In vitro studies confirm that the two viruses infect different cell types, and generate different cytopathic effects, cytokine and growth factor responses.
Two HHV-6 genes may contribute to pathogenesis of autoimmune thyroiditis
Genes U12 and U51 encode homologues of human G-protein-coupled receptors, and are potential triggers of autoimmunity.
Murine roseolovirus (MRV) infection experiments are only partially supportive of role of HHV-6A/B in Alzheimer’s disease
While MRV administered peripherally led to brain infection and neuroinflammation, it did not increase Aß deposition
HHV-6A promotes inflammation in astrocytoma cells by dysregulating autophagy
Infection increases ROS, induces ER stress and activates STAT3, NF-κB and mTOR pathways.
EBV and HHV-6 plasma viremia is infrequent at Day 7 during acute COVID-19
Other studies have suggested that reactivation of these viruses could theoretically contribute to a hyperinflammatory state or autoimmune disorders in acute COVID-19, but this study does not provide evidence of that.
Possible link between depression and HHV-6 infection in childhood
Serologic studies of several herpesviruses find that only HHV-6 may be linked to depression.
Does inherited chromosomal integration of HHV-6 at 9q increase the risk of malignancy?
A large study of iciHHV-6 integration sites found integration at 9q more common in hematologic malignancies—but the study lacked power to draw firm conclusions.
New seroepidemiological evidence that HHV-6 contributes to MS disease progression
Longitudinal study of people with a single initial episode of demyelination provides stronger evidence for HHV-6 than EBV in the pathogenesis of MS, but the evidence is not robust.
Development of highly sensitive technique for detecting viral DNA sequences in cell-free plasma
Isolating DNA fragments less than 120 base pairs enriches for viral vs. cellular DNA.
Resected tonsil and adenoid tissues harbor high viral loads of HHV-6, HHV-7 and EBV as well as respiratory viruses
HHV-6 was found in 33% of adenoid and 45% of tonsil tissues, with the highest rates found in younger children.
G-1082A polymorphism of IL-10 may protect against HHV-6/EBV adenoid hypertrophy
The presence of HHV-6 and EBV DNA in nasal secretions correlates with the degree of adenoid hypertrophy in children.
HHV-6A U14 protein and NFκB activate each other
The late protein U14 of HHV-6A can induce the pro-inflammatory transcription factor NFκB, and NFκB, in turn, can encourage the replication of HHV-6A.
Different isoforms of CD46 affect infectivity and replication of HHV-6A and HHV-6B
While CD134 remains the more important receptor for HHV-6B, HHV-6B can use the CD46 receptor when a T cell has the C1 isoform of CD46.
HHV-6B may enter cells that don’t express CD134 via the nectin-2 receptor
If confirmed, finding could explain ability of HHV-6B to infect salivary, liver and neural cells.
Adding an adoptive NK cell infusion to naïve T-Cell-depleted grafts may reduce the rate of HHV-6B reactivation and encephalitis
A small pediatric study found that adoptive NK cell infusions eliminated HHV-6B encephalitis, while maintaining a low rate of GVHD. At a ratio of NK/CD4 >2, the HHV-6B reactivation rate dropped dramatically.
Murine roseolovirus (MRV) infection experiments are only partially supportive of role of HHV-6A/B in Alzheimer’s disease
While MRV administered peripherally led to brain infection and neuroinflammation, it did not increase Aß deposition
HHV-6A promotes inflammation in astrocytoma cells by dysregulating autophagy
Infection increases ROS, induces ER stress and activates STAT3, NF-κB and mTOR pathways.
A potential mechanism by which HHV-6A infection could promote Alzheimer’s Disease
HHV-6A was found to both enhance expression and inhibit degradation of amyloid precursor protein in vitro.
The role of HHV-6 in dysregulating autophagy
HHV-6, like some other herpesviruses, dysregulates autophagy in multiple cell types, with important biological consequences.
HHV-6A/B in brain disease: proposed criteria for establishing causation
Three top experts on HHV-6A/B teamed up to write a comprehensive review and propose criteria for establishing HHV-6A/B to MS, epilepsy and Alzheimer’s disease.
HHV-6A and the suppression of miR155 in Alzheimer’s pathology
Dysregulation of the microRNA miR155 is associated with pathophysiological progression of Alzheimer’s disease. HHV-6A has been shown to suppress miR155.
Clonally expanded CD8 T cells in spinal fluid of Alzheimer’s patients suggest an adaptive immune response to pathogens
Researchers at the NIH used RNA-Seq cells from skin and blood to study the underlying mechanisms in DIHS/DRESS and identified both HHV-6 and JAK-STAT pathways as potential targets. Central memory CD4+T cells were enriched with HHV-6B.
NINDS/NIH investigators find very little HHV-6 RNA or DNA in either Alzheimer’s or control brains
A team led by Steven Jacobson, PhD at NINDS analyzed RNA-seq datasets from 901 brains, and found only 1.2% of Alzheimer’s patients and 0.4% of controls positive for HHV-6 RNA. They also found HHV-6 DNA in less than 4% of samples tested by ddPCR.
The debate continues over RNA-seq analysis of HHV-6A in Alzheimer’s
Two groups have challenged the widely-publicized 2018 study in 2018, that found increased HHV-6A & 7 abundance and an association with clinical and pathology scores in Alzheimer’s. The topic has become the focus vigorous debate.
HHV-6A induces dysregulation of autophagy in neurons and astrocytoma cells, increasing beta-amyloid and tau
Building on their prior work, an Italian team has shown that HHV-6A is able to induce dysregulation of autophagy in neurons and astrocytoma cells, increasing amyloid beta and tau production.
HHV-6A activates microglia and increases Aβ and tau expression
HHV-6A infection of microglia cells increases inflammatory markers and Aβ and tau expression dramatically, supporting the hypothesis that plaque development in Alzheimer’s disease may be an innate immune response to pathogens
HHV-6B induces ER stress in primary monocytes, impairing their survival and differentiation into dendritic cells
Investigators propose that the induction of endoplasmic reticulum stress, likely exacerbated by autophagy inhibition, could contribute to the immune suppression induced by HHV-6B in exanthem subitem patients.
Differential gene expression pattern shared in herpesviruses, Alzheimer’s & Parkinson’s patients
Researchers from GlaxoSmithKline found a significant overlap in differentially expressed genes shared by those with herpesvirus infections, Alzheimer’s and Parkinson’s. On the other hand, there was no significant overlap between herpesviruses and Type 2 diabetes or Huntington’s disease.
Herpesvirus acquires protein corona that facilitates the formation of Alzheimer’s plaques
Swedish researchers report that viruses interact with proteins to form a coating or protein corona that facilitates the formation of amyloid plaque, supporting previous findings by Harvard’s Rudy Tanzi and Robert Moir.
Single-cell transcriptomic analysis of Alzheimer’s brains showed early changes that are highly cell-type specific with APOE strongly upregulated in the microglia
MIT examined transcription across tens of thousands of individual cells in both Alzheimer’s and healthy brains and found APOE strongly upregulated in the microglia and perturbation in myelination-related processes in multiple cell types including oligodendrocytes.
Murine roseolovirus (MRV) infection experiments are only partially supportive of role of HHV-6A/B in Alzheimer’s disease
While MRV administered peripherally led to brain infection and neuroinflammation, it did not increase Aß deposition
New humanized mouse model mimics HHV-6B pathogenesis
Researchers led by Yasuko Mori of Kobe University in Japan have developed an animal model will be useful for studying the pathogenicity of HHV-6B in conditions such as acute GVHD and idiopathic pneumonia
A comparison of human, porcine and murine roseoloviruses
Experts in human, murine and porcine roseolovirus combined forces to write a fascinating comparative review.
HHV-6 increases risk of an “idiopathic” pneumonia syndrome after HCT as does murine roseolovirus in a BMT mouse model. Early HHV-6 was also found to increase non-relapse mortality
Investigators from University of Michigan have demonstrated that murine roseolovirus is a useful homolog for the study of HHV-6 reactivation in lung disease. In a large retrospective study of HCT patients, they also found early HHV-6 reactivation to increase the risk of both idiopathic pneumonia syndrome and non-relapse mortality.
Porcine cytomegalovirus to be re-classified as a roseolovirus
Porcine CMV is an immunosuppressive virus that inhibits T-lymphocyte and macrophage immune functions, and like HHV-6A, it causes infertility. Porcine CMV infection also reduces the survival of pig xenotransplants.
Infection with HHV-6A/B speeds progression of disease in marmoset model of MS
Marmosets infected with HHV-6A/B intranasally were initially asymptomatic but later developed significantly accelerated disease and died in a shorter period of time. HHV-6 proteins were found at high levels in the brain lesions.
New mouse model for HHV-6 & 7
Investigators at Washington University have sequenced a murine herpesvirus and determined that it is closely related to HHV-6 & 7. Named Murine Rosesolovirus (MRV), the virus causes severe depletion of CD4+ T cells and thymic necrosis in young mice. The authors believe that MRV will be a useful mouse model to study the impact of HHV-6 & 7 in humans.
