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1.  Association of Human Herpesvirus-6B with Mesial Temporal Lobe Epilepsy 
PLoS Medicine  2007;4(5):e180.
Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)–positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters.
Methods and Findings
HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive—the first demonstration of an ex vivo HHV-6–infected astrocyte culture isolated from HHV-6–positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression.
Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.
Steve Jacobson and colleagues report finding human herpesvirus-6B DNA in brain resections from 11 of 16 patients with mesial temporal lobe epilepsy, strengthening the evidence for a role for this virus in this condition.
Editors' Summary
Epilepsy is a common brain disorder caused by a sudden, excessive electrical discharge in a cluster of neurons—the cells that transmit electrical messages between the body and the brain. Its symptoms depend on which part of the brain is affected by this electrical firestorm and how far the disturbance spreads. When only part of the brain is affected (a partial seizure or fit), patients may see or smell strange things, recall forgotten memories, or have part of their body jerk uncontrollably. When the electrical disturbance spreads across the whole brain (a generalized seizure), there may be loss of consciousness and/or the whole body may become rigid or jerk. Epilepsy is usually controlled with anti-epileptic drugs or, in very severe focal cases, surgery to the area of the brain where the seizure starts. Although head injuries or brain tumors can trigger epilepsy, the cause of most cases of epilepsy is unknown.
Why Was This Study Done?
Knowing what causes epilepsy might lead to better treatments for it. One possibility is that infections trigger epilepsy. The researchers in this study asked whether infections with human herpesvirus 6B (HHV-6B) are associated with a common type of epilepsy called mesial temporal lobe epilepsy (MTLE). Patients with MTLE often have extensive scarring in the hippocampus, a brain region responsible for memory that lies deep within a bigger region called the temporal lobe. Hippocampal scarring and MTLE are associated with a history of fever-induced fits, and HHV-6B infection can cause such fits in young children. Most people become infected with HHV-6B (or the closely related HHV-6A) early in life. The virus then remains latent for years within the brain and elsewhere. Given these facts and a previous investigation that showed that brain tissue from several patients with MTLE contained HHV-6B, the researchers reasoned that it was worth investigating HHV-6B as a cause of MTLE.
What Did the Researchers Do and Find?
The researchers first looked for HHV-6B DNA in brain tissue surgically removed from patients with MTLE or another type of epilepsy. Tissue from 11 of 16 patients with MTLE (but from 0 of 7 control patients) contained HHV-6B DNA. When the researchers grew astrocytes (a type of brain cell) from some of these samples, only those from HHV-6B DNA-positive samples from patients with MTLE expressed an HHV-6-specific protein. Next, the researchers investigated in detail a patient with MTLE who had four sequential operations to control his epilepsy. This patient's hippocampus, which was removed in his first operation, contained a higher level of HHV-6B DNA than the tissues removed in later operations. After the fourth operation (which removed half of his brain and cured his epilepsy), astrocytes grown from the temporal lobe and the frontal/parietal lobe (a brain region next to the temporal lobe) but not the frontal and occipital lobes contained HHV-6B DNA and expressed a viral protein. The researchers also measured the production by these various astrocytes of a substance that moves glutamate (an amino acid that also acts as a neurotransmitter) across cell membranes—MTLE has been associated with a glutamate transporter deficiency. Consistent with this, astrocytes from the patient's temporal lobe made no glutamate transporter mRNA (mRNA is an essential precursor for protein to be produced). Finally, infection of astrocytes isolated from a patient without MTLE with HHV-6B greatly reduced expression of glutamate transporter in these astrocytes.
What Do These Findings Mean?
