Antiviral therapy of two patients with chromosomally-integrated human herpesvirus-6A presenting with cognitive dysfunction

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Abstract

Background

Human herpesvirus 6 (HHV-6) is a neurotropic virus implicated in central nervous system (CNS) dysfunction, multiple sclerosis, seizures and encephalitis. Inherited or “chromosomally integrated” HHV-6 (CIHHV-6) is a condition characterized by high DNA loads and germ line transmission of HHV-6 genomes, which are integrated into the telomere.

Objectives

We previously reported that integrated HHV-6 can be reactivated by trichostatin A in vitro. Therefore, we hypothesized that a broad array of neurological symptoms of CIHHV-6 patients may respond to antiviral drug treatment.

Study design

The patients have been treated with antiviral drugs and monitored for viral load, late mRNA, and clinical improvement.

Results

Antiviral therapy of two CIHHV patients resulted in successful clinical resolution. However, both patients relapsed on multiple occasions within 4–6 months of cessation of antiviral therapy.

Conclusions

Successful antiviral drug treatment suggests that clinical symptoms of these patients were due to symptomatic reactivation of CIHHV-6. Alternatively, some CIHHV-6 patients may have a reduced resistance to community-acquired HHV-6 strains due to tolerance leading to persistent infections.

Section snippets

Background

Human herpesvirus 6 (HHV-6) is a neurotropic, lymphotropic, DNA virus with two variants – A and B.1 Like other herpesviruses, HHV-6 persists in latent reservoirs after primary infection. Primary HHV-6 infection is typically mild or asymptomatic in immunocompetent persons, but reactivated HHV-6 has been linked to a wide-range of conditions, including encephalitis,2 seizures,3 myocarditis,4, 5, 6 chronic fatigue syndrome (CFS)7, 8, 9 and multiple sclerosis.10, 11, 12, 13 Unique among

Objectives

In a previous study, we discovered CIHHV-6 in two patients of the current study, one of their parents, and a third sibling, the latter two of whom were asymptomatic.18 We now evaluated two siblings for possible infectious etiologies of their chronic neurological abnormalities.

Study design

Two patients with neurological abnormalities have been evaluated for HHV-6 viral load, late mRNA expression, and clinical symptoms before, during and after antiviral drug treatment.

Clinical symptoms and antiviral drug treatment of Patient A

Patient A had a history of asthma, atopic dermatitis, and persistent sinopulmonary and tonsil infections from age 5. At 12 years of age, she experienced three weeks of emotional lability and a sudden onset of severe stuttering which resolved after one week with minor residual speech difficulties. This episode was diagnosed as a seizure. Her EEG during the acute phase was abnormal with diffuse slowing and focal spikes, but an MRI was normal. At age 14, she had an evaluation by an immunologist

Discussion

In this report, we described two CIHHV-6 patients with debilitating CNS dysfunction that responded to therapy against replicating HHV-6A. In both patients, during symptomatic periods, whole blood analyses yielded high levels of HHV-6A DNA persistently greater than 5.5 log10 copies/mL. CSF analysis revealed low copy number (200–600 copies/mL) with no pleocytosis. HHV-6 late mRNA was detected in the serum at approximately 1000 copies/mL (Viracor), suggesting reactivation of the virus. Simultaneous

Funding

This study was supported by a grant from the HHV-6 Foundation.

Competing interests

All authors have no competing interest.

Ethical approval

The study was approved by the Institutional Review Board.

Acknowledgements

We would like to thank Nathan Zemke and Dharam Ablashi (HHV-6 Foundation) for their assistance with the preparation of the manuscript.

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    These authors contributed equally to the work.

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