HHV-7 homolog found in the peripheral nerve ganglia of macaques
Virologists led by Serge Barcy, PhD at the Seattle Children’s Research Institute and University of Washington have identified a homolog for HHV-7 in pigtail macaques They were surprised to learn that it could be detected in the peripheral nerve ganglia, and hope to use their new animal model to explore how HHV-7 might play a role in demyelinating diseases.
Is there a new HHV-6 animal model on the horizon?
Seattle group announces the discovery of novel HHV-6 and HHV-7 homologs in pig-tailed macaques
New mouse model of HHV-6A CNS infection developed
New model of HHV-6A infection demonstrates persistent abortive infection and neuroinflammation via TLR9
Spotlight on Horvat & Reynaud from INSERM
Branka Horvat, MD, PhD, Director of Research at the International Centre for Infectiology Research in Lyon, France (INSERM), and her doctoral student Josephine Reynaud have recently published an important paper on a new transgenic mouse model
Humanized mouse model demonstrates HHV-6A infection can cause significant immune dysfunction
Could treatment of HHV-6A co-infections slow AIDS progression?
NIH Laboratory develops novel marmoset model of HHV-6A & HHV-6B infection
Dr. Steven Jacobson’s laboratory at the US National Institute of Health has developed a novel marmoset model for the study of HHV-6 infection.
Two HHV-6 genes may contribute to pathogenesis of autoimmune thyroiditis
Genes U12 and U51 encode homologues of human G-protein-coupled receptors, and are potential triggers of autoimmunity.
HHV-6, enterovirus and parvovirus B-19 found in the thyroid tissue of both autoimmune disease patients… and controls
Failure to distinguish HHV-6A from HHV-6A/B, and questions about assay sensitivity, make results difficult to interpret.
HHV-6A and HCMV induce pro-fibrotic miRNA expression pattern in infected host cells
Pattern consistent with clinical studies suggesting these viruses may be one trigger of systemic sclerosis.
Neonatal murine roseolovirus infection induces autoimmunity
Early infection interferes with normal thymocyte development and disrupts central tolerance resulting in autoimmune disease later in life. Only infection during this critical time period resulted in autoimmunity.
A comprehensive review of the role and potential functions HHV-6A/B U94
The review covers the role the U94 gene product plays in the virus’s life cycle, replication, and latency, as well as in the immune response.
The role of HHV-6 in dysregulating autophagy
HHV-6, like some other herpesviruses, dysregulates autophagy in multiple cell types, with important biological consequences.
iciHHV-6 not found to increase the risk of chronic autoimmune disease
Japanese investigators found no cases of iciHHV6 among 846 patients with several chronic autoimmune diseases
No HHV-6 DNA found in the spinal fluid of immunocompetent adults evaluated for limbic encephalitis
While HHV-6B is well known to cause limbic encephalitis in transplant patients, it does not appear to play a role in other forms of limbic encephalitis.
HHV-6A detected in the skin biopsies of systemic sclerosis patients
A group led by Elisabetta Caselli at University of Ferrara discovered HHV-6A in the skin and elevated levels of HHV6-B in the peripheral blood of systemic sclerosis patients
HHV-6B is found at higher levels in the pancreatic islets of type 1 diabetes patients
Investigators from the La Jolla Institute of Immunology used high-resolution confocal microscopy to detect high levels of HHV-6 protein in the pancreatic islet cells from donors with type 1 diabetes.
HHV-6 and EBV found in the brain tissue of Rasmussen’s Encephalitis patients
Chinese investigators found a high prevalence of HHV-6 and Epstein Barr virus in the brain tissues of children with Rasmussen’s encephalitis but in none of the controls. There was a significant association between viral presence and brain atrophy, raising a strong suspicion for the involvement of both viruses.
HHV-6B found in the islet cells of both type 1 diabetes patients and controls
Swedish investigators have found HHV-6 protein in the pancreatic islet cells of both type 1 diabetes patients and controls. The viral load was higher in the islet cells than in surrounding tissues. Unfortunately, they did not provide data on the difference between patients and controls in the viral load.
Antibodies to herpesvirus dUTPase a potential biomarker for Gulf War Illness and CFS
Antibodies to HHV-6 and VZV dUTPases were significantly elevated in Gulf War Illness patients compared to controls, and EBV dUTPase antibodies were elevated in Chronic Fatigue Syndrome patients.
miRNA changes by HHV-6A parallel those found in autoimmune thyroid disease
Investigators by at the University of Ferrara report intriguing alterations in intracellular regulation of HHV-6A-infected thyrocytes and T cells. HHV-6A, but not HHV-6B nor HHV-7, altered expression of several microRNAs in a pattern that is considered a marker for patients with autoimmune thyroid disease.
GAD antibodies & HHV-6 limbic encephalitis – a case of molecular mimicry?
A fifth case of limbic encephalitis associated with GAD antibodies and HHV-6 infection has been reported, this time in an immunocompetent woman with chromosomally integrated HHV-6, epilepsy, and psychosis. The patient’s condition improved (with a drop in GAD antibody titers and stabilization of psychotic symptoms) in response to three weeks of antiviral therapy but relapsed when antiviral therapy was withdrawn.
HHV-6 is the most common virus found in trigeminal and facial nerves
Herpesviruses are common in the trigeminal and facial ganglia, latently infecting 64% of cases. HHV-6 was the most commonly identified herpesvirus in these tissues — about half of all autopsy specimens were found to have the virus in trigeminal and/or facial ganglia.
HHV-6 may play a significant role in patients with Bell’s Palsy
Study finds high prevelence, high viral loads of HHV-6 in patients with Bell’s Palsy
HHV-6A promotes inflammation in astrocytoma cells by dysregulating autophagy
Infection increases ROS, induces ER stress and activates STAT3, NF-κB and mTOR pathways.
Does inherited chromosomal integration of HHV-6 at 9q increase the risk of malignancy?
A large study of iciHHV-6 integration sites found integration at 9q more common in hematologic malignancies—but the study lacked power to draw firm conclusions.
Adult patients with lower levels of anti-HHV-6 IgG are significantly more likely to experience HHV-6 reactivation following cord blood transplant
Patients with low levels of HHV-6 antibodies might benefit from treatment from IVIG or novel neutralizing antibodies before cord blood transplantation
HHV-6 encephalitis can occur in CAR T-cell therapy and biologic immunotherapy
As with chemotherapy, immunotherapies for cancer can lead to HHV-6 encephalitis
HHV-6 reactivation following haploidentical hematopoietic stem-cell transplant found to predict acute graft versus host disease in China
25% of the patients with HHV-6 reactivation developed aGVHD compared to 18% in those without reactivation.
Relationships between malignant pleomorphic adenoma and herpesviruses
HHV-6B and HHV-7 DNA found in malignant tumors that derive from common salivary gland adenomas
CMV & HHV-6 cause severe complications in non-transplant acute leukemia patients
Herpesvirus co-infections, particularly HHV-6 and CMV, cause severe lymphopenia, pneumonia, and an increased risk of acquiring bacterial and fungal infections in non-transplant acute leukemia patients undergoing chemotherapy.
Co-infections of C. trachomatis and HHV-6 in ovarian cancer: casual or causal?
C. trachomatis infection activates latent HHV-6, and HHV-6 in turn promotes persistence of C. trachomatis. Both have been reported in cases of ovarian cancer, leaving the authors to wonder if a co-infection might increase the risk for developing ovarian cancer.
HHV-6 latency gene U94 has anti-cancer effects in triple-negative breast cancer cells
The U94 “latency” gene of HHV-6, interferes with breast cancer proliferation and potentiates chemotherapy.
HHV-6 DR7 found to promote glioma development and progression
A Chinese group found HHV-6 direct repeat 7 in 48% of glioma tumors. Furthermore, they determined that DR7 overexpression could promote glioma cell migration, invasion and angiogenesis. Expression profiles showed that DR7 created an inflammatory microenvironment that enhanced degradation of the extracellular matrix.
HHV-6 in Cancer: Does it play a role?
Since its discovery, HHV-6 has been studied in the context of lymphoproliferative disorders and various types of cancer. Several obstacles, particularly the ubiquitous nature of the virus, have made it difficult to determine exactly how HHV-6 might, or might not, be involved in tumor development.
Cancer related fatigue and HHV-6 & HHV-7 saliva DNA levels
Investigators from Japan looked at HHV-6 and HHV-7 DNA levels in saliva to see if they might be biomarkers for cancer-related fatigue (CRF) in multiple myeloma patients.
HHV-6+ lymph nodes can lead to a faulty cancer diagnosis
Investigators at the National Cancer Institute found that HHV-6+ lymph nodes can be identified in biopsies from both lymphadenopathy and malignancies. They warn that failing to identify HHV-6 in these biopsies can lead to misdiagnosis in lymphoma cases.