These findings, together with those from the previous study, reveal that nearly two-thirds of patients with MTLE (but no patients with other forms of epilepsy) have an active HHV-6B infection in the brain region where their epilepsy originates. Overall, they provide strong support for the idea that HHV-6B infections might cause MTLE, particularly given the results obtained from the patient whose condition only improved after multiple brain operations had removed all the virally infected material. Furthermore, the demonstration that HHV-6B infection reduces glutamate transporter expression in astrocytes suggests that HHV-6B infection might cause astrocyte dysfunction. This dysfunction could lead to injury of the sensitive neurons in the hippocampus and trigger MTLE. Additional patients now need to be studied both to confirm the association between HHV-6B infection and MTLE and to discover exactly how this virus triggers epilepsy.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia page on epilepsy (in English and Spanish)
World Health Organization fact sheet on epilepsy (in English, French, Spanish, Russian, Arabic, and Chinese)
US National Institute for Neurological Disorders and Stroke epilepsy information page (in English and Spanish)
UK National Health Service Direct information for patients on epilepsy (in several languages)
Neuroscience for kids, an educational Web site prepared by Eric Chudler (University of Washington, Seattle, Washington, United States), who also has a site that includes information on epilepsy and a list of links to epilepsy organizations (mainly in English but some sections in other languages as well)
A short scientific article on human herpes virus 6 in the journal Emerging Infectious Diseases
PMCID: PMC1880851  PMID: 17535102
2.  Human herpesvirus 6 infections after liver transplantation 
Human herpesvirus 6 (HHV-6) infections occur in > 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection (reactivation in the transplanted organ). In a minority of cases, however, primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus (CMV), hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6-specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir, or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.
PMCID: PMC2691485  PMID: 19496184
Immunocompromised; Antivirals; Human herpesvirus 6; Liver transplantation; Opportunistic infections
3.  Impact of human herpes virus 6 in liver transplantation 
World Journal of Hepatology  2010;2(9):345-353.
Human herpes virus 6 (HHV-6) infects > 95% of humans. Primary infection which occurs mostly during the first 2 years of life in the form of roseola infantum, non-specific febrile illness, or an asymptomatic illness, results in latency. Reactivation of latent HHV-6 is common after liver transplantation. Since the majority of human beings harbor the latent virus, HHV-6 infections after liver transplantation are most probably caused by endogenous reactivation or superinfection. In a minority of cases, primary HHV-6 infection may occur when an HHV-6-seronegative individual receives a liver allograft from an HHV-6-seropositive donor. The vast majority of HHV-6 infections after liver transplantation are asymptomatic. Only in a minority of cases, when HHV-6 causes a febrile illness associated with rash and myelosuppression, hepatitis, gastroenteritis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been implicated in a variety of indirect effects, such as allograft rejection and increased predisposition to and severity of other infections, including cytomegalovirus, hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6-specific approach prevention after liver transplantation. Asymptomatic HHV-6 infection does not require antiviral treatment, while treatment of established HHV-6 disease is treated with intravenous ganciclovir, foscarnet, or cidofovir and this should be complemented by a reduction in immunosuppression.
PMCID: PMC2998978  PMID: 21161019
Human herpes virus 6; Opportunistic infections; Liver transplantation; Antivirals
4.  Challenging complications of treatment – human herpes virus 6 encephalitis and pneumonitis in a patient undergoing autologous stem cell transplantation for relapsed Hodgkin's disease: a case report 
Virology Journal  2009;6:111.
Reactivation of human herpesvirus 6 (HHV-6) occurs frequently in patients after allogeneic stem cell transplantation and is associated with bone-marrow suppression, enteritis, pneumonitis, pericarditis and also encephalitis. After autologous stem cell transplantation or intensive polychemotherapy HHV-6 reactivation is rarely reported.
Case report
This case demonstrates a severe symptomatic HHV-6 infection with encephalitis and pneumonitis after autologous stem cell transplantation of a patient with relapsed Hodgkin's disease.
Careful diagnostic work up in patients with severe complications after autologous stem cell transplantation is mandatory to identify uncommon infections.
PMCID: PMC2718875  PMID: 19619326
5.  Human Herpesvirus-6 Pneumonitis around the Engraftment of Cord Blood Transplantation following Foscarnet Prophylaxis in a Patient with Acute Leukemia 
Case Reports in Hematology  2015;2015:949265.
