Outcomes worse for the subtype linked to EBV and HHV-6.
iciHHV-6B linked to systemic lupus erythematosus (SLE) in Japanese and European populations
iciHHV-6B, when integrated into chromosome 22q, was strongly associated with SLE and with SLE severity.
HHV-6 reactivation in patients with DRESS associated with worse outcomes
Similar findings with EBV and CMV reactivation; causation vs. correlation unclear.
A retrospective study of haploidentical alloHCT patients found no outcome differences between treated patients with high viral loads (log10 4.65) and untreated patients with lower viral loads (log10 3.84)
Controlled studies are needed to determine the benefit of antiviral therapy in patients with high viral >10,000 copies/ mL.
While frequently detected in immunocompromised patients, HHV-6 is rarely found in the lungs of immunocompetent patients
Two groups of investigators in China used next-generation sequencing to identify EBV, HHV-7, HSV1 and CMV as the most common herpesviruses in immunocompetent pneumonia patients.
A variety of techniques greatly increase the efficiency of HHV-6A reconstitution and replication using BACs
Improving efficiency of reconstitution may aid in study of HHV-6 biology.
HHV-6 and HHV-7 frequently identified in the spinal fluid of patients with suspected encephalitis
Next-generation sequencing proves valuable for identifying CNS infections in the immunocompetent.
Could herpesvirus infection of endothelial cells be important in the pathophysiology of ME/CFS?
A recent review summarizes evidence that HHV-6 can cause endothelial dysfunction, which often is seen in both Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome.
Antibodies to HHV-6 during acute COVID-19 may help predict development of Long COVID
Autoantibodies directed against neural targets have most predictive power.
HHV-6-IgG antibodies correlate with evidence of leaky gut in patients with Long COVID
Whether HHV-6 has a causal role in leaky gut is not addressed.
Telomeric repeats (TMRs) important for Marek’s Disease virus live vaccine efficacy
Chromosomal integration and maintenance, as well as vaccine efficacy, severely impaired in the absence of TMRs.
What went wrong with posoleucel: a virus-specific cytotoxic T cell therapy?
Results from preclinical and Phase 2 studies were encouraging, but Phase III trials were cancelled.
HHV-6 reactivation may influence graft rejection in pediatric kidney and liver transplantation
Cytokines IL-4, IL-8 and IL-10 correlated with graft rejection and were elevated in HHV-6+ patients.
A remarkably low prevalence of iciHHV-6 (0- 0.24%) reported in two Finnish studies
Out of 1,276 pregnancies all three iciHHV-6 cases involved preeclampsia or growth restriction.
Clinical evidence that infections, including with herpesviruses, increase risk for neurodegeneration
Epidemiologic research supports the provocative hypothesis.
Japanese study confirms cognitive problems from post-transplant HHV-6B reactivation
Those with the highest viral loads suffered deficits in verbal memory and reduced quality of life.
Individuals seropositive for herpesviruses may have greater risk of dementia
Large study from UK Biobank finds that people seropositive for all of these four herpesviruses—HSV-1, HHV-6, HHV-7 and VZV—have greatly increased risk of developing dementia.
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.
Telomeric repeats (TMRs) important for Marek’s Disease virus live vaccine efficacy
Chromosomal integration and maintenance, as well as vaccine efficacy, severely impaired in the absence of TMRs.
Single-cell RNA sequencing was used to determine the tropism of MRV in the thymus and how central tolerance is disrupted
A new cell culture model for MRV could offer insights on the development of autoimmunity after neonatal infection.
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.
iciHHV-6B linked to systemic lupus erythematosus (SLE) in Japanese and European populations
iciHHV-6B, when integrated into chromosome 22q, was strongly associated with SLE and with SLE severity.
Single-cell RNA sequencing was used to determine the tropism of MRV in the thymus and how central tolerance is disrupted
A new cell culture model for MRV could offer insights on the development of autoimmunity after neonatal infection.
Co-infection of HHV-6A and EBV results in a 6.7 fold increased risk of developing multiple sclerosis
The increased risk occurred only in adults who were infected with EBV after their teenage years, and had elevated EBNA-1 antibodies.