HHV-6A IE1 antibodies associated with increased risk of non-Hodgkin lymphoma
Using a novel serological assay that can differentiate HHV-6A from HHV-6B, investigators found HHV-6A immediate early antibodies to be associated with an increased risk of non-Hodgkin lymphoma.
Cross-sectional analysis of CD8 T cell immunity to HHV-6B identifies new targets for adoptive T cell therapy
German investigators conducted a broad scale analysis of CD8 T cell responses to HHV-6B, identifying novel epitopes with potential for immunotherapy or vaccines. The strongest responses were directed against an epitope from IE-2.
A large scale whole genome sequencing study sheds light on HHV-6 integration events
Investigators at the Riken Institute in Japan developed new computational methods to detect virus induced structural variants in the human genome
New technique for precisely identifying integration site of HHV-6 in telomeres
Using whole genome optical mapping, investigators found that contrary to previous findings, the length of telomeres with viral integration was not unusually short.
Telomeric integration, excision and subsequent and transmission in people with inherited chromosomally integrated HHV-6B (iciHHV-6B)
Exploiting a hypervariable region of the HHV-6B genome, investigators achieve new insights about integration, excision, and genomic stability of iciHHV-6B
Japanese study supports evidence of iciHHV-6 reactivation in vivo
Surprisingly, 72% of integrated genomes were found on chromosome 22q. Solo-DR sequences of HHV-6B were left behind after excision and reactivation.
One step closer to understanding HHV-6A/B chromosomal integration
The mechanisms leading to HHV-6A/B integration are a subject of intense research by several laboratories. A new paper in PLoS Pathogens provides some understanding as to how HHV-6A/B may integrate host chromosomes.
iciHHV-6 may modulate human gene expression
A Japanese group found that ciHHV6 genes encoding for immunoglobulins were decreased in ciHHV6 individuals, possibly modulating immune responses.
Multiplex FilmArray Meningitis/Encephalitis assay is useful for diagnosing HHV-6 encephalitis
This multiplex qualitative test for cerebrospinal fluid helps physicians diagnose HHV-6 encephalitis quickly, but interpretation must take into account imaging, ciHHV-6 status and other markers.
Patients with iciHHV-6 have higher inflammatory cytokines and develop acute graft vs host disease a week earlier
Transplant patients born with chromosomally integrated HHV-6 have elevated levels of C-reactive protein and tumor necrosis factor receptor 1, both markers associated with increased risk of acute graft-versus-host disease.
Spontaneous gene expression in iciHHV-6A/B individuals leads to increased HHV-6 IE-1A/B and CMV antibody response; higher levels of RNA were found in iciHHV-6A brains
A comprehensive study of DNA and RNA-Seq data demonstrated in vivo gene expression in many iciHHV-6 tissues, with strong expression of IE-1 and matching elevated antibody response in iciHHV-6 individuals compared to controls.
Genomic analysis finds a surprising association between ciHHV-6 and two genes
A genomic analysis of samples from 141,431 Chinese women found a highly significant association between ciHHV-6 and a variant in the MLCI-MOV10L region. The MLC1 gene is involved in myeloid cell differentiation and the MOV10L1 gene may allow for more efficient integration during spermatogenesis.
Apparent activation of ciHHV-6 in response to HDACi cancer drug vorinostat
Inherited ciHHV-6 has been shown to activate under conditions of immunosuppression and and the pan-HDAC inhibitor TSA activates integrated ciHHV-6 in vitro. This is the first case report of HHV-6 activation in a ciHHV-6 patient who received a pan-HDAC inhibitor drug.
Ancient iciHHV-6 genomes vary considerably from community strains, but still capable of reactivation
British researchers used molecular dating methods to determine that most strains of iciHHV-6 come from a small number of ancient human ancestors; the youngest found lived over 24,000 years ago. These ancient strains vary considerably from modern non-inherited strains of HHV-6A and appear just as likely to activate as their more modern cousins.
Multiple herpesvirus infections lead to telomere shortening
Investigators at Kings College London report that seropositivity for CMV, Herpes simplex 1 and HHV-6 are all associated with a significant shortening of telomeres over a three-year period. Furthermore, the magnitude of the changes was large. For example, CMV seropositivity was associated with the equivalent of almost 12 years of chronological age.
Blood virome sequencing reveals new data on roseolovirus prevalence and epidemiology
Sequencing of over 8,000 individuals were used to determined the prevalence of 94 different viruses. HHV-7 was the most common virus, with HHV-6B and HHV-6A 4th and 5th respectively.
In Japan, inherited ciHHV-6A likely derived from common ancestor
A team in Japan has reports that ciHHV-6A prevalence is influenced by a “founder effect” and is likely derived from a common ancestor. All of the individuals in the small study were found to have HHV-6A integrated into the telomeric region of chromosome 22, a common site of integration.
Antibodies to herpesvirus dUTPase a potential biomarker for Gulf War Illness and CFS
Antibodies to HHV-6 and VZV dUTPases were significantly elevated in Gulf War Illness patients compared to controls, and EBV dUTPase antibodies were elevated in Chronic Fatigue Syndrome patients.
Decreased HHV-6 IgG in Alzheimer’s
Investigators from Uppsala University in Sweden found that HHV-6 IgG reactivity was significantly lower in Alzheimer’s Disease patients compared to controls. The authors suggest reduced immunity may be one reason why past studies have found increased levels of HHV-6 DNA in the brains of Alzheimer’s patients compared to controls.
Can depression, psychiatric disorders and fatigue be triggered by a neurovirulent latent HHV-6B protein?
Three virologists led by Kazuhiro Kondo, MD, PhD, a professor of virology at Jikei University School of Medicine, have filed a patent on a method to diagnose and treat prevent mood disorders which he says are initiated by latent and neurovirulent HHV-6B residing in glial cells, and that this condition can be treated effectively with nasal sprays, using the olfactory nerve as a route to the brain. Dr. Kondo has named this protein SITH-1 or “small protein encoded by intermediate state transcript”.
HHV-6 induced Parkinsonism post-transplant
A group of researchers from Sao Paulo, Brazil reported the development of HHV-6 infection in the striatum of a 32-year-old man six weeks after allogeneic hematopoietic stem cell transplantation. This is the first reported case of HHV-6 infection affecting the striatum and presenting with Parkinsonism post-HSCT.
Delirium associated with HHV-6B reactivation in cord blood transplant patients: time for an antiviral prophylaxis trial?
A prospective study authored by Joshua Hill and Danielle Zerr determined that higher than average HHV-6B DNA levels increased the odds of developing delirium after cord blood transplantation (CBT) by almost three fold. Patients with DNA loads in the top quartile had a 4.5 fold increase in delirium.
HHV-6B infection promotes unique pro-inflammatory effects tied to neurocognitive decline and artherosclerosis
HHV-6A and HHV-6B each express distinct chemokines that are uniquely capable of activating key inflammatory cytokines.
High rate of active HHV-6 detected among patients with cardiac disease
Unusually high rate of active HHV-6 infection detected among hospital patients with cardiac disease.
The role of OX40 in DIHS/DRESS and HHV-6 reactivation
OX40 levels distinguished DIHS/DRESS from other inflammatory dermatologic conditions, and were associated with HHV-6 reactivation
In DRESS/DIHS, early treatment with high dose steroids may suppress HHV-6; late treatment may prolong viremia
High dose steroids given in the first week appears to prevent HHV-6 reactivation in DRESS/DIHS patients by suppressing T-cell activation and serum interleukin-2 receptor (sIL-2R) levels. In contrast, a late start of steroid therapy resulted in a persistently high viral load for at least three weeks.
An explanation for why HHV-6 reactivation and DRESS lead to autoimmunity
Patients with DRESS/DIHS hypersensitivity reactions and active HHV-6 often develop autoimmune diseases such as type 1 diabetes and autoimmune thyroiditis. Investigators at National Taiwan University Hospital believe that IP-10 is key to this process.
Single-cell RNA sequencing analysis implicates HHV-6B in DIHS/DRESS.
RNA-Seq analysis of cells from skin and blood identified both HHV-6 and JAK-STAT pathways inhibitors as potential targets. Central memory CD4+T cells were enriched with HHV-6B.
HHV-6 interacts with HLA-B*13:01 to confer a 92-fold increased risk of trichloroethylene hypersensitivity reaction
Chinese investigators determined that human leukocyte antigen polymorphism HLA-B*13:01 and HHV-6 DNA blood positivity were not only independently associated with occupational trichloroethylene hypersensitivity, they had an interactive effect, increasing the odds ratio to 92.
HHV-6 and lymphoproliferative syndromes: a review
The authors discuss how HHV-6 may contribute to the progression of reactive lymphoproliferative disorders by spurring a dysfunctional immune response.
