Israeli scientists have identified hundreds of new open reading frames, generating an unbiased atlas of the HHV-6 proteome. They also identified three highly abundant long non-coding RNAs.
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 DNA in bile fluid correlates with higher mortality in liver transplant patients
Persistent HHV-6 infection in the liver is hard to detect from plasma samples and liver biopsies may miss spotty infections. Bile fluid may be the best method for detecting herpesviruses that impact the liver.
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.
Yasuko Mori awarded Lifetime Achievement Award
Yasuko Mori, PhD, Professor of Clinical Virology at the Kobe University Graduate School of Medicine was awarded the HHV-6 Foundation’s Dharam Ablashi Lifetime Achievement Award at the 11th International Conference on HHV-6 & 7.
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.
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.
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.
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.
49 new CD4 T-cell-recognized HHV-6B antigens identified using genome-wide approach
University of Washington investigators utilized rare cell enrichment and an HLA-agnostic, proteome-wide approach to expand the library of known HHV-6 T cell antigens from 11 to 60.
New HLA-DR3-restricted HHV-6B peptides demonstrate broadly recognized polyfunctional and cytotoxic CD4 T-cell responses
University of Massachusetts investigators have identified 25 new naturally processed peptide sequences using mass spectrometry.
HHV-6 infection induces a high percentage of virus-specific suppressive Tregs compared to CMV
A French group studied immunological responses to HHV-6 and CMV in healthy adults ex vivo and found that HHV-6 induces an excessive number of potently immunosuppressive T regulatory cells that block dendritic cell maturation and functions.
An elevated CD134/CD4+ ratio before conditioning results in a 10 fold increased risk of HHV-6B reactivation
A prospective study of allogenic stem cell transplant patients in Japan suggests that the percentage of CD134+ T cells could be used to predict which patients are vulnerable to HHV-6 reactivation. The authors propose that further investigation into the effect of elevated CD134+ T cells pre-transplant is warranted.
HHV-6 linked to neutropenia, thrombocytopenia, longer hospital stays and a 5X increased risk of serious complications after autologous transplant
In a prospective study, patients with HHV-6 infection took longer to recover neutrophils and platelets. They also spent significantly more time in the hospital with complications.
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.
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.
Could autophagy dysregulation link neurotropic viruses to Alzheimer’s disease?
The cellular housekeeping function of autophagy may play a role in Alzheimer’s as dysfunction could result in the accumulation of amyloid. HHV-6A, HHV-6B and HSV1 can infect central nervous system cells and dysregulate autophagy.
Herpesviruses may reduce NK cell cytotoxicity in Alzheimer’s
MS patients with a particular haplotype on natural killer cells are more susceptible to HHV-6A infection. Similarly, HHV-6A/B may contribute to Alzheimer’s by utilizing a specific NK cell inhibitory receptor to disrupt the ability of NK cells to clear infected cells.
HHV-6 small non-coding RNA proposed as an indicator of an early stage of HHV-6 reactivation
German investigators have identified a marker for what they believe is the earliest stage of viral reactivation, or “transactivation” marked by transcription of several viral small non-coding RNAs in the absence of detectable viral replication. The group believes that these viral small RNAs could be developed as biomarkers.
Biospecimen Repositories for Alzheimer’s Disease
NIH NeuroBioBank (brain tissues from various neurological diseases) BrainNet Europe – 19 brain banks in 11 European countries UK Brain Banks Network Australian Brain Bank Network – accepts requests from outside Australia
Private funding available for Alzheimer’s research
Alzheimer’s Disease Research Grants–Private sources of funds
National Institute on Aging encourages grant proposals on HHV-6A & HHV-7 in Alzheimer’s
NIH leaders of the National Institute on Aging (NIA) encouraged investigators with experience in virology and infectious disease to apply for funding to study Alzheimer’s disease. The encouragement came at a workshop held at the Alzheimer’s Association International Conference in Chicago on July 22nd.
Gene-expression network analysis points to HHV-6A as a key driver in upregulating genes leading to Alzheimer’s disease progression
Investigators at Mt Sinai used “big data” models to determine that the genes involved with fighting Alzheimer’s are the same ones that fight virus. They found HHV-6A and HHV-7 to be more abundant in Alzheimer’s brains, and singled out HHV6-A as a key modulator of the genes involved in amyloidosis and neuronal death.
HHV-6 and HSV1 dramatically accelerate amyloid plaque production in Alzheimer’s model
Researchers at Harvard studied how neurons responded to the presence of herpesviruses HSV1 and HHV-6, and found that they rapidly induce amyloid plaque production within 24 to 48 hours.
