Rev. Med. Virol. (2011)
Published online in Wiley Online Library
(wileyonlinelibrary.com)
Reviews in Medical Virology DOI: 10.1002/rmv.715
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**
1
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA
2
HHV-6 Foundation, Santa Barbara, CA, USA
3
Children’s Cancer Research Institute, Vienna, Austria
4
Service of Virology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
5
Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY, USA
6
Department of Dermatology, Bichat Claude Bernard Hospital, Paris, France
7
Rheumatology and Immunology Research Center, Université Laval, Quebec, Canada
8
Departments of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry,
Rochester, NY, USA
9
Hematology & Oncology, Baylor College of Medicine, Houston, TX, USA
10
Cardiology and Pneumonology, Charite University Berlin, Berlin, Germany
11
Institute for Cardiac Diagnosis & Treatment, Berlin, Germany
12
Department of Virology, HUSLAB & University of Helsinki, Helsinki, Finland
13
University of Modena and Reggio Emilia, Emilia–Romagna, Italy
14
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
15
Department of Molecular Medicine, University of South Florida, Tampa, FL, USA
16
Department of Infectious Disease, Stanford University, Stanford, CA, USA
17
Division of Clinical Virology, Kobe University, Kobe, Hyōgo, Japan
18
Hematology, Blood Transfusion Center, Oita University, Oita, Japan
19
Department of Virology, CHRU Dupuytren, Limoges, France
20
Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, USA
21
Department of Infection, University College London, London, UK
22
Department of Pediatrics, Fujita Health University, Toyoake, Aichi, Japan
23
Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA
S U M M A RY
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 vertically 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 Canfield Avenue, Detroit, MI 48201.
E-mail:
**Correspondence to: R. Razonable, MD, Associate Professor, Division of Infectious Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905.
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; HSCT, hematopoietic stem cell transplantation; SJS, Stevens–Johnson syndrome; SOT, solid organ
transplantation; TEN, toxic epidermal necrolysis.
Copyright © 2011 John Wiley & Sons, Ltd.
, P. E. Pellett et al.
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 subjects 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 risk 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
put at clinical risk by the use of drugs that have been associated with HHV-6 reactivation in vivo or in 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 ciHHV-6 develop immune tolerance for viral proteins.
Further research is needed to determine the role of ciHHV-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 What is human herpesvirus 6?
This is a review of chromosomally integrated Human herpesvirus 6 is the collective name for
human herpesvirus 6 (ciHHV-6) and its potential HHV-6A and HHV-6B, which are two closely related
clinical implications (Table 1), in the form of a series herpesviruses that have a combined seroprevalence
of questions and answers. The major points are of >90% in adults. HHV-6B is typically transmitted
summarized in Table 2. In many areas, available via saliva and primary infection usually occurs
data are insufficient to support evidence-based between 6 months and 2–3 years of age. Many
guidance, leaving us with our opinions. We provide primary HHV-6B infections are not associated
a list of research questions (Table 3) to motivate with any specific clinical features, although the
studies that will allow more extensive evidence- virus causes roseola infantum (exanthema subitum
based guidance to be offered in several years. Table 4 or sixth disease) in ~30% of children, presenting
lists drugs associated with HHV-6 reactivation; an with high-grade fever followed by a characteristic
expanded version is provided in Supplemental rash that is sometimes accompanied by benign
Table 1. Background information about human febrile convulsions, and rarely by status epilepticus.
herpesvirus 6 (HHV-6) and ciHHV-6 is available Little is known about primary HHV-6A infection
elsewhere [1–6]. 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.
Copyright © 2011 John Wiley & Sons, Ltd. Rev. Med. Virol. (2011)
DOI: 10.1002/rmv
Published online in Wiley Online Library
(wileyonlinelibrary.com)
Reviews in Medical Virology DOI: 10.1002/rmv.715
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**
1
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA
2
HHV-6 Foundation, Santa Barbara, CA, USA
3
Children’s Cancer Research Institute, Vienna, Austria
4
Service of Virology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
5
Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY, USA
6
Department of Dermatology, Bichat Claude Bernard Hospital, Paris, France
7
Rheumatology and Immunology Research Center, Université Laval, Quebec, Canada
8
Departments of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry,
Rochester, NY, USA
9
Hematology & Oncology, Baylor College of Medicine, Houston, TX, USA
10
Cardiology and Pneumonology, Charite University Berlin, Berlin, Germany
11
Institute for Cardiac Diagnosis & Treatment, Berlin, Germany
12
Department of Virology, HUSLAB & University of Helsinki, Helsinki, Finland
13
University of Modena and Reggio Emilia, Emilia–Romagna, Italy
14
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
15
Department of Molecular Medicine, University of South Florida, Tampa, FL, USA
16
Department of Infectious Disease, Stanford University, Stanford, CA, USA
17
Division of Clinical Virology, Kobe University, Kobe, Hyōgo, Japan
18
Hematology, Blood Transfusion Center, Oita University, Oita, Japan
19
Department of Virology, CHRU Dupuytren, Limoges, France
20
Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, USA
21
Department of Infection, University College London, London, UK
22
Department of Pediatrics, Fujita Health University, Toyoake, Aichi, Japan
23
Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA
S U M M A RY
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 vertically 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 Canfield Avenue, Detroit, MI 48201.
E-mail:
**Correspondence to: R. Razonable, MD, Associate Professor, Division of Infectious Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905.
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; HSCT, hematopoietic stem cell transplantation; SJS, Stevens–Johnson syndrome; SOT, solid organ
transplantation; TEN, toxic epidermal necrolysis.
Copyright © 2011 John Wiley & Sons, Ltd.
, P. E. Pellett et al.
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 subjects 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 risk 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
put at clinical risk by the use of drugs that have been associated with HHV-6 reactivation in vivo or in 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 ciHHV-6 develop immune tolerance for viral proteins.
Further research is needed to determine the role of ciHHV-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 What is human herpesvirus 6?
This is a review of chromosomally integrated Human herpesvirus 6 is the collective name for
human herpesvirus 6 (ciHHV-6) and its potential HHV-6A and HHV-6B, which are two closely related
clinical implications (Table 1), in the form of a series herpesviruses that have a combined seroprevalence
of questions and answers. The major points are of >90% in adults. HHV-6B is typically transmitted
summarized in Table 2. In many areas, available via saliva and primary infection usually occurs
data are insufficient to support evidence-based between 6 months and 2–3 years of age. Many
guidance, leaving us with our opinions. We provide primary HHV-6B infections are not associated
a list of research questions (Table 3) to motivate with any specific clinical features, although the
studies that will allow more extensive evidence- virus causes roseola infantum (exanthema subitum
based guidance to be offered in several years. Table 4 or sixth disease) in ~30% of children, presenting
lists drugs associated with HHV-6 reactivation; an with high-grade fever followed by a characteristic
expanded version is provided in Supplemental rash that is sometimes accompanied by benign
Table 1. Background information about human febrile convulsions, and rarely by status epilepticus.
herpesvirus 6 (HHV-6) and ciHHV-6 is available Little is known about primary HHV-6A infection
elsewhere [1–6]. 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.
Copyright © 2011 John Wiley & Sons, Ltd. Rev. Med. Virol. (2011)
DOI: 10.1002/rmv