HHV-6 reactivation tied to early hypogammaglobulinemia in drug hypersensitivity syndrome
A Spanish study of drug-induced eosinophilia found that early hypogammaglobulinemia was associated with subsequent HHV-6 reactivation in patients with severe drug hypersensitivity syndromes. This study of 274 cases at La Paz University Hospital in Madrid confirms earlier reports from Japan and France that described transient reductions of total IgG at the outset of drug hypersensitivity reactions leading to HHV-6 reactivation.
Does CD134 upregulation explain why HHV-6 reactivates preferentially in DRESS/ DIHS?
It has long been a mystery why HHV-6 is preferentially reactivated in drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). HHV-6 reactivation occurs in over 60% of severe cases and is part of the definition of DIHS in Japan. Investigators in Japan suspect that the explanation may lie with the CD134 receptor on activated CD4 cells.
HHV-6 as a cause of liver failure in an immunocompetent patient with hypersensitivity
A group from University of Chicago Medicine urged physicians to consider testing for HHV-6 in cases of unexplained liver failure in immunocompetent patients, especially those with skin rash and upper respiratory symptoms, citing evidence from past studies as well as their own recent case experience.
HHV-6 induced kidney damage in drug hypersensitivity
A new case study suggests that HHV-6 might play a role in the multi-organ failure that often follows extreme cases of drug hypersensitivity. Although there have been many studies documenting HHV-6 viremia in drug hypersensitivity (DIHS/DRESS) cases, this is the first to examine an affected organ for signs of HHV-6 DNA and proteins. The mortality rate from severe drug hypersensitivity is approximately 10%, and death usually results from a late flare in symptoms and failure of one or more organ, typically the liver, kidney, lungs or heart. HHV-6 viremia occurs in the majority of extreme drug hypersensitivity cases (Pritchett 2012) but the reason for the disproportionate reactivation of HHV-6 is not understood. The case, which is presented by a Japanese …
Pediatric drug hypersensitivity cases with HHV-6 reactivation have a more severe disease and longer hospital stays
A group at the University of Pennsylvania performed a retroactive study of 29 pediatric patients hospitalized with drug hypersensitivity reactions and found that those who reactivated with HHV-6 had longer lengths of stay (11.5 days vs. 5. days) and more severe illness. They were not able to determine the impact of steroid administration in HHV-6 positive patients.
Interview with Drs. Ishida and Shiohara
Drs. Ishida and Shiohara from Kyorin University in Tokyo have publised an inportant new study on the dynamics of herpesvirus reactivations during and after severe drug reactions. We asked them their thoughts on the implications of their findings.
Steroids increase HHV-6 but reduce EBV viral loads in DIHS/DRESS
In a recent study published in the European Journal of Allergy and Clinical Immunology, a group from Kyorin University School of Medicine in Tokyo sought to comprehensively record the dynamics of key herpesviruses beyond the acute stage of SJS/TEN. While EBV loads were higher in patients not receiving systemic corticosteroids, CMV and HHV-6 loads were higher in those receiving them.
HMGB-1 found to be preferentially elevated in DIHS/DRESS: the key to HHV-6 reactivation?
A group of investigators in Japan have determined that HMGB-1, an inflammatory cytokine released in response to trauma, stress, and surgery, is highly elevated in DIHS/DRESS patients.
TNF-α predicts HHV-6 reactivation and disease progression in patients with DIHS/DRESS
While elevated TNF-a detected at the early onset of disease is a strong indicator for the early recognition of HHV-6 reactivation, this finding also reflects important therapeutic information that could be used as an early diagnostic marker of DIHS/DRESS.
Imunocompromised patients with HHV-6 encephalitis have a ratio of CSF/blood viral load >1, whereas children with encephalitis due to primary infection have ratios of <1
Immunocompetent cases are typically children experiencing primary infection with high viral loads in the blood; cases in the immunocompromised typically involve reactivation in the brain tissue, with lower viral loads in the periphery
HHV-6 accounted for 5% of all herpetic viral encephalitis in immunocompetent Mexican patients
Psychiatric disorders were the most common prodomal symptom (58%) and this was significantly different from patients with non-herpesvirus encephalitis.
HHV-6 reactivation following haploidentical hematopoietic stem-cell transplant found to predict acute graft versus host disease in China
25% of the patients with HHV-6 reactivation developed aGVHD compared to 18% in those without reactivation.
HHV-6 DNA found in spinal fluid of 8% of patients with aseptic meningitis
Multiplex testing for the causative agents of aseptic meningitis in Saudi Arabia identifies possible etiologic role for HHV-6
No HHV-6 DNA found in the spinal fluid of immunocompetent adults evaluated for limbic encephalitis
While HHV-6B is well known to cause limbic encephalitis in transplant patients, it does not appear to play a role in other forms of limbic encephalitis.
HHV-6 found in spinal fluid of an immunocompetent patient with possible temporal lobe epilepsy and post-ictal psychosis
A case report suggests possibility that HHV-6 encephalitis may be cause a temporal lobe epilepsy-like episode with associated psychosis
Multiplex FilmArray Meningitis/Encephalitis assay is useful for diagnosing HHV-6 encephalitis
This multiplex qualitative test for cerebrospinal fluid helps physicians diagnose HHV-6 encephalitis quickly, but interpretation must take into account imaging, ciHHV-6 status and other markers.
New recommendations for HHV-6 encephalitis from Japan
New guidelines from Japan recommend foscarnet as the first-line treatment for HHV-6 encephalitis, with ganciclovir as second choice. They also recommend a combination therapy in severe cases.
Pruritis, pain and numbness are signs of HHV-6 myelitis: a review of 19 cases
A review of post-transplant cases found that the incidence of HHV-6 myelitis was 4.1%; symptoms of pruritus without rash, pain, numbness, dysuria and constipation are potential signs.
Could anti-cytokine therapy be the key to reducing CNS damage in HHV-6 encephalitis?
Japanese investigators evaluated cytokines and chemokines in the CSF and plasma in HHV-6 encephalitis patients with good and poor prognoses. They found IL-6, IL-7, MCP-1 to be elevated one week before onset, suggesting that these cytokines may be effective targets for intervention.
Differential gene expression pattern shared in herpesviruses, Alzheimer’s & Parkinson’s patients
Researchers from GlaxoSmithKline found a significant overlap in differentially expressed genes shared by those with herpesvirus infections, Alzheimer’s and Parkinson’s. On the other hand, there was no significant overlap between herpesviruses and Type 2 diabetes or Huntington’s disease.
HHV-6 encephalitis: Mayo clinic finds a high rate of severe hippocampal atrophy and neurological deficits
A Mayo clinic review of long-term outcome of patients with HHV-6 encephalitis showed that over 60% showed persistent sequelae associated with severe bilateral hippocampal atrophy. Symptoms included anterograde amnesia, aphasia, headaches, confusion and persistent memory deficits.
BioFire’s FilmArray multiplex encephalitis panel is causing headaches due to confusion over ciHHV-6 status and the meaning of a qualitative positive result
A rapid point-of-care test for patients with encephalitis and meningitis was heralded as a breakthrough, but because the test is not able to determine ciHHV-6 status or viral load, it now has physicians frustrated over how to interpret a positive result.
Oral brincidofovir cut the rate of high level HHV-6 viremia by 80%, suggesting that IV brincidofovir may have potential to prevent HHV-6 encephalitis.
An abstract at the Transplantation & Cellular Therapy Meeting in Houston showed that only 2% of 92 patients treated with oral brincidofovir developed high level reactivation compared to 11% of 61 patients taking the placebo. The results came from an analysis of stored samples from their previous Phase III SUPPRESS trial for CMV prophylaxis. Chimerix’s Phase III trial for cytomegalovirus failed. Although oral brincidofovir reduced CMV viremia during the first 14 weeks, CMV infections bounced back during the 10-week observation period that followed, and there was a higher mortality rate in the drug group. Analysts blamed the higher death rate on the inability of participating physicians to differentiate between bleeding (a side effect of the drug) and acute GVHD. Instead …
89% of the virus found in the spinal fluid of HCT patients in the first 60 days is HHV-6
An analysis of 165 central nervous system viral infections by the Center for International Blood and Bone Marrow Transplant Research found that most were positive for HHV-6. The outcome for patients with viral infection was poor with 50% mortality within 6 months and only 30% survival at 5 years.
Abnormal cytokine levels in children with epilepsy suggest link to inflammation
Unique pathways and significantly elevated cytokines were associated with a small cohort of pediatric seizure patients.
Study of fresh brain tissue confirms a role for HHV-6 in mesial temporal sclerosis
NINDS investigators studied fresh resected brain tissue and found 29 of 54 positive for HHV-6 DNA. Previous studies using formalin fixed and paraffin embedded samples have yielded much lower rates of positivity.
A clinically significant viral load of HHV6 DNA was found in children with febrile seizures
HHV-6 most common virus found in nasopharyngeal aspirates from young children with febrile seizures, followed by influenza and adenovirus.