MicroRNA expression patterns suggest that HHV-6 may play a role in triggering systemic sclerosis
Expression pattern of several miRNAs in SS tissue parallels the pattern generated when dermal fibroblasts and endothelial cells are infected by HHV-6A and CMV.
Could HHV-6 reactivation in drug hypersensitivity trigger fulminant type 1 diabetes?
Small study demonstrates increased HHV-6 antibodies in all patients shortly before the onset of DIHS-associated fulminant diabetes.
EBV DNA found in 42% of lupus patients compared to 3% of controls; 25% had EBV IgM antibodies compared to <1% of controls
HHV-6 DNA is not elevated in lupus patients but may have a role in reactivating EBV.
Are herpesviruses reactivated more often in acute COVID-19?
Systematic review and meta-analysis found strong evidence for EBV in the seriously ill; only 6 of 36 studies included HHV-6 testing.
Coinfection of CMV and HHV-6A boosts fibrosis-associated microRNAs in fibroblasts
Investigators see possible links to systemic sclerosis, liver fibrosis and cardiovascular remodeling.
Increased HHV-6B viral load and levels of autonomic autoantibodies in ME/CFS
Biomarkers distinguish cases from healthy controls, but don’t all correlate with disease severity.
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.
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
Hodgkin’s lymphoma has 3 subtypes, one linked to infection with EBV and HHV-6
Outcomes worse for the subtype linked to EBV and HHV-6.
Although 28% of children undergoing chemotherapy develop herpesvirus viremia, there is minimal clinical impact
HHV-6, CMV and HSV1/2 were the most likely to reactivate, but herpesvirus reactivation was just as likely prior to chemotherapy.
How frequent are HHV-6-related complications with CAR-T cell therapy?
A combination of studies find that both reactivation and disease are infrequent after CAR-T therapy.
HHV-6B DNA associated with worse clinical outcomes in high grade serous epithelial ovarian cancer
Multiplex assay for 113 viruses in tumor tissue finds six viruses, including HHV-6B, linked to reduced overall survival.
HHV-6A infection of thyroid cancer cells induces various growth-promoting changes
Oncogene activation, pro-inflammatory cytokines, genomic instability, expression of oncogenic miRNAs are induced by infection.
HHV-6 detectable in some urine samples, but not linked to disease
In contrast, human papillomavirus found more often in urine of bladder cancer patients than in urine of patients with non-cancerous urinary tract conditions.
Part 1: Latent HHV-6 is reactivated in patients receiving CAR-T cell therapy
Investigators urge careful monitoring for HHV-6 and ciHHV-6.
Part 2: CAR-T cell therapy and its complications
Could some complications of CAR-T cell therapy be secondary to HHV-6 infection?
Part 3. HHV-6 Encephalitis in CAR-T Cell therapy
Clearly documented cases of HHV-6 encephalitis have been reported, but some are missed because they were classified as ICAN or because HHV-6 testing was not performed in patients with mental status changes.
Part 4. Might HHV-6 contribute to some cases of cytokine release syndrome, pneumonia, and cytopenias in CAR-T Cell therapy?
While unlikely to trigger the cytokine storm, HHV-6 infection may perpetuate it, and contribute directly to cytopenias and pneumonia.
Differentially expressed HHV-6A/B and HHV-7 genes may have prognostic value in gliomas
Unclear if viral gene expression signature confers prognostic information that is independent of host cell gene expression signatures.
HHV-6 encephalitis following CAR-T cell therapy
A growing number of case reports reveal reactivation similar to that seen after hematopoietic stem cell therapy. Could CAR-T cells be a source of lytic HHV-6?
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
Telomeric repeats (TMRs) important for Marek’s Disease virus live vaccine efficacy
Chromosomal integration and maintenance, as well as vaccine efficacy, severely impaired in the absence of TMRs.
A remarkably low prevalence of iciHHV-6 (0- 0.24%) reported in two Finnish studies
Out of 1,276 pregnancies all three iciHHV-6 cases involved preeclampsia or growth restriction.