Antiviral therapy reduces risk of dementia in Taiwan seniors with a history of acute herpesvirus infections
Large insurance data studies in Taiwan have found that seniors with shingles or serious HSV1 infections have a 2-3 fold increased risk of certain forms of dementia, and that antiviral treatment can reduce that risk by 90%.
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.
CXCL11 and CCL2 are specific to HHV-6B in febrile infants
Japanese investigators from Kobe University identified CXC11 as a chemokine uniquely expressed in primary HHV-6B infections. They also confirmed a previous finding that cytokine CCL2 (MCP-1) plays a role in HHV-6B primary infections. Both CXCL11 and CCL2 are expressed in several neuroinflammatory conditions including epilepsy, Alzheimer’s disease and traumatic brain injury.
Elevated levels of HHV-6 DNA in Alzheimer’s, linked to variants in antiviral genes
A group from Italy’s University of Bologna report that genetic defects in antimicrobial defense mechanisms can leave some individuals vulnerable to sub-clinical infections that lead to cognitive decline as they age. They found variations in specific antiviral genes that correlate with HHV-6 DNA levels in brain tissue and blood from patients with Alzheimer’s disease.
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.
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.
Epstein-Barr Virus and Human herpes virus 6 Type A DNA Enhance IL-17 Production in Mice
Since both HHV-6 and EBV have been associated with an increased risk of autoimmune disease development, a group at the American University of Beirut studied whether viral DNA might be capable of triggering IL-17, a cytokine associated with autoimmune disease. They injected BALB/c mice intraperitoneally with either EBV or HHV-6A DNA. They found that both IL-17 and IL-23 were markedly elevated.
HHV-6 as a trigger of autoimmune disease?
Researchers discuss the potential mechanisms by which HHV-6A/B may contribute to autoimmune disease
Does HHV-6 cause thyroiditis and autoimmunity in patients with drug hypersensitivity?
Case report describes two cases of DRESS related thyroiditis with very high levels of HHV-6 reactivation that go on to develop autoimmunity.
Study shows HHV-6 reactivation is disproportionately elevated among patients with autoimmune connective tissue disease
New study from Italy indicates that HHV-6 reactivation is selectively increased among patients suffering from autoimmune connective tissue diseases (ACTD).
HHV-6A linked to Thyroiditis, Autoimmune Disease
A group from Italy has linked HHV-6A to Hashimoto’s Thyroiditis, and provides evidence for autoimmune disease associated with HHV-6A and HHV-6B.
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-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.
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-6A sequences found in ovarian cancer tissues but not in controls
A broadscale investigation of the ovarian cancer oncobiome using a microarray system PathoChip found HHV-6A sequences at or near genes associated with tumorigenesis in ovarian cancer tissue samples.
Deep sequencing analysis finds HHV-6, CMV and EBV in a subset of stomach and colon cancers
A team at University of Pittsburgh analyzed a large database of deep sequencing data from tumor and control tissues to look for viral sequences in 22 different cancers. They were surprised to find several herpesviruses in gastrointestinal cancers but not in control tissues.
Inherited ciHHV-6 increases risk of developing acute GVHD and CMV in transplant patients
A higher prevalence of inherited virus was found in patients
Investigators at Fred Hutchinson Cancer Center determined that transplant patients with inherited ciHHV-6 were twice as likely to develop acute graft vs host disease and three times more likely to develop high level CMV viremia. Transplant patients were also significantly more likely to have inherited ciHHV-6 than donors.
Could HHV-6 U94 attenuate tumor cell growth and metastasis?
Italian investigators found that HHV-6 latency-associated gene U94, inserted in a HSV1 vector, inhibited the development of breast cancer, cervical cancer, and lung metastasis. It also impaired tumor driven angiogenesis.
Neoplasia: could iciHHV-6A cause a benign HPV strain to turn deadly?
Human papillomavirus 4 is a benign strain not associated with cancer. However, in a woman with inherited chromosomally integrated HHV-6A, a high grade vaginal squamous lesion developed rapidly. The authors warn that there may be a synergistic effect between HPV4 and iciHHV6A.
Does the high level of U94 in iciHHV-6 contribute to abnormal ‘marker’ chromosomes and cancer?