Active HHV-6/7 infection found in subset of adult epilepsy patients
HHV-6/7 DNA was found in the plasma of 19.6% of epilepsy patients compared to none of the controls. Protein expression indicating active infection was found in 53% of the HHV-6/7 positive patients.
MAPK upregulation by HHV-6B proposed as the mechanism behind link to epilepsy.
Swedish investigators set out to uncover the pathways that HHV-6B might utilize in triggering MTLE. They found that HHV-6B infection altered expression of MAPK genes, suggesting a possible pathogenic mechanisms of HHV-6B in mesial temporal lobe epilepsy.
Infants with HHV-6B seizures are 15X more likely to develop febrile status epilepticus
A large prospective study in Africa adds weight to argument that HHV-6B infection is an important cause of febrile status epilepticus.
HHV-6B induces telomeric hypomethylation, possibly facilitating integration
HHV-6B induces unique, region-specific DNA hypomethylation, and findings suggest that the epigenetic modification may facilitate HHV-6B integration.
HHV-6 identified in 12% of simple and 42% of complex pediatric febrile seizures
Australian investigators studied 143 young children with febrile seizures for signs of viral infection and found that HHV-6 was the fifth most common virus after rhinovirus (22%), enterovirus (20%), adenovirus (21%) and influenza (13%). Overall, a virus was found in 71% of cases. Virus found in complex seizures was associated with HHV-6 (42%) or influenza (41%).
GAD antibodies & HHV-6 limbic encephalitis – a case of molecular mimicry?
A fifth case of limbic encephalitis associated with GAD antibodies and HHV-6 infection has been reported, this time in an immunocompetent woman with chromosomally integrated HHV-6, epilepsy, and psychosis. The patient’s condition improved (with a drop in GAD antibody titers and stabilization of psychotic symptoms) in response to three weeks of antiviral therapy but relapsed when antiviral therapy was withdrawn.
Pathogenic role for HHV-6B in in mesial temporal lobe epilepsy
Japanese investigators published findings suggesting that HHV-6B plays a pathogenic role in epilepsy by enhancing gene expression that induces neuroinflammation and sclerosis in the temporal lobe. HHV-6 DNA levels were significantly higher in the resected tissue of epilepsy patients with sclerosis compared to those without it.
Interview with Tetsushi Yoshikawa: Treating HHV-6B seizures
Tetsushi Yoshikawa and Yoshiki Kawamura just published an important study linking HHV-6B in brain tissues to sclerosis in mesial temporal lobe epilepsy. We asked him about this future plans and whether he plans to treat these patients.
ApoE4+ epilepsy patients have higher HHV-6B viral loads and more seizures
A team of Chinese investigators led by Dr. Jin-Mei Li at West China Hospital has identified a possible synergy between a polymorphism of Apolipoprotein E (ApoE) and HHV-6B infection, resulting in a higher viral load and seizure frequency in these patients.
High HHV-6B viral loads found in a subset of epilepsy brain resections
Investigators at the University of Bonn Medical Center in Germany have screened 346 fresh-frozen brain tissue resections from temporal lobe epilepsy (TLE) patients for all nine herpesviruses as well as for RNA viruses including Paramyxovirinae, Phleboviruses, Enteroviruses, and Flavivirus, using qPCR. HHV-6B was the only virus identified.
Interview with Dr. Pitt Niehusmann: HHV-6 & MTLE
Pitt Niehusmann has completed the largest study to date on the question of whether viruses play a role in refractory mesial temporal lobe epilepsy (MTLE), with 346 samples analyzed. We asked Pitt a few questions about his work.
HHV-6 status epilepticus in an immunocompetent adult
Immunocompetent adults are not supposed to get HHV-6 encephalitis or status epilepticus (SE) and HHV-6 testing is rarely performed in these patients. A new case report from Baylor suggests that testing for HHV-6 in these patients may be worthwhile.
Oral brincidofovir cut the rate of high level HHV-6 viremia by 80%, suggesting that IV brincidofovir may have potential to prevent HHV-6 encephalitis.
An abstract at the Transplantation & Cellular Therapy Meeting in Houston showed that only 2% of 92 patients treated with oral brincidofovir developed high level reactivation compared to 11% of 61 patients taking the placebo. The results came from an analysis of stored samples from their previous Phase III SUPPRESS trial for CMV prophylaxis. Chimerix’s Phase III trial for cytomegalovirus failed. Although oral brincidofovir reduced CMV viremia during the first 14 weeks, CMV infections bounced back during the 10-week observation period that followed, and there was a higher mortality rate in the drug group. Analysts blamed the higher death rate on the inability of participating physicians to differentiate between bleeding (a side effect of the drug) and acute GVHD. Instead …
Comprehensive new ASM review on HHV-6 (Free Download)
A comprehensive review of HHV-6 has been published in the American Society for Microbiology’s Clinical Microbiology Reviews.
Coppe Labs to offer mRNA, ciHHV-6 testing and Immunohistochemistry for HHV-6
Three important tests for HHV-6 will now be available at Coppe Labs, including two that are not available commercially at any other location: the mRNA test for assessing active infection and immunohistochemistry analysis for biopsy samples.
Persistence and reactivation of parvovirus B19 and HHV-6B in the myocardium of children with dilated cardiomyopathy
Parvovirus B19 and HHV-6B were detected more often than enterovirus or adenovirus, the pathogens typically suspected in pediatric heart disease.
High rate of HHV-6 end-organ disease and mortality in pediatric transplant patients
Stanford investigators found that high levels of HHV-6 viremia following allogeneic stem cell transplants were associated end organ disease and greater non-relapse mortality.
HHV-6 in end organ disease: liver transplantation and inflammatory cardiomyopathy in immunocompetent children
Two reviews have been published on the roles of HHV-6 in liver transplantation and in pediatric inflammatory cardiomyopathy in the immunocompetent. Both reviews stress the importance of biopsies for diagnosis since HHV-6 DNA is rarely found in the plasma in spite of persistent reactivation in the organ.
Review of HHV-6 induced inflammatory cardiomyopathy in immunocompetent children
Although only a small number of pediatric cases have been reported in literature, the authors conclude that evidence suggests HHV-6 should be considered as a causative agent of inflammatory cardiomyopathy, particularly in young children (under 3 years of age) who might be experiencing a primary infection.
Superinfection of HHV-6A in ciHHV6A patients with recurrent cardiac disease: a full genome analysis
A group led by Ursula Gompels from the London School of Hygiene & Tropical Medicine, University of London, did next generation sequencing on three ciHHV6A cardiac patients and found superinfections of HHV-6A in two of the three. They characterized the first full genome sequence of ciHHV-6A and demonstrated the inherited ciHHV6 genome was similar but distinct from known exogenous (community acquired) strains of HHV-6A .
Fatal HHV-6 pediatric myocarditis following immunosuppression
A case report published by a group at the University of Minnesota details two cases of fatal myocarditis associated with HHV-6 in two immunosuppressed children.
Stanford uses non-invasive new assay to detect occult infections including HHV-6 after lung transplantion
Researchers from Stanford University successfully used circulating cell-free DNA to identify infections in lung transplants that can often be found only with a more invasive transbronchial biopsy. This hypothesis free approach led to find HHV-6 & 7 at high levels in patients with infections, even though these viruses are not generally considered lung pathogens.
HHV-6 myocarditis, pericarditis following transplantation
A hematology group in Australia reported a case of biopsy-proven HHV-6 myocarditis post-hematopoietic stem cell transplantation (HSCT). he post-mortem exam confirmed dilated cardiomyopathy and focal changes consistent with viral myocarditis and cardiac tissue was positive for HHV-6 DNA by nested and quantitative PCR. Separately, A Japanese group reported a worman who developed pericarditis with over 10,000 copies/ml of HHV-6 DNA in the pericardial fluid, after a cord blood transplant.
HHV-6, enterovirus and parvovirus B-19 DNA found in the blood of immunocompetent infants with myocarditis
80% of infants with myocarditis were positive for a cardiotropic virus compared to less than 4% of healthy controls, according to a multicenter study led by researchers at Washington University in St. Louis. This was a far higher rate than in older children.
ciHHV-6 is a risk factor for angina pectoris
In an article published this month in the Proceedings of the National Academy of Sciences, Dr. Louis Flamand’s team has described a relationship between inherited chromosomally integrated HHV-6 (iciHHV-6) and the development of angina pectoris.
Heart failure worsens in patients with persistent HHV-6B positive biopsies
Numerous case reports and studies have now tied HHV-6 to myocarditis and cardiomyopathies. To further investigate this relationship, investigators from one of the top cardiology clinics in Europe performed a study to determine the outcome of patients discovered to have HHV-6 in their cardiac tissue during the initial biopsy screen.
