Human Herpesvirus Type 6

Viral Variants and Genome

Human herpesvirus type 6 (HHV-6), first isolated in 1986, is an enveloped DNA virus that belongs to the β-herpesviridae family. HHV-6 encompasses two different species: HHV-6A and HHV-6B, that share 90% homology. The HHV-6 genome is a linear, double-stranded DNA molecule, 160 to 162 kb in size, and consists of a 143- to 145-kb unique (U) region, flanked by terminal direct repeats (DR) of 8 to 9 kb and interrupted by three intermediate repeats, designated R1, R2, and R3, in the immediate-early A (IE-A) region. The HHV-6B genome contains 119 open reading frames (ORFs) (encoded by 97 genes), 9 of which are absent in HHV-6A (109).

Fig.1 Illustration of the structure of HHV virion. (Hornig, 2014)

Pathogenesis

HHV-6A and HHV-6B entry via interaction between gH/gL/gQ1/gQ2 complex and specific entry receptors (Fig.2). HHV-6 enters a cell using the regulator of complement activation receptor CD46 that is expressed on all nucleated cells, allowing the virus to infect a broad range of cell lines in vitro. The cell tropism of certain strains of HHV-6B is more restricted as it uses CD134 for entry, which is only present on activated T lymphocytes. Entry occurs through receptor-mediated endocytosis. Subsequent stages of viral replication include latent and lytic phases. The virus can enter the central nervous system (CNS) during initial viremia or retrograde neuronal spread and establish chronic latency in brain tissue and peripherally in tonsils/salivary glands. A third disease stage, infection reactivation, usually is observed in the context of immunosuppression and documented by viremia. HHV-6 can also integrate near telomeres of infected cells, a mechanism known as chromosomal integration.

Fig.2 Viral ligands of HHV-6A and HHV-6B and entry receptors. (Nishimura, 2019)

Epidemiology

HHV-6A and HHV-6B are ubiquitous viruses that are detected in all human populations around the world. HHV-6 infection is usually acquired very early in life, between 6 months and 2 years of age, and is almost exclusively caused by HHV-6B, not HHV-6A. It is currently not known at what age seroconversion to the A variant, which is frequently recovered from adults, takes place, but it is thought to occur after the acquisition of the B variant and without manifest clinical symptoms. HHV-6A is less prevalent than HHV-6B, and its causal role in disease and route of transmission remains poorly understood. Saliva is assumed to be the main vehicle for virus transmission, and intrauterine transmission has been reported.

Symptoms and Complications

HHV-6 infections cause the most emblematic one being exanthema subitum (also known as roseola infantum or sixth disease). Other, less typical combinations of fever, cough, skin rash, and gastrointestinal and respiratory tract symptoms have been reported, with most of them leading to a quick, favorable outcome. HHV-6 is neurotropic and has been associated with neurological diseases in humans including encephalitis and seizures. In addition, they have been linked to acute graft-versus-host disease, drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms, Hashimoto's thyroiditis, gastrointestinal diseases, female infertility, myocarditis, and multiple sclerosis.

Anti-HHV-6 Products and Services

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References

1. Hornig, J.; McGregor, A. Design and development of antivirals and intervention strategies against human herpesviruses using high-throughput approach. Expert Opin Drug Discov. 2014, 9(8): 891-915.
2. Nishimura, M.; Mori, Y. Entry of betaherpesviruses. Adv Virus Res. 2019, 104: 283-312.

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