Investigators from the University of Ferrara, Italy have found evidence suggesting that high levels of U94 in ciHHV6 may predispose to the formation of marker chromosomes. A patient with diffuse large B-cell lymphoma positive for inherited chromosomally integrated HHV-6A and HHV-6A was also found in a marker chromosome, an abnormal piece of chromosome that is seen in some leukemia and lymphomas.
HHV-6 lymphadenopathy mimicking lymphoma
Investigators at Yale University warn that hypersensitivity-associated HHV-6 lymphadenopathy can have the same presentation as lymphoma.
Herpesvirus saliva DNA increases dramatically during spaceflight
A number of astronauts have complained about herpesvirus reactivations during flight, and several developed shingles. Investigators at NASA determined that space flight increases herpesvirus shedding in saliva, compared to levels before and after their missions.
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.
HHV-6 but not HHV-7 correlates with nerve fiber damage in fibromyalgia patients
HHV-6 was found to be significantly correlated with nerve fiber damage severity by Latvian investigators. 51% of fibromyalgia patients had detectable HHV-6 DNA in whole blood compared to just 6% of controls.
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.
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.
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.
Valganciclovir shows promise during first randomized clinical trial for treatment of HHV-6 & EBV in CFS patients
Stanford clinical trial indicates that VGCV may have a clinical benefit among a subset of CFS patients with HHV-6 and EBV infection
CFS patients with ciHHV-6 may benefit from antiviral treatment
Researchers at the University Of South Florida’s Morsani College Of Medicine have published findings that suggest ciHHV-6 is the possible cause of some CFS cases
CFS: a herpesvirus infection of the vagus nerve?
A new theory suggests CFS may be the result of a pathological infection of the vagus nerve.
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.
Inherited ciHHV-6 increases risk of developing acute GVHD and CMV in transplant patients
A higher prevalence of inherited virus was found in patients
Investigators at Fred Hutchinson Cancer Center determined that transplant patients with inherited ciHHV-6 were twice as likely to develop acute graft vs host disease and three times more likely to develop high level CMV viremia. Transplant patients were also significantly more likely to have inherited ciHHV-6 than donors.
A more efficient form of latency? HHV-6A persistence depends on telomeric repeats, not circular episomes
Most herpesviruses maintain latency by forming circular episomes in the nucleus of the cell. Investigators in Germany have provided further evidence that HHV-6A relies on their telomeres, not circular episomes, to maintain a persistent latent infection by integrating into the host chromosome.
New cell culture system established to study HHV-6A/B chromosomal integration
A group led by Louis Flamand, PhD in Canada has developed a culture system that can be used to determine how the virus enters latency by integrating into the chromosome, and which drugs cause it to activate.
Solo DR and non-telomeric chromosomal integration
A new study shows that HHV-6A direct repeats can survive alone in an integrated state without the rest of the viral genome. The study also identified non-telomeric integration of HHV-6A in both in vitro cultured cells as well as one iciHHV-6A patient.
Neoplasia: could iciHHV-6A cause a benign HPV strain to turn deadly?
Human papillomavirus 4 is a benign strain not associated with cancer. However, in a woman with inherited chromosomally integrated HHV-6A, a high grade vaginal squamous lesion developed rapidly. The authors warn that there may be a synergistic effect between HPV4 and iciHHV6A.
Opinion: call for ciHHV6 screening in transplantion
Two physicians from Texas propose that ciHHV6 status of donors and recipients be determined before solid organ transplantion, using a single pre-transplant qPCR test on whole blood, and that patients with ciHHV-6 or ciHHV-6 donors be carefully monitored for signs of active HHV-6 infection.
Does the high level of U94 in iciHHV-6 contribute to abnormal ‘marker’ chromosomes and cancer?
Investigators from the University of Ferrara, Italy have found evidence suggesting that high levels of U94 in ciHHV6 may predispose to the formation of marker chromosomes. A patient with diffuse large B-cell lymphoma positive for inherited chromosomally integrated HHV-6A and HHV-6A was also found in a marker chromosome, an abnormal piece of chromosome that is seen in some leukemia and lymphomas.
Possible inherited chromosomally integrated HHV-7 identified in two patients
Investigators led by Bhupesh Prusty, PhD at University of Wurzbürg in Germany have identified two cases of possible germline inherited chromosomally integrated HHV-7.
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.
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 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.
French dermatologists call for antiviral therapy in DRESS
French panel of experts has proposed that DRESS patients be treated with antivirals and/or immunoglobulins.
Does HHV-6 cause thyroiditis and autoimmunity in patients with drug hypersensitivity?
Case report describes two cases of DRESS related thyroiditis with very high levels of HHV-6 reactivation that go on to develop autoimmunity.
