Inherited Chromosomally Integrated Human Herpesvirus 6: Laboratory and Clinical Features

Inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) is a condition in which the complete HHV-6 genome is integrated into the chromosomes of the host germ cell and is vertically transmitted. The aims of this study were to identify iciHHV-6 prevalence in hospitalized patients and clinical features in individuals carrying this integration. HHV-6 PCR on hair follicles was used to confirm iciHHV-6 status when the blood viral load was more than 5 Log10 copies/mL. From January 2012 to June 2022, HHV-6 DNAemia was investigated in 2019 patients. In particular, 49 had a viral load higher than 6 Log10 copies/mL and HHV-6 DNA in hair follicles was positive. A viral load between 5.0 and 5.9 Log10 copies/mL was observed in 10 patients: 6 infants with acute HHV-6 infection and 4 patients with leukopenia and HHV-6 integration. Therefore, the iciHHV-6 prevalence in our population was 2.6% (53/2019). Adult patients with integration presented hematological (24%), autoimmune (11%), autoimmune neurological (19%), not-autoimmune neurological (22%), and other diseases (19%), whereas 5% had no clinically relevant disease. Although in our study population a high percentage of iciHHV-6 adult hospitalized patients presented a specific pathology, it is still unknown whether the integration is responsible for, or contributes to, the disease development.

[1]  T. Olsson,et al.  High antibody levels against human herpesvirus-6A interact with lifestyle factors in multiple sclerosis development , 2021, Multiple sclerosis.

[2]  T. Stevens-Ayers,et al.  Association of inherited chromosomally integrated human herpesvirus 6 with neurologic symptoms and management after allogeneic hematopoietic cell transplantation. , 2021, Transplantation and cellular therapy.

[3]  Shyam A. Patel,et al.  Post-allogeneic hematopoietic stem cell transplantation viral reactivations and viremias: a focused review on human herpesvirus-6, BK virus and adenovirus , 2021, Therapeutic advances in infectious disease.

[4]  R. Rizzo,et al.  The U94 Gene of Human Herpesvirus 6: A Narrative Review of Its Role and Potential Functions , 2020, Cells.

[5]  B. Kaufer,et al.  Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6 , 2020, Proceedings of the National Academy of Sciences.

[6]  B. Kaufer,et al.  Current understanding of human herpesvirus 6 (HHV-6) chromosomal integration. , 2020, Antiviral research.

[7]  H. Agut,et al.  Evaluation of liver failure in a pediatric transplant recipient of a liver allograft with inherited chromosomally integrated HHV‐6B , 2020, Journal of medical virology.

[8]  A. Komaroff,et al.  Summary of the 11th International Conference on Human Herpesviruses‐6A, ‐6B, and ‐7 , 2019, Journal of medical virology.

[9]  J. Crawford,et al.  Human Herpesvirus 6 and Malignancy: A Review , 2018, Front. Oncol..

[10]  C. Gaudy-Graffin,et al.  Fatal outcome after reactivation of inherited chromosomally integrated HHV‐6A (iciHHV‐6A) transmitted through liver transplantation , 2018, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  M. Boeckh,et al.  Human Herpesvirus-6B Reactivation Is a Risk Factor for Grades II to IV Acute Graft-versus-Host Disease after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis , 2018, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[12]  B. Sandmaier,et al.  Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. , 2017, Blood.

[13]  R. Neumann,et al.  Inherited Chromosomally Integrated Human Herpesvirus 6 Genomes Are Ancient, Intact, and Potentially Able To Reactivate from Telomeres , 2017, Journal of Virology.

[14]  Shara N. Pantry,et al.  Latency, Integration, and Reactivation of Human Herpesvirus-6 , 2017, Viruses.

[15]  N. Royle,et al.  Chromosomally Integrated Human Herpesvirus 6: Models of Viral Genome Release from the Telomere and Impacts on Human Health , 2017, Viruses.

[16]  L. Flamand,et al.  HHV-6A/B Integration and the Pathogenesis Associated with the Reactivation of Chromosomally Integrated HHV-6A/B , 2017, Viruses.

[17]  A. Cuneo,et al.  Detection of inherited chromosomally integrated HHV‐6 (ciHHV‐6) in a marker chromosome , 2017, European journal of haematology.

[18]  K. Kapur,et al.  HHV‐6 and seizure: A systematic review and meta‐analysis , 2017, Journal of medical virology.