Reactivation of a transplant recipient’s iciHHV-6B resulted in an active infection of his donated liver
Investigators from the University of Helsinki used highly sophisticated techniques to establish that the donor’s integrated virus reactivated and then infected the graft. This thorough investigation highlights the potential pathological impact of iciHHV-6B in transplantation.
HHV-6B IE1 inhibits DNA damage signaling pathway leading to genomic instability
Results suggest a possible link between genomic instability and iciHHV-6 associated disease.
BioFire assay identifies HHV-6 as the most frequent cause of meningoencephalitis in infants 4-11 months
All cases found to be iciHHV-6 were assumed to be false positives.
The relationship of telomere length to HHV-6 integration
Telomere length does not appear to influence the efficiency of viral integration, and viral integration may not affect telomere length.
Uncontrolled evidence suggests immunosuppression may be safe and effective in lymphocytic myocarditis patients with biopsies positive for HHV-6 by qPCR
Steroids reduced cardiac inflammation in 70% and improved ejection fraction in 80% without an increase in viral load.
German HCT specialists call for iciHHV-6 screening of patients and donors
Study finds value in HHV-6 testing of other tissues, as well as blood, and of routine testing for iciHHV-6 in both donors and recipients of allo-HCT.
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.
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.
HHV-6 reactivation in patients with DRESS associated with worse outcomes
Similar findings with EBV and CMV reactivation; causation vs. correlation unclear.
Could HHV-6 reactivation in drug hypersensitivity trigger fulminant type 1 diabetes?
Small study demonstrates increased HHV-6 antibodies in all patients shortly before the onset of DIHS-associated fulminant diabetes.
International expert panel publishes guidelines for management of DRESS
Guidelines recommend routinely assessing HHV-6 viral load, but not antiviral treatment when HHV-6 reactivation identified.
Increased expression of HHV-6B receptor CD134/OX40 found in DIHS/DRESS skin lesions
The severity of DIHS/DRESS cases was significantly correlated with the frequency of CD134+ cells.
Thorough review of the role of HHV-6 in DIHS/DRESS
HHV-6 reactivation much more frequent than reactivation of other herpesviruses.
Investigators find HHV-6 in the skin of DRESS patients two weeks before it is found in the blood in a large, multi-center case series
HHV-6 reactivation in both skin and blood was found frequently in severe cases.
DRESS, a syndrome linked to viral reactivation, may be triggered by several antivirals
Ribavarin, ritonavir, abacavir and lamivudine were the primary triggers.
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 and HHV-7 frequently identified in the spinal fluid of patients with suspected encephalitis
Next-generation sequencing proves valuable for identifying CNS infections in the immunocompetent.
A systematic review and meta-analysis confirms an association between HHV-6B reactivation and increased mortality after hematopoietic cell transplant
Randomized trials are warranted to evaluate if treating HHV-6B reactivation improves outcomes.
Large study from China identifies adverse outcomes associated with, and risk factors for, HHV-6 encephalitis in post-HSCT patients
Greatly increased risk of death, acute GVHD, transplant-associated microangiopathy found.
Growing evidence of rare HHV-7 associated encephalitis and seizures in the immunocompetent
The clinical picture is very similar to HHV-6B encephalitis.
BioFire assay identifies HHV-6 as the most frequent cause of meningoencephalitis in infants 4-11 months
All cases found to be iciHHV-6 were assumed to be false positives.
Small study finds relatively high foscarnet concentrations in CSF in HHV-6 encephalitis
CSF foscarnet concentrati.ons were very near IC50 and were followed by sharp reductions in viral load.
Individuals seropositive for herpesviruses may have greater risk of dementia
Large study from UK Biobank finds that people seropositive for all of these four herpesviruses—HSV-1, HHV-6, HHV-7 and VZV—have greatly increased risk of developing dementia.
HHV-6 DNA often found in cerebrospinal fluid in samples tested for meningitis
Those with viral infections showed no difference in white or red blood cell counts or the protein and glucose levels.
HHV-6 encephalitis following CAR-T cell therapy
A growing number of case reports reveal reactivation similar to that seen after hematopoietic stem cell therapy. Could CAR-T cells be a source of lytic HHV-6?