Saliva testing found to be useful for herpesvirus detection in patients with drug hypersensitivity
A french group has found preliminary evidence that PCR saliva testing is useful for the detection of herpesvirus reactivation among patients with drug hypersensitivity syndromes.
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.
Mycophenolate mofetil tied to increased risk of HHV-6 encephalitis after allogenic transplantation
Japanese investigators found that those who were administered mycophenolate mofetil along with a calcineurin inhibitor developed a much higher rate of infection: 12% in cord blood and 6% in other transplants.
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.
Acute seizures in children: a new study highlights the role of infections and inflammation
NINDS investigators found that children with febrile seizures have elevated inflammatory cytokines compared to healthy controls and children with fever. One of those cytokines, Il-1β, correlated with HHV-6 saliva viral load.
Why did these transplant protocols result in such a high rate of HHV-6 encephalitis (32%) and organ disease (46%)?
Investigators in Spain and Italy attempted to reduce the rate of acute GVHD in pediatric transplant patients by infusing manipulated stem cells. Not only was there no reduction in expected acute GVHD, the patients experienced an unusually high rate of HHV-6 disease.
HHV-6 encephalitis in 32% of pediatric leukemia patients depleted of naïve T cells
Although depleting naïve T cells has been successful in preventing acute graft vs host disease in several studies, investigators from Spain reported an unexpectedly high incidence of HHV-6 encephalitis in a cohort of haploidentical transplant patients.
FilmArray encephalitis/meningitis panel causing confusion due to undiagnosed ciHHV-6
Many institutions are now using a new multiplex qualitative assay to get rapid diagnosis in encephalitis cases in the clinic. Unfortunately, this system cannot identify cases of inherited chromosomal integration, which creates confusion.
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.
Dense infection of the hippocampus in primary HHV-6B encephalitis
The autopsy of an infant with HHV-6B encephalitis showed a 4-5 fold increase in the viral load of the hippocampus compared to other parts of the brain. Neurons, oligodendrocytes and vascular endothelial cells were infected, but not astrocytes or microglia.
New study details devastating impact of HHV-6 encephalitis
Investigators in Japan studied 145 patients who developed HHV-6 encephalitis. At 100 days after transplantation, the overall survival rate was just 58.3%, compared with 80.5% for patients who did not develop encephalitis. High-dose antiviral therapy was shown to mitigate high mortality rates in these patients.
HHV-6 induced amnesia after rituximab therapy for autoimmune disease
A young woman on rituximab and two other immunomodulatory agents for the treatment of dermatomyositis developed encephalitis with severe anterograde amnesia. As the use of biologic treatments for refractory autoimmune disease has been increasing, physicians are advised to consider HHV-6 and offer prompt antiviral therapy to limit irreversible morbidity.
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.
HHV-6 reactivation with status epilepticus and hyponatremia after transplantation
A report published by a group from the University of Minnesota details the case of a 59-year-old male who developed non-convulsive status epilepticus and hyponatremia in addition to HHV-6 reactivation following umbilical cord blood transplantation.
Reported case of chorea and febrile status epilepticus caused by HHV-6 encephalitis
Case report describes child with multiple episodes of febrile status epilepticus, followed by chorea and developmental regression, caused by human herpes virus-6 encephalitis.
Confirmation of new epilepsy syndrome in children with HHV-6 PALE
A group from Spain has confirmed the existence of a novel epilepsy syndrome featuring generalized seizures and epileptic encephalopathy after HHV-6-associated PALE (posttransplant limbic encephalitis) in children.
Febrile Status Epilepticus linked to active HHV-6B and HHV-7 infection
A ten-year NIH-funded study has determined that a third of infants with prolonged seizures and fever suffer from either a new or reactivated roseola virus infection.
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.
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
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.
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.
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.
Weizman Institute study reveals a comprehensive annotation of HHV-6A/B, providing a rich resource for future studies
Israeli scientists have identified hundreds of new open reading frames, generating an unbiased atlas of the HHV-6 proteome. They also identified three highly abundant long non-coding RNAs.
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.
Yasuko Mori awarded Lifetime Achievement Award
Yasuko Mori, PhD, Professor of Clinical Virology at the Kobe University Graduate School of Medicine was awarded the HHV-6 Foundation’s Dharam Ablashi Lifetime Achievement Award at the 11th International Conference on HHV-6 & 7.
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.
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.