[19]  D. Clark,et al.  Clinical and laboratory features of human herpesvirus 6 chromosomal integration. , 2016, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[20]  M. Boeckh,et al.  Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR , 2016, Journal of Clinical Microbiology.

[21]  H. Kurahashi,et al.  A simple cytogenetic method to detect chromosomally integrated human herpesvirus-6. , 2016, Journal of virological methods.

[22]  G. Morissette,et al.  Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris , 2015, Proceedings of the National Academy of Sciences.

[23]  H. Agut,et al.  Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections , 2015, Clinical Microbiology Reviews.

[24]  B. Kaufer,et al.  Chromosomally integrated HHV-6: impact on virus, cell and organismal biology. , 2014, Current opinion in virology.

[25]  T. Morio,et al.  Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency. , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  H. Kurahashi,et al.  Dual roles for the telomeric repeats in chromosomally integrated human herpesvirus-6 , 2014, Scientific Reports.

[27]  A. Jeffreys,et al.  Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome , 2013, Nucleic acids research.

[28]  H. Agut,et al.  Classification of HHV-6A and HHV-6B as distinct viruses , 2014, Archives of Virology.

[29]  E. Nacheva,et al.  Chromosomal integration of the HHV‐6 genome in a patient with nodular sclerosis Hodgkin lymphoma , 2013, British journal of haematology.

[30]  A. Takaori-Kondo,et al.  Human herpesvirus‐6 encephalitis during hematopoietic stem cell transplantation leads to poor prognosis , 2013, Transplant infectious disease : an official journal of the Transplantation Society.

[31]  M. J. Adams,et al.  Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2012) , 2012, Archives of Virology.

[32]  H. Agut,et al.  Chromosomally integrated human herpesvirus 6: questions and answers , 2011, Reviews in medical virology.

[33]  Jesse H. Arbuckle,et al.  The molecular biology of human herpesvirus-6 latency and telomere integration. , 2011, Microbes and infection.

[34]  L. Chin,et al.  Telomere dysfunction induces metabolic and mitochondrial compromise , 2011, Nature.

[35]  H. Schouten,et al.  Temporal relationship between HHV 6 and graft vs host disease in a patient after haplo-identical SCT and severe T-cell depletion , 2011, Bone Marrow Transplantation.

[36]  K. Akashi,et al.  High incidence of human herpes virus 6-associated encephalitis/myelitis following a second unrelated cord blood transplantation. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[37]  A. Komaroff,et al.  Review Part 3: Human herpesvirus‐6 in multiple non‐neurological diseases , 2010, Journal of medical virology.

[38]  Louis Flamand,et al.  Herpesviruses and Chromosomal Integration , 2010, Journal of Virology.

[39]  C. Hall,et al.  Diagnostic assays for active infection with human herpesvirus 6 (HHV-6). , 2010, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[40]  Jesse H. Arbuckle,et al.  The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro , 2010, Proceedings of the National Academy of Sciences.

[41]  T. Saikawa,et al.  Correlations of HHV-6 viral load and plasma IL-6 concentration with HHV-6 encephalitis in allogeneic stem cell transplant recipients , 2010, Bone Marrow Transplantation.

[42]  H. Agut,et al.  Different expression of human herpesvirus-6 (HHV-6) load in whole blood may have a significant impact on the diagnosis of active infection. , 2009, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[43]  M. Luppi,et al.  Prevalence of Human Herpesvirus‐6 Chromosomal Integration (CIHHV‐6) in Italian Solid Organ and Allogeneic Stem Cell Transplant Patients , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[44]  P. Hubáček,et al.  HHV‐6 DNA throughout the tissues of two stem cell transplant patients with chromosomally integrated HHV‐6 and fatal CMV pneumonitis , 2009, British journal of haematology.

[45]  P. Hubáček,et al.  Prevalence of HHV‐6 integrated chromosomally among children treated for acute lymphoblastic or myeloid leukemia in the Czech Republic , 2009, Journal of medical virology.

[46]  E. Estey,et al.  Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia , 2009, Proceedings of the National Academy of Sciences.

[47]  H. Leong,et al.  Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal Sites , 2008, Journal of medical virology.

[48]  P. Hubáček,et al.  Disappearance of pre-existing high HHV-6 DNA load in blood after allogeneic SCT , 2007, Bone Marrow Transplantation.

[49]  H. Heslop,et al.  Transmission of integrated human herpesvirus-6 in allogeneic hematopoietic stem cell transplantation , 2007, Bone Marrow Transplantation.