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
Febrile status epilepticus in infants with MRI-confirmed brain abnormalities linked to temporal lobe epilepsy later in life
Surprisingly, although HHV-6B has been linked to febrile seizures, febrile status epilepticus and temporal lobe epilepsy, the report contains no mention of the virus.
BioFire assay identifies HHV-6 as the most frequent cause of meningoencephalitis in infants 4-11 months
All cases found to be iciHHV-6 were assumed to be false positives.
Another report links HHV-6B nucleic acid and antigen to mesial temporal lobe epilepsy
Viral DNA and antigen found at higher levels in MTLE than in control brains.
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.
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 …
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.
Review: HHV-6 is an important cause of persistent viral myocarditis, along with Parvovirus B-19 and adenovirus
SARS CoV-2 may lead to the activation of persistent herpesviruses in heart tissue.
Stanford WGS study: Widespread integration and reactivation of HHV-6B and HHV-7 in lymphoblastoid cells immortalized with EBV
EBV infected B cells may represent a site of HHV-6 latency.
Parvovirus B19 and HHV-6 in biopsies of South African patients with acute myocarditis
Parvovirus B19 was the most common virus found, followed by EBV and HHV-6.
Coronary artery spasm often occurs in myocarditis cases with biopsy-proven HHV-6 and parvovirus B19 infection
Both viruses were associated with large vessel spasm, but parvovirus B19 was also associated with microvascular spasm.
Evidence for viral myocarditis in 2.3% of infant sudden death cases
Enteroviruses and parvovirus B19 were found more frequently than HHV-6.
Fatal myocarditis from HHV-6 in immunocompetent adult suspected of COVID-19
Case report does not distinguish HHV-6A from HHV-6B nor possible role of virus in other organ pathology.
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.
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.
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.
A remarkably low prevalence of iciHHV-6 (0- 0.24%) reported in two Finnish studies
Out of 1,276 pregnancies all three iciHHV-6 cases involved preeclampsia or growth restriction.
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 reactivation may influence graft rejection in pediatric kidney and liver transplantation
Cytokines IL-4, IL-8 and IL-10 correlated with graft rejection and were elevated in HHV-6+ patients.
Lower levels of torque teno virus correlate with higher HHV-6A viral loads and higher rejection rates in kidney transplantation
Value of this observation in determining prognosis or guiding treatment remains to be studied.
High levels of HHV-6A DNA found in blood of 52% of kidney transplant patients
HHV-6A was the most common virus identified, but was not linked to worse outcomes compared to other viral infections.
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 …
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.
Using CRISPR to excise integrated HHV-6A from latently infected cells and iciHHV6 patient cell lines, in vitro
Advance may aid the study of integration and excision and might ultimately have clinical application.
The relationship of telomere length to HHV-6 integration
Telomere length does not appear to influence the efficiency of viral integration, and viral integration may not affect telomere length.
Uncontrolled evidence suggests immunosuppression may be safe and effective in lymphocytic myocarditis patients with biopsies positive for HHV-6 by qPCR
Steroids reduced cardiac inflammation in 70% and improved ejection fraction in 80% without an increase in viral load.
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.
HHV-6 reactivation may influence graft rejection in pediatric kidney and liver transplantation
Cytokines IL-4, IL-8 and IL-10 correlated with graft rejection and were elevated in HHV-6+ patients.
Coinfection of CMV and HHV-6A boosts fibrosis-associated microRNAs in fibroblasts
Investigators see possible links to systemic sclerosis, liver fibrosis and cardiovascular remodeling.
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.
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.
While frequently detected in immunocompromised patients, HHV-6 is rarely found in the lungs of immunocompetent patients
Two groups of investigators in China used next-generation sequencing to identify EBV, HHV-7, HSV1 and CMV as the most common herpesviruses in immunocompetent pneumonia patients.
HHV-7 found in the bronchial lavage of 6.2% of Chinese patients with severe pneumonia
It is unknown whether high viral loads correlate with worse prognosis.
