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Chromosomally integrated human herpesvirus 6: questions and answers
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Misdiagnosis of active HHV-6 infection in ciHHV-6 individuals presenting with unconnected illnesses. Incidental positivity of CSF PCR for HHV-6 in ciHHV-6 patients with CSF pleocytosis resulting in erroneous diagnosis and unnecessary treatment.

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REVIEW
Chromosomally integrated human herpesvirus
6: questions and answers
Philip E. Pellett1*, Dharam V. Ablashi2, Peter F. Ambros3, Henri Agut4,
Mary T. Caserta5, Vincent Descamps6, Louis Flamand7,
Agnès Gautheret-Dejean4, Caroline B. Hall8, Rammurti T. Kamble9,
Uwe Kuehl10, Dirk Lassner11, Irmeli Lautenschlager12,
Kristin S. Loomis2, Mario Luppi13, Paolo Lusso14, Peter G. Medveczky15,
Jose G. Montoya16, Yasuko Mori17, Masao Ogata18, Joshua C. Pritchett2,
Sylvie Rogez19, Edward Seto20, Katherine N. Ward21, Tetsushi Yoshikawa22
and Raymund R. Razonable23**
1Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA
2HHV-6 Foundation, Santa Barbara, CA, USA
3Children ’s Cancer Research Institute, Vienna, Austria
4Service of Virology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
5Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY, USA
6Department of Dermatology, Bichat Claude Bernard Hospital, Paris, France
7Rheumatology and Immunology Research Center, Université Laval, Quebec, Canada
8Departments of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry,
Rochester, NY, USA
9Hematology & Oncology, Baylor College of Medicine, Houston, TX, USA
10Cardiology and Pneumonology, Charite University Berlin, Berlin, Germany
11Institute for Cardiac Diagnosis & Treatment, Berlin, Germany
12Department of Virology, HUSLAB & University of Helsinki, Helsinki, Finland
13University of Modena and Reggio Emilia, Emilia –Romagna, Italy
14National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
15Department of Molecular Medicine, University of South Florida, Tampa, FL, USA
16Department of Infectious Disease, Stanford University, Stanford, CA, USA
17Division of Clinical Virology, Kobe University, Kobe, Hy ōgo, Japan
18Hematology, Blood Transfusion Center, Oita University, Oita, Japan
19Department of Virology, CHRU Dupuytren, Limoges, France
20Department of Molecular Oncology, Mof fitt Cancer Center & Research Institute, USA
21Department of Infection, University College London, London, UK
22Department of Pediatrics, Fujita Health University, Toyoake, Aichi, Japan
23Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA
SUMMARY
Chromosomally integrated human herpesvirus 6 (ciHHV- 6) is a condition in which the complete HHV-6 genome
is integrated into the host germ line genome and is vert ically transmitted in a Mendelian manner. The condition
*Correspondence to: P. E. Pellett, PhD, Professor, Department of Immunology, and Microbiology, Wayne State University, 6225 Scott Hall, 540
East Can field Avenue, Detroit, MI 48201.
E-mail:
**Correspondence to: R. Razonable, MD, Associate Professor, Division of In fectious Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 559 05.
E-mail:
Abbreviations used:
AHS, anticonvulsant-induced hypersensitiviy syndrome; ALL, acute lymphocytic leukemia; DIHS, drug-induced hypersensitivity syndrome; DRESS, drug
rash with eosinophilia and systemic symptoms; FDA, United States ’Food and Drug Administration; FISH, fluorescence in situ hybridization; GVHD,
graft-versus-host disease; HDAC, histone deacetylase; HSC T, hematopoietic stem cell transplantation; SJS, Stevens –Johnson syndrome; SOT, solid organ
transplantation; TEN, toxic epidermal necrolysis.Rev. Med. Virol. (2011)
Published online in Wiley Online Library
(wileyonlinelibrary.com)
DOI: 10.1002/rmv.715 Reviews in Medical Virology
Copyright © 2011 John Wiley & Sons, Ltd. is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in
transplant recipients and other patient populations in several small studies. HHV-6 levels in whole blood that
exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV-6. Monitoring DNA load in plasma and serum is
unreliable, both for identifying and for monitoring subje cts with ciHHV-6 due to cell lysis and release of cellular
DNA. High HHV-6 DNA loads associated with ciHHV-6 can lead to erroneous diagnosis of active infection.