CiHHV-6A is the dominant virus in malignancy and inflammatory disease cases, while ciHHV-6B is the dominant virus in myocarditis cases
A sequencing study led by Ursula Gompels of London School of Hygiene & Tropical Medicine, found that 95% (19/21) of Czech ciHHV-6 malignancy and inflammatory disease patients had ciHHV6A while 65% (13/20) of a German myocarditis cohort had ciHHV-6B. The authors propose that this divergence suggests different disease links for the two viruses.
Active ciHHV-6 linked to heart failure, a condition treatable by antiviral therapy
Berlin Charite study shows heart failure patients with active ciHHV-6 can be treated successfully with antivirals.
Diagnosing infections in myocardial biopsies: Interview with Cardiologist Uwe Kühl and IKDT Lab Director Dirk Lassner
The cardiology clinic at the Campus Benjamin Franklin, Charité – University Medicine Berlin is recognized as leading center for using state-of-the art mRNA analysis to diagnose active infections the biopsy tissue of myocarditis and heart failure patients.
Another fatal case of HHV-6 myocarditis in an immunocompetent adult
Group suggests cardiac magnetic resonance (CMR) may be an important tool for the timely diagnosis
HHV-6 shedding correlates negatively with IL-6 and other inflammatory cytokines in HIV+ patients on antiretroviral therapy
HIV+ patients on antiretrovrial therapy with high levels of HHV-6 shedding had lower levels of IL-6 and other inflammatory markers. While HIV+ patients had increased shedding of EBV and CMV, there was no difference in shedding between patients and controls for HHV-6.
Similar prevalence of HHV-6A and HHV-6B found in African HIV+ patients
Prevalence of HHV-6A and HHV-6B was evenly divided in HIV+ patients in Western Africa, with over 6.3% positive for HHV-6 A and 5.0% for HHV-6B. HHV-6A was more common among those with a low viral HIV viral load.
HHV-6 and EBV elevated in the GI tract of HIV+ patients
A group from Sapienza University in Rome has found a significantly elevated prevalence of HHV-6 and a higher viral load for EBV in the stomach and duodenum biopsies of patients with HIV compared to controls, suggesting that these viruses may contribute to the development of gastric cancer in immunocompromised patients.
Understanding the association between ciHHV-6 and HIV disease
HIV+ individuals with ciHHV-6 may experience lower severity HIV disease.
Human Herpesviruses-6A/6B linked to important reproductive diseases
A recent review from the Departments of Medicine and Obstetrics/Gynecology at Harvard Medical School and the University of Ferrara, Italy, summarizes evidence linking HHV6-A/B to several important reproductive diseases: primary unexplained infertility, preeclampsia, congenital infection and, possibly, spontaneous abortion and intrauterine growth restriction.
Mothers with iciHHV6 have an increased risk of spontaneous abortion
27.6% of Japanese mothers with iciHHV6 had a spontaneous abortion compared to 14.8% of controls. iciHHV6 mothers were also 6.4X more likely to have two or more spontaneous abortions.
Fetal iciHHV-6 associated with a 3-fold increased risk of preeclampsia
A large UK study utilizing RNA sequencing metagenomics of placental samples identified HHV-6 RNA in 6.1% of pre-eclampsia cases and 2.2% of healthy pregnancies. HHV-6 was the only virus found and it was iciHHV-6 in 70% of cases.
2nd study implicates HHV-6A in unexplained infertility
In 2016, Italian investigators found HHV-6A in the uterus of 43% of women with unexplained infertility but 0% on controls. Now, a second study found localized HHV-6 infection in women with recurrent implantation failure, but not in controls.
HHV-6A, infertility and miscarriage: a hypothesis
Growing evidence implicates HHV-6, especially HHV-6A, in some cases of female infertility, miscarriage, and other gestational problems affecting both the mother and child. The authors of the paper wonder if heparin, an anticoagulant with antiviral properties often used to treat infertility, might mitigate the detrimental effects of HHV-6 in the uterine environment.
ciHHV-6B activation and fetal transmission in response to high dose progesterone?
A pregnant ciHHV-6B woman with a history of miscarriages was given weekly doses of high dose progesterone. Could progesterone, like hydrocortisone, activate integrated ciHHV-6 in vitro.
HHV-6A infection of the uterus linked to infertility
A new study reported that HHV-6A infects the lining of the uterus in 43% of women with unexplained infertility but cannot be found in uterine lining of fertile women. Furthermore, the cytokine and the natural killer cell profiles were very different in patients with the infection. HHV-6A was found only in uterine endothelial cells, and not in the blood.
Pityriasis rosea, HHV-6, and the increased risk of miscarriage
Italian study finds 62% of women who developed PR early in their pregnancies miscarried
Does HHV-6 infection of the sperm contribute to infertility?
A group of researchers from Denmark have shown that HHV-6B binds specifically to the acrosome of sperm
HHV-6 is a greater risk than CMV for rejection in pediatric kidney transplantation
Investigators from the Children’s Hospital of Mexico found that although CMV caused the biggest increase in risk for liver rejection, HHV-6 was the more important infection associated with rejection of kidney transplants. A single HHV-6 infection resulted in an increased risk of over 5 fold, while a coinfection of EBV, HHV-6 and HHV-7 increased the risk of kidney rejection by over 17 fold.
HHV-6 induced kidney damage in drug hypersensitivity
A new case study suggests that HHV-6 might play a role in the multi-organ failure that often follows extreme cases of drug hypersensitivity. Although there have been many studies documenting HHV-6 viremia in drug hypersensitivity (DIHS/DRESS) cases, this is the first to examine an affected organ for signs of HHV-6 DNA and proteins. The mortality rate from severe drug hypersensitivity is approximately 10%, and death usually results from a late flare in symptoms and failure of one or more organ, typically the liver, kidney, lungs or heart. HHV-6 viremia occurs in the majority of extreme drug hypersensitivity cases (Pritchett 2012) but the reason for the disproportionate reactivation of HHV-6 is not understood. The case, which is presented by a Japanese …
Role for HHV-6 in patients with renal failure?
A new study from Brazil indicates that active HHV-6 infection may play a role in patients with renal failure prior to transplantation.
Differences in the cytopathic effect of HHV-6A and HHV-6B infection of neurons and glia
In vitro studies confirm that the two viruses infect different cell types, and generate different cytopathic effects, cytokine and growth factor responses.
Murine roseolovirus (MRV) infection experiments are only partially supportive of role of HHV-6A/B in Alzheimer’s disease
While MRV administered peripherally led to brain infection and neuroinflammation, it did not increase Aß deposition
HHV-6A promotes inflammation in astrocytoma cells by dysregulating autophagy
Infection increases ROS, induces ER stress and activates STAT3, NF-κB and mTOR pathways.
EBV and HHV-6 plasma viremia is infrequent at Day 7 during acute COVID-19
Other studies have suggested that reactivation of these viruses could theoretically contribute to a hyperinflammatory state or autoimmune disorders in acute COVID-19, but this study does not provide evidence of that.
Does inherited chromosomal integration of HHV-6 at 9q increase the risk of malignancy?
A large study of iciHHV-6 integration sites found integration at 9q more common in hematologic malignancies—but the study lacked power to draw firm conclusions.
Development of highly sensitive technique for detecting viral DNA sequences in cell-free plasma
Isolating DNA fragments less than 120 base pairs enriches for viral vs. cellular DNA.
G-1082A polymorphism of IL-10 may protect against HHV-6/EBV adenoid hypertrophy
The presence of HHV-6 and EBV DNA in nasal secretions correlates with the degree of adenoid hypertrophy in children.
HHV-6A U14 protein and NFκB activate each other
The late protein U14 of HHV-6A can induce the pro-inflammatory transcription factor NFκB, and NFκB, in turn, can encourage the replication of HHV-6A.
Different isoforms of CD46 affect infectivity and replication of HHV-6A and HHV-6B
While CD134 remains the more important receptor for HHV-6B, HHV-6B can use the CD46 receptor when a T cell has the C1 isoform of CD46.
HHV-6B may enter cells that don’t express CD134 via the nectin-2 receptor
If confirmed, finding could explain ability of HHV-6B to infect salivary, liver and neural cells.
HHV-6A and HCMV induce pro-fibrotic miRNA expression pattern in infected host cells
Pattern consistent with clinical studies suggesting these viruses may be one trigger of systemic sclerosis.
HHV-6 miRNA inhibits host miRNA to trigger reactivation from latency
A viral miRNA disrupts mitochondrial architecture, suppresses type I interferon production, is necessary for productive infection and for virus reactivation, all by inhibiting multiple members of the host miR-30 family—creating a therapeutic target to suppress reactivation.
4C-seq genomic methodology used to examine HHV-6A integration sites
Chromatin interactions help silence transcription of HHV-6A genes following integration
The effects of HHV-6B infection on immune checkpoint inhibition
HHV-6B infection of primary monocytes induces cell-associated and soluble PD-L1 production, increased intracellular ROS and activation of STAT1 and STAT3 pathways
The importance of individual glycoprotein components of the HHV-6A/6B envelope tetramer on essential viral functions
The combination of gQ1 and gQ2 tetramer components of both HHV-6A/6B are important for viral propagation, probably by affecting attachment to their different receptors.