Human herpesvirus-6 (HHV-6) reactivation is sometimes observed in immunocompromised patients, especially after allogeneic stem cell transplantation. The complications of HHV-6 reactivation in this setting are mainly recognized as HHV-6 encephalitis. We herein report the case of a patient who developed HHV-6 pneumonitis after cord blood transplantation (CBT). A 35-year-old male underwent CBT for T-cell/myeloid mixed phenotype acute leukemia and achieved neutrophil engraftment on day 31. He had received foscarnet as prophylaxis for HHV-6 reactivation. A computed tomography (CT) scan to evaluate the leukemic tumor showed bilateral interstitial pneumonitis on day 33, although he had no respiratory symptoms. The findings of the CT scan were consistent with those of HHV-6 pneumonitis that were reported previously. HHV-6 DNA, but no other pathogens, was detected in his bronchoalveolar lavage (BAL) fluid. The patient was successfully treated with a therapeutic dose of foscarnet. This case indicates that performing a CT scan around the time of neutrophil engraftment can play an important role in detecting the early phase of HHV-6 pneumonia, and BAL should be considered if features consistent with HHV-6 pneumonitis are observed in patients with a risk of HHV-6 reactivation.
PMCID: PMC4306254  PMID: 25650037
6.  Quantitative analysis of human herpesvirus-6 genome in blood and bone marrow samples from Tunisian patients with acute leukemia: a follow-up study 
Infectious etiology in lymphoproliferative diseases has always been suspected. The pathogenic roles of human herpesvirus-6 (HHV-6) in acute leukemia have been of great interest. Discordant results to establish a link between HHV-6 activation and the genesis of acute leukemia have been observed. The objective of this study was to evaluate a possible association between HHV-6 infection and acute leukemia in children and adults, with a longitudinal follow-up at diagnosis, aplasia, remission and relapse.
HHV-6 load was quantified by a quantitative real-time PCR in the blood and bone marrow samples from 37 children and 36 adults with acute leukemia: 33 B acute lymphoblastic leukemia (B-ALL), 6 T acute lymphoblastic leukemia (T-ALL), 34 acute myeloid leukemia (AML).
HHV-6 was detected in 15%, 8%, 30% and 28% of the blood samples at diagnosis, aplasia, remission and relapse, respectively. The median viral loads were 138, 244, 112 and 78 copies/million cells at diagnosis, aplasia, remission and relapse, respectively. In the bone marrow samples, HHV-6 was detected in 5%, 20% and 23% of the samples at diagnosis, remission and relapse, respectively. The median viral loads were 34, 109 and 32 copies/million cells at diagnosis, remission and relapse, respectively. According to the type of leukemia at diagnosis, HHV-6 was detected in 19% of the blood samples and in 7% of the bone marrow samples (with median viral loads at 206 and 79 copies/million cells, respectively) from patients with B-ALL. For patients with AML, HHV-6 was present in 8% of the blood samples and in 4% of the bone marrow samples (with median viral loads at 68 and 12 copies/million cells, respectively). HHV-6 was more prevalent in the blood samples from children than from adults (25% and 9%, respectively) and for the bone marrow (11% and 0%, respectively). All typable HHV-6 were HHV-6B species. No link was shown between neither the clinical symptoms nor the abnormal karyotype and HHV-6 activation. A case of HHV-6 chromosomal integration was shown in one patient with AML.
This study confirms the absence of role of HHV-6 in the genesis of acute leukemia but the virus was reactivated after chemotherapy treatment.
PMCID: PMC3527176  PMID: 23146098
Human herpesvirus-6; Acute leukemia; Viral load; Bone marrow; Whole blood; Chemotherapy
7.  Prevalence of human herpesvirus 6 antibodies and DNA in allogeneic stem cell transplant patients: two-year single centre experience 
Human herpesvirus 6 (HHV-6) has been recognized as a potentially significant pathogen in hemopoietic stem cell transplant (HSCT) recipients. Different clinical manifestations have been described, including fever, skin rash, bone marrow suppression, and encephalitis.