Transplant recipients with ciHHV-6 may be at increased r isk for bacterial infection and graft rejection. ciHHV-6
can be induced to a state of active viral replication in vitro . It is not known whether ciHHV-6 individuals are
p u ta tc l i n i c a lr i s kb yt h eu s eo fd r u g st h a th a v e been associated with HHV-6 reactivation in vivo orin vitro .
Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have
ciHHV-6. Little is known about whether individuals with c iHHV-6 develop immune tolerance for viral proteins.
Further research is needed to determine the role of ciHH V-6 in disease. Copyright © 2011 John Wiley & Sons, Ltd.
Supporting information can be found in the online version of this article
Received: 9 August 2011; Revised: 2 September 2011; Accepted: 15 September 2011
INTRODUCTION
This is a review of chromosomally integrated
human herpesvirus 6 (ciHHV-6) and its potential
clinical implications (Table 1), in the form of a series
of questions and answers. The major points are
summarized in Table 2. In many areas, available
data are insuf ficient to support evidence-based
guidance, leaving us with our opinions. We provide
a list of research questions (Table 3) to motivate
studies that will allow more extensive evidence-
based guidance to be offered in several years. Table 4
lists drugs associated with HHV-6 reactivation; an
expanded version is provided in Supplemental
Table 1. Background information about human
herpesvirus 6 (HHV-6) and ciHHV-6 is available
elsewhere [1 –6].What is human herpesvirus 6?
Human herpesvirus 6 is the collective name for
HHV-6A and HHV-6B, which are two closely related
herpesviruses that have a combined seroprevalence
of>90% in adults. HHV-6B is typically transmitted
via saliva and primary infection usually occurs
between 6 months and 2 –3 years of age. Many
primary HHV-6B infections are not associated
with any speci fic clinical features, although the
virus causes roseola infantum (exanthema subitum
or sixth disease) in ~30% of children, presenting
with high-grade fever followed by a characteristic
rash that is sometimes accompanied by benign
febrile convulsions, and rarely by status epilepticus.
Little is known about primary HHV-6A infection
and its disease associations. For the 99% of the
Table 1. Clinical scenarios that may be associated with ciHHV-6
Misdiagnosis of active HHV-6 infection in ciHHV-6 individuals presenting with unconnected illnesses.
Incidental positivity of CSF PCR for HHV-6 in ciHHV-6 patients with CSF pleocytosis resulting in
erroneous diagnosis and unnecessary treatment.
Persistence of high levels of HHV-6 genomes (high HHV-6 DNA copy numbers).
Transmission of ciHHV-6 hematopoietic cells from donor to recipient following allogeneic HSCT.
Presence of high levels of HHV-6 DNA in the non-hematopoietic tissues but not in the hematopoietic
tissues of a ciHHV-6 individual who received a non-ciHHV-6 HCST.
Transplantation of a solid organ from an individual with ciHHV-6 to a recipient without ciHHV-6.
Potential for ciHHV-6 reactivation in immunocompromised hosts.
Potential for ciHHV-6 reactivation in individuals treated with certain drugs.
Increased risk of bacterial infection in SOT recipients with ciHHV-6.
Uncertainty as to whether to treat ciHHV-6 patients who have symptoms associated with HHV-6 activity,
such as CNS dysfunction.
ciHHV-6, chromosomally integrated human herpesvirus 6; HHV-6, human herpesvirus 6; HSCT, hematopoietic stem
cell transplantation; SOT, solid organ transplantation.P. E. Pellett et al .
Copyright © 2011 John Wiley & Sons, Ltd. Rev. Med. Virol. (2011)
DOI: 10.1002/rmv

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