Seronegative pediatric liver transplant patients frequently acquire clinically significant HHV-6 infections from the donor liver or accompanying leucocytes
HHV-6 seronegativity pre-transplantation predicts HHV-6 viremia post-transplantation
Breakthrough reactivation of HHV-6 occurs with liver transplantation in spite of valganciclovir preemptive therapy for CMV
High-grade HHV-6 viremia is independently associated with rejection of liver transplants within 12 months
HHV-6 found in 22% of acute liver failure of “unknown etiology”
A third of patients with acute liver failure were found to have a betaherpesvirus infection when tested for all herpesviruses. HHV-6 was the most common infection, followed by CMV and HHV-7. No other herpesviruses were found.
High rate of HHV-6 end-organ disease and mortality in pediatric transplant patients
Stanford investigators found that high levels of HHV-6 viremia following allogeneic stem cell transplants were associated end organ disease and greater non-relapse mortality.
HHV-6 acute liver failure in an immunocompetent child: case report
HHV-6 is rarely identified as the cause of liver dysfunction in immunocompetent children, in part because HHV-6 is not included in routine testing, and HHV-6 infections can be highly localized to the liver. In this case, an alert team in Arizona identified HHV-6 by needle biopsy.
HHV-6 in end organ disease: liver transplantation and inflammatory cardiomyopathy in immunocompetent children
Two reviews have been published on the roles of HHV-6 in liver transplantation and in pediatric inflammatory cardiomyopathy in the immunocompetent. Both reviews stress the importance of biopsies for diagnosis since HHV-6 DNA is rarely found in the plasma in spite of persistent reactivation in the organ.
Review of HHV-6 in Liver Transplantation
HHV-6 infections in the liver transplant patients can’t be diagnosed in the blood. Ganciclovir prophylaxis for CMV cuts the rate of HHV-6 reactivation from 39% to 11%.
HHV-6, EBV and CMV found in GI tract cancers
A group from Washington University used a bioinformatics system called VirusScan to analyze RNA-Seq data sets from 6,813 human tumors compared to those of adjacent normal tissue. Tumor samples representing 23 different forms of cancer were analyzed. HHV-6, EBV and CMV were found at significantly high levels in GI tract cancer tissue.
Drug-induced liver injury and HHV-6 reactivation without rash or fever
Another case of drug induced liver injury accompanied by HHV-6 reactivation has been reported in Japan, the second such case without exanthema to be described. An earlier case was reported last year (Fujita 2015). The authors suggest that drug-induced liver injury cases be investigated for HHV-6 reactivation when liver dysfunction begins several weeks after the initiation of a new drug typically associated with hypersensitivity syndromes.
HHV-6 as a cause of liver failure in an immunocompetent patient with hypersensitivity
A group from University of Chicago Medicine urged physicians to consider testing for HHV-6 in cases of unexplained liver failure in immunocompetent patients, especially those with skin rash and upper respiratory symptoms, citing evidence from past studies as well as their own recent case experience.
HHV-6B: an underappreciated cause of hepatitis in HCT
New article describes acute HHV-6B hepatitis in an HCT recipient and reviews the current literature
Acute hepatitis associated with HHV-6 infection in liver transplant patients
French study suggests HHV-6 is a pathological cause of confluent necrosis.
HHV-6 in the liver associated with decreased graft survival
Researchers from the University of Hannover have found a significant association between HHV-6 and decreased graft survival in liver transplant patients.
Does HHV-6B reactivate in COVID-19 patients?
So far only one case report has documented HHV-6B reactivation in COVID-19, but the rise in Kawasaki-like symptoms and pityriasis rosea has at least one dermatology group suspicious of HHV-6/7 reactivation.
European guidelines published for diagnosing, preventing, and managing HHV-6 disease
European guidelines recommend treating HHV-6 disease with either foscarnet or ganciclovir, in contrast to the Japanese guidelines that recommend foscarnet as first line treatment due to a lower mortality rate.
HHV-6B lung infection doubles the mortality rate of transplant patients with respiratory disease
Investigators at the Fred Hutchinson Cancer Research Center and University of Washington in Seattle found that HHV-6B in lung fluid of bone marrow transplant recipients with pneumonia is associated with a 2-fold increased risk of death. Importantly, HHV-6B positive patients who were treated with an antiviral had a 60% lower risk of death.
HHV-6 increases risk of an “idiopathic” pneumonia syndrome after HCT as does murine roseolovirus in a BMT mouse model. Early HHV-6 was also found to increase non-relapse mortality
Investigators from University of Michigan have demonstrated that murine roseolovirus is a useful homolog for the study of HHV-6 reactivation in lung disease. In a large retrospective study of HCT patients, they also found early HHV-6 reactivation to increase the risk of both idiopathic pneumonia syndrome and non-relapse mortality.
High rate of HHV-6 end-organ disease and mortality in pediatric transplant patients
Stanford investigators found that high levels of HHV-6 viremia following allogeneic stem cell transplants were associated end organ disease and greater non-relapse mortality.
HHV-6 can cause “idiopathic” pneumonia
A pivotal study, led by Michael Boeckh at the Fred Hutchinson Cancer Research Center, has determined that occult infections contribute to 57% of all cases of “idiopathic” pneumonia syndrome (IPS), a condition previously assumed to be non-infectious. HHV-6 was the dominant pathogen representing 29% of cases.
HHV-6 associated with ‘fever of unknown origin’ and cough in pediatric patients
Study finds HHV-6 DNA in children with unexplained fever at significantly higher levels than in patients without fever
Differences in the cytopathic effect of HHV-6A and HHV-6B infection of neurons and glia
In vitro studies confirm that the two viruses infect different cell types, and generate different cytopathic effects, cytokine and growth factor responses.
HHV-6A promotes inflammation in astrocytoma cells by dysregulating autophagy
Infection increases ROS, induces ER stress and activates STAT3, NF-κB and mTOR pathways.
New seroepidemiological evidence that HHV-6 contributes to MS disease progression
Longitudinal study of people with a single initial episode of demyelination provides stronger evidence for HHV-6 than EBV in the pathogenesis of MS, but the evidence is not robust.
A relationship between human endogenous retroviruses and HHV-6A/B in multiple sclerosis patients
Significant positive correlations were found between HERV family proteins and antibodies to HHV-6A/B but not antibodies to EBV
CMV infection may diminish the risk of developing MS
Studies conducted on serum obtained before development of MS indicate possible protective role
Detection of HHV-6 miRNA in Multiple Sclerosis patients
HHV-6 miRNAs and antibodies were identified and significantly correlated with each other in serum and CSF of MS patients
Metagenomic and reverse transcriptase methodologies employed to detect herpesvirus DNA in spinal fluid of multiple sclerosis (MS) patients
Study provides little evidence for or against a possible role for HHV-6 or EBV in the pathogenesis of MS
Neonatal murine roseolovirus infection induces autoimmunity
Early infection interferes with normal thymocyte development and disrupts central tolerance resulting in autoimmune disease later in life. Only infection during this critical time period resulted in autoimmunity.
Large serologic study incriminates both EBV and HHV-6A as triggers of multiple sclerosis
HHV-6A infection at any age, and EBV infection after age 20, were found to be significant risk factors
A review of the role of HHV-6A in multiple sclerosis and HHV-6B in epilepsy
Neuroscientists at Karolinska Institute in Sweden summarized the growing literature linking HHV-6A/B to both illnesses.
A review of evidence linking HHV-6A/B to neurological diseases: association or causation?
A thorough review examines the possible role of HHV-6A/B in febrile seizures, mesial temporal lobe epilepsy, multiple sclerosis and Alzheimer’s disease, proposing evidence to distinguish association from causation.
HHV6A/B as a clinical marker of multiple sclerosis relapse during the postpartum period
HHV-6 IgM antibodies were higher in pregnant MS patients than in healthy controls. Women with elevated HHV-6 IgM titers were more likely to relapse postpartum.
Lifestyle factors interact with HHV-6A in the development of multiple sclerosis
Smoking, low ultraviolet radiation exposure, and low vitamin D levels interact with HHV-6A to increase the risk of developing multiple sclerosis
Latent HHV-6, mitochondrial fragmentation and a hypometabolic state in ME/CFS patients
A team of virologists and metabolomics specialists collaborated to demonstrate how chromosomally integrated HHV-6 can be stimulated to secrete factors that simultaneously cause mitochondrial fragmentation, a reduction in intracellular ATP reserve and an expanded antiviral defense by their neighboring cells.
HHV-6A (but not HHV-6B) linked to increased risk of multiple sclerosis
Karolinska Institute researchers developed a novel serological assay to determine that individuals with antibodies to HHV-6A early proteins are more likely to develop MS. HHV-6A antibodies were the highest in the presence of elevated EBV antibodies, suggesting that the two viruses could jointly contribute to the development of MS.