Materials and Methods:
A retrospective review of a group of 26 adult recipients of allogeneic HSCTs was conducted. Serum samples taken before transplant were examined for the presence of specific anti-HHV-6 IgM and IgG antibodies. After transplantation, quantitative real-time PCR was used to determine viral load in plasma samples from days 0–80 post-transplant.
HHV-6 DNA was detected in plasma samples in 8 (30%) of the 26 recipients between days 18 and 40 after transplantation. All of them developed fever of unknown origin and over 50% had graft-versus-host disease features. Three individuals from this group died during detectable HHV-6 viremia. Another two recipients showed a single positive PCR result at a later time. Infection with HHV-6 was thus confirmed in 10 (38.5%) of the 26 graft recipients.
There is a high frequency of detectable HHV-6 viral load in stem cell transplant recipients in Poland. Further investigation to monitor HHV-6 reactivation in graft recipients will be important to improve outcome for these patients.
PMCID: PMC2766496  PMID: 18512026
HHV-6; hemopoietic stem cells transplant; real-time PCR; GvHD
8.  Prevalence of human herpesvirus 6 in lung tissue from children with pneumonitis. 
Journal of Clinical Pathology  1996;49(10):802-804.
AIMS/BACKGROUND: Human herpesvirus type 6 (HHV-6) is the aetiological agent of exanthem subitum, and has also been linked with a variety of other diseases. The aim of this study was to investigate the role of HHV-6 in pneumonitis in children. METHODS: Formalin fixed, paraffin wax embedded lung tissue from 33 children (age range two months to 16 years) who died with pneumonitis was subjected to immunohistochemical staining for HHV-6 using an avidin-biotin method. RESULTS: Active HHV-6 infection was demonstrated in four children: a bone marrow transplant recipient with concomitant adenovirus infection, a patient with hepatitis of unknown aetiology, a patient with congenital anomalies, and a patient with congenital immunodeficiency. CONCLUSION: Accurate localisation of HHV-6 is possible in postmortem lung tissue. HHV-6 either alone or in combination with other pathogens may play a role in the development of pneumonitis.
PMCID: PMC500772  PMID: 8943744
9.  Virologic and Immunologic Evidence Supporting an Association between HHV-6 and Hashimoto's Thyroiditis 
PLoS Pathogens  2012;8(10):e1002951.
Hashimoto's thyroiditis (HT) is the most common of all thyroid diseases and is characterized by abundant lymphocyte infiltrate and thyroid impairment, caused by various cell- and antibody-mediated immune processes. Viral infections have been suggested as possible environmental triggers, but conclusive data are not available. We analyzed the presence and transcriptional state of human herpesvirus 6 (HHV-6) in thyroid fine needle aspirates (FNA) and peripheral blood mononuclear cells (PBMCs) from 34 HT patients and 28 controls, showing that HHV-6 DNA prevalence (82% vs. 10%, p≤0.001) and viral load were significantly increased in FNA from HT patients, and thyrocytes from HT FNA displayed a 100-fold higher HHV-6 DNA load compared to infiltrating lymphocytes. In addition, while HHV-6 was strictly latent in positive samples from controls, a low grade acute infection was detected in HT samples. HHV-6 variant characterization was carried out in 10 HT FNA samples, determining that all specimens harbored HHV-6 Variant A.
The tropism of HHV-6 for thyroid cells was verified by infection of Nthy-ori3-1, a thyroid follicular epithelial cell line, showing that thyrocytes are permissive to HHV-6 replication, which induces de novo expression of HLA class II antigens. Furthermore, HHV-6-infected Nthy-ori3-1 cells become targets for NK-mediated killing, NK cells from HT patients show a significantly more efficient killing of HHV-6 infected thyroid cells than healthy controls, and HT patients have increased T-cell responses to HHV-6 U94 protein, associated to viral latency. These observations suggest a potential role for HHV-6 (possibly variant A) in the development or triggering of HT.