Coinfection of CMV and HHV-6A boosts fibrosis-associated microRNAs in fibroblasts
Investigators see possible links to systemic sclerosis, liver fibrosis and cardiovascular remodeling.
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
Co-infection of HHV-6A and EBV results in a 6.7 fold increased risk of developing multiple sclerosis
The increased risk occurred only in adults who were infected with EBV after their teenage years, and had elevated EBNA-1 antibodies.
MS drug teriflunomide dramatically reduces antibody titers to EBV and HHV-6
Study results are consistent with a pathogenetic role for viruses in relapsing-remitting MS.
New Evidence that HHV-6A, like EBV, May Trigger Some Cases of Multiple Sclerosis (MS)
Sera drawn before vs. after onset of MS find seropositivity for HHV-6A more likely in MS.
Meta-Analysis links EBV, HHV-6 and VZV to multiple sclerosis
Study pools data from nearly 30,000 people with MS.
HHV-6 DNA load in whole blood and elevated EBNA antibodies predict progression in first clinical episodes of demyelination in multiple sclerosis
Patients with viral loads suggestive of iciHHV-6 had the greatest risk of developing demyelinating disease.
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 retrospective study of haploidentical alloHCT patients found no outcome differences between treated patients with high viral loads (log10 4.65) and untreated patients with lower viral loads (log10 3.84)
Controlled studies are needed to determine the benefit of antiviral therapy in patients with high viral >10,000 copies/ mL.
While frequently detected in immunocompromised patients, HHV-6 is rarely found in the lungs of immunocompetent patients
Two groups of investigators in China used next-generation sequencing to identify EBV, HHV-7, HSV1 and CMV as the most common herpesviruses in immunocompetent pneumonia patients.
What went wrong with posoleucel: a virus-specific cytotoxic T cell therapy?
Results from preclinical and Phase 2 studies were encouraging, but Phase III trials were cancelled.
HHV-6 reactivation may influence graft rejection in pediatric kidney and liver transplantation
Cytokines IL-4, IL-8 and IL-10 correlated with graft rejection and were elevated in HHV-6+ patients.
A systematic review and meta-analysis confirms an association between HHV-6B reactivation and increased mortality after hematopoietic cell transplant
Randomized trials are warranted to evaluate if treating HHV-6B reactivation improves outcomes.
Large study from China identifies adverse outcomes associated with, and risk factors for, HHV-6 encephalitis in post-HSCT patients
Greatly increased risk of death, acute GVHD, transplant-associated microangiopathy found.
Lower levels of torque teno virus correlate with higher HHV-6A viral loads and higher rejection rates in kidney transplantation
Value of this observation in determining prognosis or guiding treatment remains to be studied.
How frequent are HHV-6-related complications with CAR-T cell therapy?
A combination of studies find that both reactivation and disease are infrequent after CAR-T therapy.
Centrilobular necroinflammation associated with pediatric HHV-6+ acute liver failure
Would early treatment with antiviral therapy prevent the need for a liver transplant?
Why does substituting CMV-specific letermovir for broad-spectrum anti-viral prophylaxis reduce the rate of HHV-6B encephalitis?
Japanese study replicates the paradoxical results of a prior US study, but fails to explain the paradox.
Reactivation of a transplant recipient’s iciHHV-6B resulted in an active infection of his donated liver
Investigators from the University of Helsinki used highly sophisticated techniques to establish that the donor’s integrated virus reactivated and then infected the graft. This thorough investigation highlights the potential pathological impact of iciHHV-6B in transplantation.
Biofire multiplex PCR assay accurately detects HHV-6 meningitis/encephalitis in immunocompromised adults
Utility of the assay in immunocompetent patients requires further study.
Reactivated HHV-6, CMV, adenovirus and BK virus associated with increased mortality in pediatric sepsis
Odds of mortality were 2.6-3X higher in patients with detectable viral DNA; odds were even higher with multiple herpesviruses.
Japanese study confirms cognitive problems from post-transplant HHV-6B reactivation
Those with the highest viral loads suffered deficits in verbal memory and reduced quality of life.
