value of Molecular Detection of HHV-6 and -7

 

Although isolation of a virus in cell culture can unambiguously demonstrate the presence of the virus in a sample, both HHV-6 and -7 are fastidious, in that they are very difficult to grow in culture. Neither has yet been cultured in cerebrospinal fluid (CSF), for instance. However, both have been detected in a number of body fluids used PCR.8

 

Serological assays are less useful for diagnosis of HHV infections. Serology provides readily accessible methods and easy collection and storage of samples. However, serology may have poor sensitivity for primary HHV infections, is unable to distinguish between subtypes HHV-6A and HHV-6B, is unable to identify reactivations, and can cross-react with other herpesviruses.3

 

In the case of HHV6 and HHV7 infections in the bladder, the minimum detection levels are high enough to detect replicating viral particles.

 

VI. Treatment algorithm

 

While it appears that there are no approved guidelines for treatment of HHV-6 and -7, several drugs have been approved for antiviral therapy on the diagnosis of HHV-6 and/or HHV-7 infection.3,10–13

 

Drugs used to treat HHV-6:

 

Drug Prodrug Structure Activity Uses Adverse Effects
Foscarnet None Nucleoside Analogue • Target: DNA polymerase• Active against EBV, KSHV, human herpesvirus 6, acyclovir-resistant (and acyclovir-susceptible) HSV and VZV, and ganciclovir-resistant (and ganciclovir-susceptible) CMV• Some anti-HIV activity • IV or intravitreal injection: Efficacy similar to that of ganciclovir for treating and delaying progression of CMV retinitis Renal toxicity in up to one third of patients if foscarnet is given without adequate hydration, electrolyte imbalances
Ganciclovir Valganciclovir Nucleoside Analogue • Target: DNA polymerase
• In vitro activity against all herpesviruses, including CMV, but HSV strains that are resistant to acyclovir also cross-resistant to ganciclovir
• Typically drug of choice for CMV
• Used in patients with both HIV and CMV retinitis
• IV form: Most common
• Intravitreal injection: For CMV retinitis
• Oral: Only 6 to 9% bioavailable; requires 12 capsules/day for a standard dose (1 g tid), limiting its usefulness
Primarily, bone marrow suppression, particularly neutropenia, which sometimes requires treatment*
Valganciclovir
(prodrug of ganciclovir)
Similar to ganciclovir Oral: More bioavailable than oral ganciclovir Similar to ganciclovir
(r)-9-[4-hydroxy-2-(hydroxymethyl)butyl]
guanine (H2G) 14
Valomaciclovir Nucleoside Analogue DNA polymerase
Cidofovir Brincidofovir Nucleoside Analogue Target: DNA polymerase
Artesunate None Semisynthetic derivative of artemisinin Target: Sp1/NF-κB activation pathways
Approved for treatment of malaria

 

Drugs used to treat HHV-7:

 

Drug Prodrug Structure Activity Uses Adverse Effects
Ganciclovir • In vitro activity against all herpesviruses, including CMV, but HSV strains that are resistant to acyclovir also cross-resistant to ganciclovir
• Typically drug of choice for CMV
• Used in patients with both HIV and CMV retinitis
• IV form: Most common
• Intravitreal injection: For CMV retinitis
• Oral: Only 6 to 9% bioavailable; requires 12 capsules/day for a standard dose (1 g tid), limiting its usefulness
Primarily, bone marrow suppression, particularly neutropenia, which sometimes requires treatment*
Valganciclovir
(prodrug of ganciclovir)
Similar to ganciclovir Oral: More bioavailable than oral ganciclovir Similar to ganciclovir
Cidofovir
guanine (H2G) 14
Brincidofovir Nucleoside Analogue DNA polymerase

 

 

References

1. 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).
2. 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).
3. Agut, H., Bonnafous, P. & Gautheret-Dejean, A. Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections. Clin. Microbiol. Rev. 28, 313–335 (2015).
4. Kempf, W. Human herpesvirus 7 in dermatology: what role does it play? Am J Clin Dermatol 3, 309–315 (2002).
5. Whitley, R. J. Herpesviruses. in Medical Microbiology (ed. Baron, S.) (University of Texas Medical Branch at Galveston, 1996).
6. Hall, C. B. et al. Characteristics and Acquisition of Human Herpesvirus (HHV)–7 Infections in Relation to Infection with HHV-6. J Infect Dis 193, 1063–1069 (2006).
7. 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).
8. Human Herpesvirus-6 and -7 (HHV-6 and HHV-7). American Journal of Transplantation 4, 66–67
9. Bressollette-Bodin, C. et al. Quantification of two viral transcripts by real-time PCR to investigate human herpesvirus type 6 active infection. J. Clin. Virol. 59, 94–99 (2014).
10. HHV-6 Treatment | HHV-6 Foundation | HHV-6 Disease Information for Patients, Clinicians, and Researchers | Apply for a Grant. Available at: https://hhv-6foundation.org/clinicians/hhv-6-treatment. (Accessed: 13th August 2018)
11. Overview of Herpesvirus Infections – Infectious Diseases. Merck Manuals Professional Edition Available at: https://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/overview-of-herpesvirus-infections. (Accessed: 11th August 2018)
12. 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).
13. Yao, K., Hoest, C., Rashti, F., Schott, T. C. & Jacobson, S. Effect of (r)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) and AZT-lipid-PFA on Human Herpesvirus-6B infected cells. J Clin Virol 46, 10–14 (2009).