Fundamentals of HHV-6

Wisconsin Viral Research Group, Ltd.

Physician's Corner: HHV-6

Fundamentals of HHV-6

Basic Science

Human herpesvirus 6 (HHV-6) is a beta-herpesvirus, first isolated from the peripheral blood of six patients with lymphoproliferative disorders in 1986. The sixth member of the herpes family of viruses discovered, this virus is a double-stranded DNA virus, which is most closely related to cytomegalovirus (CMV) in terms of DNA homology. Two variants or subtypes of HHV-6 are recognized based on DNA sequencing, cell tropism, and pathogenicity. These are designated HHV-6A and HHV-6B. Although these variants are closely related (>90% DNA homology), there are differences in epidemiology and pathogenicity. HHV-6 can infect and is cytolytic for several cell types including CD4 lymphocytes (probably a primary target), CD8 cells, NK cells, oligodendrocytes, and microglial cells. The pathogenicity of HHV-6 probably relates to several mechanisms: cytopathic effect for the cells it infects, induction of cytokines, effects on immune function (immune suppressive), and effects on other viruses (e.g. transactivation). As with all herpesviruses, after primary infection, the virus becomes latent in various cells (salivary epithelial cells, CD4 lymphocytes, monocytes, and neural cells). Subsequent infections are a result of reactivation. Reactivation clearly occurs in the immunocompromised host. Reactivation may also occur in normal individuals. The factors that may lead to reactivation in the normal host are unclear (genetic, environmental, etc.).

The epidemiology of HHV-6 infection differs with the variant. HHV-6B is endemic and is acquired early in childhood with rapid seroconversion after 6 months of age. Most children seroconvert by age 2. The virus is readily found in saliva and is presumably acquired through exposure to secretions or droplets. HHV-6A is not seen to any significant degree until adulthood, in which an unknown but probably small percentage of adults are seropositive for this variant. Whether past infection with HHV-6B in childhood provides protection against HHV-6A later in life is unclear. However, there may be individuals in which cross-protection does not occur.

Clinical

Primary infection with HHV-6B may be asymptomatic. Symptomatic HHV-6 infection in children is the cause of roseola (exathem subitum). This is a febrile illness of early childhood that usually lasts 3-5 days; characterized by fever, maculopapular rash, respiratory symptoms and less commonly neurologic symptoms. Neurologic entities seen with primary HHV-6 infection include encephalitis, meningitis, and febrile seizures. HHV-6 infection accounts for 10% of all clinic visits in the first three years of life. Primary infection with HHV-6A is less well understood, but can likely be asymptomatic as well as cause a viral syndrome. Reactivation of HHV-6 infection (active/productive infection) has been associated with several syndromes in both immunocompetent and immunocompromised hosts. In "normal" patients it has been associated with a mononucleosis syndrome, autoimmune disorders (e.g. Sjorgren's syndrome), focal encephalitis, demyelinating encephalitis, demyelinating myelitis, among others. In immunocompromised patients, in particular transplant patients, these viruses can cause encephalitis, pneumonitis, hepatitis, and bone marrow suppression. Fatal encephalitis has also been demonstrated in HIV/AIDS cases.

The association with HHV-6 and multiple sclerosis is intriguing. HHV-6 has clearly been shown to be neuroinvasive. Oligodendrocytes are a target for lytic HHV-6 infection in the CNS tissues of patients with HHV-6 encephalitis. The histopathologic findings in AIDS patients, transplant patients, and normal patients with HHV-6 encephalitis have shown either focal or diffuse demyelination (ref. 9, 11, 17). The autopsy study by Challoner detected high levels of HHV-6 DNA and viral antigens in the CNS tissues of MS patients (ref 12). Autopsy studies by our group in MS cases demonstrated cells actively infected with HHV-6 in the inflammatory/demyelinated lesions of the CNS tissues. In control cases (normal brains and non-MS inflammatory CNS diseases) no active HHV-6 was found. Autopsy studies have detected both the A and B variant in CNS tissues, however, whether one predominates (e.g. A variant) is unresolved. A case of acute MS has been reported, which showed a demyelinating leukoencephalitis at autopsy secondary to HHV-6 (ref. 10).

