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

Montoya, José G.; Neely, Michael; Gupta, Sudhir; Lunn, Mitchell R.; Loomis, Kristin S.; Pritchett, Joshua C.; Polsky, Bruce; Medveczky, Peter G.

doi:10.1016/j.jcv.2012.05.016

Cited by 33 publications

(28 citation statements)

References 46 publications

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“…FISH results and patient background were provided for both of these patients in previous publications (patient one is sibling three(7) and patient B(22), and patient two is the father of sibling three(7)). Only two buffy coat samples were available given the low number of confirmed samples available worldwide.…”

Section: Resultsmentioning

confidence: 99%

“…Several recent reports have suggested links between ciHHV-6 and long-term sequelae;(22, 25–29) however, no larger studies have systematically examined how often clinical disease occurs in persons with ciHHV-6. In addition to preventing misdiagnosis of active HHV-6 infection, our ddPCR assay should also help identify individuals with ciHHV-6 to aid in determining how this condition may contribute to disease states.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Chromosomally Integrated Human Herpesvirus 6 by Droplet Digital PCR

Sedlak¹,

Cook²,

Huang³

et al. 2014

Clinical Chemistry

118

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Background Human Herpesvirus-6 (HHV-6) latently infects a majority of adults. In about 1% of the population HHV-6 exists in a chromosomally integrated form (ciHHV-6) that resides in every somatic and germ cell and can be transmitted through the germ line. Patients with ciHHV-6 have been misdiagnosed and unnecessarily treated for active HHV-6 infection, sometimes with significant side effects, based on results from quantitative molecular HHV-6 tests. Methods A droplet digital PCR (ddPCR) assay was developed to identify ciHHV-6 in cellular patient specimens by precisely determining the ratio of HHV-6 to cellular DNA. We validated the assay on confirmed ciHHV-6 patient specimens and a cell line derived from a ciHHV-6 patient, and analyzed hematopoietic stem cell transplant patients suspected of ciHHV-6. We additionally evaluated whether the assay could be applied to stored plasma samples from a study of clinical correlates of HHV-6. Results The ddPCR assay accurately identified ciHHV-6 in cellular samples (buffy coat, PBMCs), giving a ratio very close to 1 HHV-6/cell (1.02 ± .03 in FISH-confirmed samples). In stored plasma samples, the assay performance was set by design to have 100% sensitivity, which resulted in 82% specificity for ciHHV-6. Conclusions The possibility of ciHHV-6 is often overlooked in patients with detectable HHV-6 viral loads by quantitative PCR. Our ddPCR test provides rapid and accurate laboratory identification of ciHHV-6 from easily obtained cellular specimens. In addition, the assay provides excellent sensitivity and specificity using stored plasma samples, facilitating retrospective analysis of the clinical significance of ciHHV-6.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of Chromosomally Integrated Human Herpesvirus 6 by Droplet Digital PCR

Sedlak¹,

Cook²,

Huang³

et al. 2014

Clinical Chemistry

118

View full text Add to dashboard Cite

show abstract

“…Some experts have called for screening of all patients and donor organs or cells for ciHHV6 . Although antiviral therapy has been associated with clinical improvement of ciHHV‐6+ patients, a report of 21 transplant recipients, including five liver and two combined liver‐kidney, highlights the common misdiagnosis of ciHHV‐6 as active HHV‐6 infection …”

Section: Diagnosismentioning

confidence: 99%

HHV‐6 in liver transplantation: A literature review

Phan

Lautenschlager

Razonable

et al. 2017

Liver International

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Human herpesvirus 6 (HHV-6A and HHV-6B) can cause primary infection or reactivate from latency in liver transplant recipients, which can result in a variety of clinical syndromes, including fever, hepatitis, encephalitis and higher rates of graft dysfunction as well as indirect effects including increased risks of mortality, CMV disease, hepatitis C progression and greater fibrosis scores. Although HHV-6 infection is currently diagnosed by quantifying viral DNA in plasma or blood, biopsy to demonstrate

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“…While in malignancy patients, ciHHV-6A/B appeared to have similar prevalence to the general population, suggesting they were genetically silent in this context (Hubacek et al, 2013). However, case reports link ciHHV-6A with neuroinflammatory disease and further show response to antiviral treatment, suggesting effects of virus reactivation or superinfection, though effects on inflammation require further investigation (Arbuckle et al, 2010;Montoya et al, 2012).…”

Section: Uk-hivaids-u46-aj O Uganda-hivaids-u46-u1102mentioning

confidence: 97%

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

Tweedy

Spyrou

Hubáček

et al. 2015

Journal of General Virology

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Human herpesvirus-6A (HHV-6A) is rarer than HHV-6B in many infant populations. However, they are similarly prevalent as germline, chromosomally integrated genomes (ciHHV-6A/B). This integrated form affects 0.1-1 % of the human population, where potentially virus gene expression could be in every cell, although virus relationships and health effects are not clear. In a Czech/ German patient cohort ciHHV-6A was more common and diverse than ciHHV-6B. Quantitative PCR, nucleotide sequencing and telomeric integration site amplification characterized ciHHV-6 in 44 German myocarditis/cardiomyopathy and Czech malignancy/inflammatory disease (MI) patients plus donors. Comparisons were made to sequences from global virus reference strains, and blood DNA from childhood-infections from Zambia (HHV-6A mainly) and Japan (HHV-6B). The MI cohort were 86 % (18/21) ciHHV-6A, the cardiac cohort 65 % (13/20) ciHHV-6B, suggesting different disease links. Reactivation was supported by findings of 1) recombination between ciHHV-6A and HHV-6B genes in 20 % (4/21) of the MI cohort; 2) expression in a patient subset, of early/late transcripts from the inflammatory mediator genes chemokine receptor U51 and chemokine U83, both identical to ciHHV-6A DNA sequences; and 3) superinfection shown by deep sequencing identifying minor virus-variants only in ciHHV-6A, which expressed transcripts, indicating virus infection reactivates latent ciHHV-6A. Half the MI cohort had more than two copies per cell, median 5.2, indicative of reactivation. Remarkably, the integrated genomes encoded the secreted-active form of virus chemokines, rare in virus from childhoodinfections. This shows integrated virus genomes can contribute new human genes with links to inflammatory pathology and supports ciHHV-6A reactivation as a source for emergent infection.

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

Cited by 33 publications

References 46 publications

Identification of Chromosomally Integrated Human Herpesvirus 6 by Droplet Digital PCR

Identification of Chromosomally Integrated Human Herpesvirus 6 by Droplet Digital PCR

HHV‐6 in liver transplantation: A literature review

Analyses of germline, chromosomally integrated human herpesvirus 6A and B genomes indicate emergent infection and new inflammatory mediators

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