Alexander Greninger awarded the Koichi Yamanishi Young Investigator Award for Basic Science
Alex Greninger, PhD, was awarded the Junior Investigator award for Basic Science at the 11th international HHV-6 & 7 Conference in Quebec City, Canada.
Xiaofeng Zhou awardeed Young Investigator Award for Clinical Research
Xiafeng Zhou was awarded the Young Investigator Award for Clinical Research at the 11th International HHV-6 & 7 Conference in Quebec City, Canada.
An elevated CD134/CD4+ ratio before conditioning results in a 10 fold increased risk of HHV-6B reactivation
A prospective study of allogenic stem cell transplant patients in Japan suggests that the percentage of CD134+ T cells could be used to predict which patients are vulnerable to HHV-6 reactivation. The authors propose that further investigation into the effect of elevated CD134+ T cells pre-transplant is warranted.
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.
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.
Herpesvirus saliva DNA increases dramatically during spaceflight
A number of astronauts have complained about herpesvirus reactivations during flight, and several developed shingles. Investigators at NASA determined that space flight increases herpesvirus shedding in saliva, compared to levels before and after their missions.
$4 million in prizes for literature reviews that explain Alzheiemer’s
The Oskar Fischer prize is named after a neuropathologist who was the first to describe neuritic plaques in 1907 in Prague. James Truchard, the former CEO and Chairman of National Instruments has donated funds for a prize to scientists who can review the existing medical literature to come up with a theory on what causes Alzheimer’s. Truchard points out that there have been 130,000 scientific papers on Alzheimer’s but that each paper focuses only on a narrow aspect of the disease and brain science. He wants someone to comb through all of the literature and find a unifying “big picture” explanation. “Just like someone like Einstein did in creating the theory of general relativity or Darwin did in looking at …
Research Priorities
Note: we welcome your input. Please send comments to: Kristin_Loomis@HHV-6Foundation.org PROPOSED NEW PRIORITIES FOR ALZHEIMER’S RESEARCH Exploration of HHV-6A and HHV-7 in the development and progression of Alzheimer’s Disease Background: Two recent papers published in Neuron have strongly implicated herpesviruses in the pathogenesis of Alzheimer’s disease. Moir and Tanzi showed that amyloid plaques develop rapidly in response to infection by HHV-6A, HHV-6B and HSV1 (Eimer 2018). In addition, a comprehensive NIH funded “multiomic” evaluation of the Alzheimer’s brain tissue using next generation sequencing data strongly implicated two roseoloviruses: HHV-6A and HHV-7 (Readhead 2018). Among the findings: Contrary to popular belief, HHV-6A is not ubiquitous. Only HHV-6B, which is spread via the saliva, is ubiquitous. HHV-6A is not found in the …
HHV-6A receptor CD46 identified as a critical factor in ‘awakening’ endogenous retrovirus
Both infectious and UV-inactivated HHV-6A activate endogenous retrovirus envelope protein – but so does selective stimulation of HHV-6A’s CD46 receptor. This “cross-talk” between HHV-6A and endogenous retrovirus appears to play an important role in the pathogenesis of inflammatory diseases.
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.
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
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.
Latent HHV-6A may impair myelin repair in multiple sclerosis
A group at University of Rochester demonstrated that the HHV-6A latency gene, U94, inhibits migration of cells involved in myelin repair. Inefficient myelin repair is associated with progression MS, and the ability of HHV-6A to impede this process suggests that it could be involved in the progression of MS, and raises questions about the virus’s role in other chronic demyelinating diseases.
HHV-6 U24 tightly linked to specific E3 ubiquitin ligases
The group that recently discovered a ligand for U24 has expanded upon their previous experiments to further elucidate the viral protein’s interactions and functions as they pertain to MS.
New evidence linking HHV-6A U24 protein to MS
HHV-6 has been linked in numerous studies to multiple sclerosis. Now, investigators at the University of British Columbia have published new data suggesting that HHV-6A may be a key player in the development of multiple sclerosis. The investigators propose that the viral protein U24 may dysregulate myelination.
CXCL11 and CCL2 are specific to HHV-6B in febrile infants
Japanese investigators from Kobe University identified CXC11 as a chemokine uniquely expressed in primary HHV-6B infections. They also confirmed a previous finding that cytokine CCL2 (MCP-1) plays a role in HHV-6B primary infections. Both CXCL11 and CCL2 are expressed in several neuroinflammatory conditions including epilepsy, Alzheimer’s disease and traumatic brain injury.