Soldan and associates detected HHV-6 specific IgM antibodies and HHV-6 DNA with a higher frequency in the serum of MS patients than controls. We have found active HHV-6 infection of the bloodstream in MS patients by rapid shell vial culture. Active HHV-6 in the bloodstream was demonstrated in over 50% of MS cases at random screening. No positive cultures were found in healthy controls (healthy blood donors randomly screened). Active HHV-6 infection has been found in both autopsy cases and the bloodstream of relapsing/remitting secondary progressive, and chronic progressive MS

Active HHV-6 infection has also been implicated in chronic fatigue syndrome. Several studies have demonstrated evidence of HHV-6 in CFS patients. CFS patients have been reported with immunologic abnormalities, neurologic features, and evidence of viral activation. HHV-6 detected by the rapid shell vial assay was positive for active infection in over 30% of CFS patients on initial screening. Follow-up cultures in patients who initially tested negative were subsequently positive in an additional 20% - 40% of cases. Positive cultures, as noted above, are not seen in healthy control patients using this method.

Diagnosis

Serologic assays can be used to establish evidence of latent infection (i.e. past exposure). IgM antibodies may be helpful in the diagnosis of primary infection, but are unreliable to detect reactivation of HHV-6.

The detection of active HHV-6 infection is more difficult. Traditional viral cultures to assess for cytopathic effect are cumbersome and basically a research tool. DNA detection by PCR methodology on cellular specimens (PBMC), cannot reliably differentiate between latent and active infection. DNA detection on acellular specimens (serum, plasma, CSF), is probably more reliable for active infection however, the presence of "inhibitors" create significant problems with false negative test results. Culturing for active HHV-6 using a more rapid technique by the shell vial assay is probably the best current method for diagnosis of active infection. The particulars of this methodology is described in the lab section of this web site. The rapid shell vial assay has a sensitivity in the 86% range, with a specificity of nearly 100%.

Treatment

In vitro studies with HHV-6 have been done by several investigators. This virus is generally considered to be resistant to acyclovir (Zovirax) with IC 50 levels unattainable using conventional dosing regimens. The same likely applies to valacyclovir (Valtrex). Both ganciclovir (Cytovene) and foscarnet (Foscavir) have shown in vitro activity for HHV-6 that would be achievable with established current dosing recommendations. This would be consistent with the large amount of data that has been collected with these drugs in the treatment of CMV infections. Both drugs have been used successfully in the treatment of life-threatening HHV-6 infections in transplant patients. The most common adverse effect of ganciclovir is reversible cytopenias, especially the WBC count. Foscarnet has numerous adverse effects including nephrotoxicity, electrolyte disturbances, anemia, etc. Based on the adverse effect profile of these drugs, ganciclovir may be a better choice between these two drugs, unless cytopenias are a major concern. The current ganciclovir dosing regimen for CMV infections which can probably be extrapolated to HHV-6, is 5mg/kg IV every 12 hours. Whether the dosing can be reduced to once daily (as with CMV infections) and the duration of therapy (i.e. ongoing therapy) is unknown and will require further study. Evidence in one MS patient that we have treated, suggests relapse of active viremia after therapy is discontinued.

Other antiviral agents may be candidates for further study as well. The fact that interferon (currently beta interferon) has been shown to be effective in MS in reducing relapses and slowing progression raises questions about the specific mechanisms involved. Since interferons have very potent antiviral activity, and are immune enhancers (T lymphocytes, NK cells), this may explain their activity in the activated HHV-6 infection with MS cases. In assuming activated HHV-6 infection in patients with MS, the goal of any therapy to control viral reactivations would be the abatement of MS relapses and cessation of progression. Control of viral reactivations would seem unlikely to reverse existing areas of neurologic damage. Clinical trials will be important to further evaluate antiviral agents in MS and other HHV-6 related diseases.