Adding an adoptive NK cell infusion to naïve T-Cell-depleted grafts may reduce the rate of HHV-6B reactivation and encephalitis
A small pediatric study found that adoptive NK cell infusions eliminated HHV-6B encephalitis, while maintaining a low rate of GVHD. At a ratio of NK/CD4 >2, the HHV-6B reactivation rate dropped dramatically.
HHV-6 found to be the most frequent cause of viremia in children following HSCT
A prospective study of children transplanted for both malignant and nonmalignant disease found HHV-6 viremia in 53% of cases.
Evidence for HHV-6-induced thrombotic microangiopathy in transplant patients undergoing HSCT
Among infectious agents, HHV-6 was found to be an independent risk factor for thrombotic microangiopathy (TMA) and only HHV-6 infection was associated with TMA-related mortality.
Breakthrough reactivation of HHV-6 occurs with liver transplantation in spite of valganciclovir preemptive therapy for CMV
High-grade HHV-6 viremia is independently associated with rejection of liver transplants within 12 months
Adult patients with lower levels of anti-HHV-6 IgG are significantly more likely to experience HHV-6 reactivation following cord blood transplant
Patients with low levels of HHV-6 antibodies might benefit from treatment from IVIG or novel neutralizing antibodies before cord blood transplantation
Quantitative PCR of serum found superior to whole blood in differentiating between latent virus and viremia following cord blood transplantation
Use of serum more easily distinguishes viremia from latent virus
HHV-6 reactivation following haploidentical hematopoietic stem-cell transplant found to predict acute graft versus host disease in China
25% of the patients with HHV-6 reactivation developed aGVHD compared to 18% in those without reactivation.
Substantial reduction in hippocampal volume found in pediatric hematopoietic stem cell transplant patients with HHV-6B reactivation
Surprisingly, the damage from HHV-6B infection often occurred in the absence of obvious neurological symptoms. Patients without HHV-6 reactivation had no reduction in volume.
Telomeric integration, excision and subsequent and transmission in people with inherited chromosomally integrated HHV-6B (iciHHV-6B)
Exploiting a hypervariable region of the HHV-6B genome, investigators achieve new insights about integration, excision, and genomic stability of iciHHV-6B
Significantly worse outcomes in critically ill hematology patients associated with HHV-6 infection.
Two reports associate detectable HHV-6 DNA in body fluids with increased risk of mortality in patients being treated for hematologic malignancies.
HHV-6 is the predominant reactivated virus, other than CMV, in post-transplant cyclophosphamide associated infections
Large, retrospective multi-institutional study of non-CMV herpesvirus infection in the HCT with cyclophosphamide prophylaxis finds higher rate of HHV-6 infection and associated higher mortality
Failure to detect iciHHV-6 leads to overtreatment in hematopoietic cell transplant recipients
Mistaking iciHHV-6 for a marked reactivation of naturally-acquired infection can lead to unnecessary diagnostic procedures and treatments, with adverse effects.
Foscarnet prophylaxis improved engraftment and survival in cord blood transplant patients
Six-month overall survival was 96% in the treated group compared to 72% in the untreated group.
In DRESS/DIHS, early treatment with high dose steroids may suppress HHV-6; late treatment may prolong viremia
High dose steroids given in the first week appears to prevent HHV-6 reactivation in DRESS/DIHS patients by suppressing T-cell activation and serum interleukin-2 receptor (sIL-2R) levels. In contrast, a late start of steroid therapy resulted in a persistently high viral load for at least three weeks.
CMV & HHV-6 cause severe complications in non-transplant acute leukemia patients
Herpesvirus co-infections, particularly HHV-6 and CMV, cause severe lymphopenia, pneumonia, and an increased risk of acquiring bacterial and fungal infections in non-transplant acute leukemia patients undergoing chemotherapy.
Virus-specific immunotherapy for transplant patients with primary immune deficiencies
A group from Baylor College of Medicine reviewed the efficacy of treating viral infections in transplant patients with primary immunodeficiencies using their viral-specific T lymphocytes. A total of 36 patients were treated with these immunotherapy infusions before or after undergoing hematopoietic stem cell transplantation, and a complete or partial antiviral response were seen in 86% of patients with CMV, 76% of patients with EBV and all patients with adenovirus or HHV-6.
Baylor’s immunotherapy technique found effective in a small clinical trial
Trial explores immunotherapy for opportunistic viruses in transplantation
Further characterization of HHV-6B immune response leads to development of virus-specific immunotherapy
A group from Baylor has further characterized the clinical HHV-6B immune response, and is using this new information to develop an enhanced adoptive T cell immunotherapy specific to HHV-6 for HSCT patients.
Novel multivirus-specific immunotherapy developed as antiviral treatment option for transplant patients.
A novel technique has been developed for the treatment of several viral infections–including HHV-6–following HSCT.
Berberine is as effective as ganciclovir in controlling CMV, and targets IE -2 protein transactivating activity
A Chinese medicine that has been used for thousands of years, berberine inhibits replication of CMV at micromolar levels in vitro. It was also effective against drug resistant strains of CMV, as well against murine cytomegalovirus.
Can a novel free radical scavenger help patients with HHV-6 encephalopathy?
Edaravone shows promise for reducing oxidation and neuronal damage in AESD.
Successful use of Artesunate to treat HHV-6B myocarditis in a child
A group from Children’s Heart Centre in Lund, Sweden, has used Artesunate as an effective antiviral therapy to aid in the treatment of a child with HHV-6B myocarditis.
Failure to detect iciHHV-6 leads to overtreatment in hematopoietic cell transplant recipients
Mistaking iciHHV-6 for a marked reactivation of naturally-acquired infection can lead to unnecessary diagnostic procedures and treatments, with adverse effects.
Foscarnet prophylaxis improved engraftment and survival in cord blood transplant patients
Six-month overall survival was 96% in the treated group compared to 72% in the untreated group.
Oral brincidofovir prophylaxis for CMV decreased incidence of HHV-6B viremia
Allogenic transplant patients who received prophylactic oral brincidofovir as part of a CMV trial had a reduced HHV-6B reactivation and lower viral loads.
Mori lab identifies a vaccine and immunotherapy target for HHV6-B
Rational vaccine design requires understanding details of protective immunity against each virus. Yasuko Mori and associates from Japan have now identified CD4+ and H-2Kd restricted CD8+ T-cell epitopes essential for HHV-6B viral entry, opening new possibilities for vaccines and immunotherapy.
Breakthrough on therapeutic HHV-6B neutralizing antibodies
Yasuko Mori and colleagues were successful in humanizing two neutralizing monoclonal antibodies to HHV-6B. The chimeric antibodies performed well enough to show promise for therapeutic use.
Foscarnet approved for HHV-6 encephalitis in Japan
Although foscarnet is widely used for HHV-6 encephalitis, it has never been specifically approved for HHV-6. Japan’s Ministry of Health, Labor and Welfare was the first to approve foscarnet (Foscavir) for the treatment of HHV-6 encephalitis.
Foscarnet prophylaxis reduces severity but does not prevent HHV-6 encephalitis
A Japanese trial of foscarnet prophylaxis in cord blood transplant patients was successful in reducing severity and mortality as well as suppressing high viral loads, but it failed to prevent encephalitis. The authors note that the blood brain barrier must be inflamed to allow effective penetration of the drug into the central nervous system and speculate that the prophylaxis may have protected the meninges.
Low dose emetine shows promise as a herpesvirus antiviral
Investigators at Johns Hopkins have determined that emetine, an older drug used to treat dysentery as well as to induce vomiting, is also effective against cytomegalovirus (CMV/HHV-5). Not only was emetine effective at an extremely low dose, it demonstrated a synergistic effect when combined with ganciclovir in a mouse model of CMV infection and it worked at a much earlier stage of viral replication than the drugs currently in use.
Genome editing to clear latent herpesvirus infection
A group from the University Medical Center in the Netherlands has shown that new gene editing technology can be used to impair viral replication and clear latent herpesvirus infections. The group used a CRISPR-Cas system to target viral genetic elements that completely eliminated CMV and HSV1 replication. They were also able to clear latent EBV from transformed human tumor cells.
Chimerix “SUPPRESS” trial to be largest ever for HHV-6 treatment
Chimerix “SUPPRESS” trial to be largest study ever conducted for treatment of HHV-6 infection
New broad-spectrum antiherpesvirus agents identified
A set of novel compounds synthesized by Microbiotix, Inc. have shown increased activity against a broad spectrum of human herpesviruses, including HHV-6.
CMX001 shows strong in-vitro activity against HHV-6
Data from a recent report may increasingly argue in favor of using the antiviral known as CMX001 for treatment of HHV-6 infection.
HHV-6 saliva DNA levels in chemotherapy patients lowered by mushroom extract
New findings suggest salivary HHV-6 levels may be a good biomarker of QOL in patients during the course of chemotherapy.