[50]  P. Lansdorp,et al.  Telomerase mutations in families with idiopathic pulmonary fibrosis. , 2007, The New England journal of medicine.

[51]  H. Leong,et al.  Human Herpesvirus 6 DNA Levels in Cerebrospinal Fluid Due to Primary Infection Differ from Those Due to Chromosomal Viral Integration and Have Implications for Diagnosis of Encephalitis , 2007, Journal of Clinical Microbiology.

[52]  P. Griffiths,et al.  The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors , 2007, Journal of medical virology.

[53]  M. Luppi,et al.  Human herpesvirus 6 latency characterized by high viral load: chromosomal integration in many, but not all, cells. , 2006, The Journal of infectious diseases.

[54]  J. Kamil,et al.  Marek's disease virus: from miasma to model , 2006, Nature Reviews Microbiology.

[55]  P. Griffiths,et al.  Human Herpesvirus 6 Chromosomal Integration in Immunocompetent Patients Results in High Levels of Viral DNA in Blood, Sera, and Hair Follicles , 2006, Journal of Clinical Microbiology.

[56]  P. Griffiths,et al.  Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis. , 2006, The Journal of infectious diseases.

[57]  K. Ward,et al.  Unexpected occasional persistence of high levels of HHV‐6 DNA in sera: Detection of variants A and B , 2005, Journal of medical virology.

[58]  S. Chanock,et al.  Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. , 2005, The New England journal of medicine.

[59]  M. Boeckh,et al.  Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[60]  E. De Clercq,et al.  Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy , 2005, Clinical Microbiology Reviews.

[61]  D. Boutolleau,et al.  Reactivation of human herpesvirus 6 during ex vivo expansion of circulating CD34+ haematopoietic stem cells. , 2004, The Journal of general virology.

[62]  H. Kurahashi,et al.  Human herpesvirus 6 (HHV‐6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV‐6 DNA , 2004, Journal of medical virology.

[63]  T. Yoshikawa Human herpesvirus 6 infection in hematopoietic stem cell transplant patients , 2004, British journal of haematology.

[64]  J. Potter,et al.  Chromosomal instability in ulcerative colitis is related to telomere shortening , 2002, Nature Genetics.

[65]  T. Vulliamy,et al.  Association between aplastic anaemia and mutations in telomerase RNA , 2002, The Lancet.

[66]  Margaret A. Strong,et al.  The Shortest Telomere, Not Average Telomere Length, Is Critical for Cell Viability and Chromosome Stability , 2001, Cell.

[67]  Lynda Chin,et al.  Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice , 2000, Nature.

[68]  K. Collins,et al.  A telomerase component is defective in the human disease dyskeratosis congenita , 1999, Nature.

[69]  H. Taguchi,et al.  Inheritance of chromosomally integrated human herpesvirus 6 DNA. , 1999, Blood.

[70]  C. Morris,et al.  Fine mapping of an apparently targeted latent human herpesvirus type 6 integration site in chromosome band 17p13.3 , 1999, Journal of medical virology.

[71]  C. Morris,et al.  Human Herpesvirus 6 Latently Infects Early Bone Marrow Progenitors In Vivo , 1999, Journal of Virology.

[72]  H. Taguchi,et al.  Chromosomal transmission of human herpesvirus 6 DNA in acute lymphoblastic leukaemia , 1998, The Lancet.

[73]  N. Young,et al.  A new syndrome of familial aplastic anemia and chronic liver disease. , 1997, Acta haematologica.

[74]  S. Ferrari,et al.  Targeted integration of human herpesvirus 6 in the p arm of chromosome 17 of human peripheral blood mononuclear cells in vivo , 1995, Journal of medical virology.

[75]  K. Ohyashiki,et al.  Telomere shortening associated with disease evolution patterns in myelodysplastic syndromes. , 1994, Cancer research.

[76]  S. Ferrari,et al.  Three cases of human herpesvirus‐6 latent infection: Integration of viral genome in peripheral blood mononuclear cell DNA , 1993, Journal of medical virology.

[77]  A. Wilkie,et al.  A truncated human chromosome 16 associated with α thalassaemia is stabilized by addition of telomeric repeat (TTAGGG)n , 1990, Nature.

[78]  K. Yamanishi,et al.  IDENTIFICATION OF HUMAN HERPESVIRUS-6 AS A CAUSAL AGENT FOR EXANTHEM SUBITUM , 1988, The Lancet.