New research shows HLA modulation caused by acute HHV-6A infection of mesothelial cells
HHV-6A infection of mesothelial cells causes HLA molecule modulation. This study demonstrates, for the first time, that human mesothelial cells are susceptible to HHV-6A infection. They also show that the virus causes modulated HLA expression on the cell surface, inducing the de novo expression of HLA class II and HLA-G
HHV-6 antibody level correlates with relapse and progression in MS patients
Anti-HHV-6 IgG titer may be a useful prognostic factor in predicting relapsing-remitting MS clinical course
Two types of HHV-6 positivity in CNS demyelinating disease
New study shows HHV-6 may induce demyelination through both B and T-cell reaction. HHV-6 oligoclonal bands were also found in cases of clinically isolated syndrome.
HHV-6A protein identified in as the target of HHV-6 specific oligoclonal bands in MS
HHV-6A major capsid protein identified in CSF of MS patients: a case of molecular mimicry?
NINDS finds 38% of MS patients harbor HHV-6 or EBV specific oligoclonal bands
A new study from NIH/NINDS further strengthens the relationship between HHV-6, EBV, and multiple sclerosis.
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.
Increased prevalence of HHV-6 antibodies discovered in multiple sclerosis patients
An increased prevalence of HHV-6 U94/REP antibodies found among Tunisian MS patients.
HHV-6 active replication genetically linked to poor treatment response among MS patients
Strong evidence of a genetic link between HHV-6 active replication and poor IFN-B treatment response among multiple sclerosis patients
Two year MS study shows that relapse correlates with HHV-6A reactivation
A new study shows that multiple sclerosis patients with HHV-6 have higher risk of relapse and poor response to IFN-beta treatment.
HHV-6A can travel through the nose to the brain
The trigger for neurological disease in a subset of patients with MS?
HHV-6 DNA in bile fluid correlates with higher mortality in liver transplant patients
Persistent HHV-6 infection in the liver is hard to detect from plasma samples and liver biopsies may miss spotty infections. Bile fluid may be the best method for detecting herpesviruses that impact the liver.
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.
HHV-6 linked to neutropenia, thrombocytopenia, longer hospital stays and a 5X increased risk of serious complications after autologous transplant
In a prospective study, patients with HHV-6 infection took longer to recover neutrophils and platelets. They also spent significantly more time in the hospital with complications.
Does corticosteroid use for aGVHD prophylaxis lower HHV-6 reactivation by reducing IL-6?
A new study reports a surprisingly low rate of HHV-6 reactivation in recipients of half-matched bone marrow grafts using a reduced-intensity conditioning regimen. The authors speculate that the corticosteroid used for prophylaxis may have suppressed cytokine production which in turn limited reactivation of HHV-6.
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.
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.
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.
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.
Stanford finds high levels of HHV-6 in the tissues of children with liver failure
A team at Stanford reported that 48% of young children with “liver failure of unknown etiology” had high viral loads of HHV-6 in their liver tissues. As a result, Stanford has now instituted routine evaluation for HHV-6 in all children who present with liver failure.
RNA sequencing of HHV-6B transcriptome identifies U38 as the best target for HHV-6 RT-PCR testing
Investigators at University of Washington studied multiple samples to develop an assay that can detect active infection in patients with chromosomally integrated HHV-6. Current quantitative PCR DNA testing cannot determine whether a ciHHV6 patient has active replication.
Rapid lymphocyte expansion after HCT predicts increased HHV-6 reactivation
A team of researchers at Kyoto University in Japan reported that rapid lymphocyte expansion is a good predictive factor for increased HHV-6 reactivation, as well as reduced CMV antigenemia. Patients with aplastic anemia as a primary disease had a 5 fold increased risk of HHV-6 reactivation.
HHV-6 encephalitis in 32% of pediatric leukemia patients depleted of naïve T cells
Although depleting naïve T cells has been successful in preventing acute graft vs host disease in several studies, investigators from Spain reported an unexpectedly high incidence of HHV-6 encephalitis in a cohort of haploidentical transplant patients.
HHV-6 reactivation associated with unexplained fever and biliary atresia in pediatric liver transplant patients
A Japanese study found that unexplained fever and biliary atresia are associated with HHV-6B infection in pediatric transplant patients. 100% of seronegative infants developed a primary infection.
Meta-analysis shows strong association of HHV-6B reactivation and subsequent aGVHD
A new meta-analysis published in Biology of Blood and Marrow Transplantation shows that transplant patients who reactivate with HHV-6 are 2-3 times more likely to develop acute GVHD.
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.
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.