Adding antithymocyte globulin to post transplant cyclophosphamide prophylaxis does not increase risk of HHV-6 reactivation after haploidentical hematopoietic cell transplantation
The main risk factor for HHV-6 reactivation was low absolute lymphocyte count.
What went wrong with posoleucel: a virus-specific cytotoxic T cell therapy?
Results from preclinical and Phase 2 studies were encouraging, but Phase III trials were cancelled.
Phase III trials suspended for T-cell therapeutic active against HHV-6
In a surprise, multi-virus cytotoxic T cell therapy trials were terminated early for failure to meet endpoints.
Virus specific T cell infusions show promise for preventing HHV-6B reactivation in transplant patients
Review highlights the importance of cell mediated immunity and the limitations of antivirals, vaccines and immunoglobulin therapy for HHV-6, VZV and HSV.
Reference values established for virus specific T-cells in healthy adults
These values may help determine the type of treatment transplant patients should receive: antiviral or adoptive T-cell therapy or a reduction in immunosuppression.
HHV-6 encephalitis following CAR-T cell therapy
A growing number of case reports reveal reactivation similar to that seen after hematopoietic stem cell therapy. Could CAR-T cells be a source of lytic HHV-6?
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.
Artesunate compares favorably to herpesvirus antivirals in suppressing HHV-6 and HHV-7
Non-randomized study finds somewhat more potent reduction of virus in leucocytes over several months of treatment.
Virus specific T cell infusions show promise for preventing HHV-6B reactivation in transplant patients
Review highlights the importance of cell mediated immunity and the limitations of antivirals, vaccines and immunoglobulin therapy for HHV-6, VZV and HSV.
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.
A retrospective study of haploidentical alloHCT patients found no outcome differences between treated patients with high viral loads (log10 4.65) and untreated patients with lower viral loads (log10 3.84)
Controlled studies are needed to determine the benefit of antiviral therapy in patients with high viral >10,000 copies/ mL.
After screening 100,000 compounds, Merck identified a potent broad-spectrum herpesvirus antiviral
The new small molecule non-nucleoside inhibitor was effective in both in vitro and in vivo studies although no testing against HHV-6 was reported.
Why does substituting CMV-specific letermovir for broad-spectrum anti-viral prophylaxis reduce the rate of HHV-6B encephalitis?
Japanese study replicates the paradoxical results of a prior US study, but fails to explain the paradox.
Metformin reduces HHV-6A replication in T cells by activating AMPK
Conversely, HHV-6A infection increases viral replication by inhibiting AMPK and enhancing mTOR signaling and glycolysis.
Adding antithymocyte globulin to post transplant cyclophosphamide prophylaxis does not increase risk of HHV-6 reactivation after haploidentical hematopoietic cell transplantation
The main risk factor for HHV-6 reactivation was low absolute lymphocyte count.
MS drug teriflunomide dramatically reduces antibody titers to EBV and HHV-6
Study results are consistent with a pathogenetic role for viruses in relapsing-remitting MS.
Strong Evidence Linking HHV-6B To Pneumonia in Transplant Patients
Levels of mRNA transcripts indicating active infection strengthen case for pathogenic role.
Substituting letermovir for broad-spectrum ganciclovir for CMV prophylaxis did not increase HHV-6 disease in allogenic transplant patients
Investigators were surprised that the use of the less toxic CMV specific antiviral did not result in a significant increase in HHV-6-related disease.
Small study finds relatively high foscarnet concentrations in CSF in HHV-6 encephalitis
CSF foscarnet concentrati.ons were very near IC50 and were followed by sharp reductions in viral load.
Artesunate compares favorably to herpesvirus antivirals in suppressing HHV-6 and HHV-7
Non-randomized study finds somewhat more potent reduction of virus in leucocytes over several months of treatment.
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.
Adding antithymocyte globulin to post transplant cyclophosphamide prophylaxis does not increase risk of HHV-6 reactivation after haploidentical hematopoietic cell transplantation
The main risk factor for HHV-6 reactivation was low absolute lymphocyte count.
Reference values established for virus specific T-cells in healthy adults
These values may help determine the type of treatment transplant patients should receive: antiviral or adoptive T-cell therapy or a reduction in immunosuppression.
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.