Author Summary
Hashimoto's thyroiditis (HT) is a very common autoimmune disease of the thyroid. In addition to genetic background, several viruses, including herpesviruses, have been suggested to play a role as possible environmental triggers of disease, but conclusive data are still lacking. The anecdotal presence of human herpesvirus 6 (HHV-6) in HT specimens prompted us to study a possible association between HHV-6 and HT. Our analysis of fine needle thyroid aspirates and blood from HT patients and controls shows that HHV-6 prevalence and load are highly increased in HT patients. Furthermore, HT-derived thyrocytes harbor active virus, whereas HHV-6 is strictly latent in the few virus-positive controls. We also report that HHV-6 infects thyroid cells, inducing de novo expression of HLA-II surface antigens. Consequently, thyrocytes might behave as antigen presenting cells. Interestingly, immune cells from HT patients kill HHV-6-infected thyrocytes more efficiently than controls. Also, HT patients, but not controls, have specific T-cell responses to HHV-6 U94 protein. It is difficult to prove etiologic links between viral infections and diseases, especially in the case of a ubiquitous agent such as HHV -6. Nevertheless, our findings indicate that HHV-6 might contribute to HT development, and argue for a pathogenic association between HHV-6 and HT.
PMCID: PMC3464215  PMID: 23055929
10.  Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9 
Journal of Virology  2014;88(10):5421-5436.
Human herpesvirus 6 (HHV-6) is widely spread in the human population and has been associated with several neuroinflammatory diseases, including multiple sclerosis. To develop a small-animal model of HHV-6 infection, we analyzed the susceptibility of several lines of transgenic mice expressing human CD46, identified as a receptor for HHV-6. We showed that HHV-6A (GS) infection results in the expression of viral transcripts in primary brain glial cultures from CD46-expressing mice, while HHV-6B (Z29) infection was inefficient. HHV-6A DNA persisted for up to 9 months in the brain of CD46-expressing mice but not in the nontransgenic littermates, whereas HHV-6B DNA levels decreased rapidly after infection in all mice. Persistence in the brain was observed with infectious but not heat-inactivated HHV-6A. Immunohistological studies revealed the presence of infiltrating lymphocytes in periventricular areas of the brain of HHV-6A-infected mice. Furthermore, HHV-6A stimulated the production of a panel of proinflammatory chemokines in primary brain glial cultures, including CCL2, CCL5, and CXCL10, and induced the expression of CCL5 in the brains of HHV-6A-infected mice. HHV-6A-induced production of chemokines in the primary glial cultures was dependent on the stimulation of toll-like receptor 9 (TLR9). Finally, HHV-6A induced signaling through human TLR9 as well, extending observations from the murine model to human infection. Altogether, this study presents a first murine model for HHV-6A-induced brain infection and suggests a role for TLR9 in the HHV-6A-initiated production of proinflammatory chemokines in the brain, opening novel perspectives for the study of virus-associated neuropathology.
IMPORTANCE HHV-6 infection has been related to neuroinflammatory diseases; however, the lack of a suitable small-animal infection model has considerably hampered further studies of HHV-6-induced neuropathogenesis. In this study, we have characterized a new model for HHV-6 infection in mice expressing the human CD46 protein. Infection of CD46 transgenic mice with HHV-6A resulted in long-term persistence of viral DNA in the brains of infected animals and was followed by lymphocyte infiltration and upregulation of the CCL5 chemokine in the absence of clinical signs of disease. The secretion of a panel of chemokines was increased after infection in primary murine brain glial cultures, and the HHV-6-induced chemokine expression was inhibited when TLR9 signaling was blocked. These results describe the first murine model for HHV-6A-induced brain infection and suggest the importance of the TLR9 pathway in HHV-6A-initiated neuroinflammation.
PMCID: PMC4019085  PMID: 24574405
11.  Human Herpesvirus 6 Infection after Hematopoietic Cell Transplantation: Is Routine Surveillance Necessary? 
Human herpesvirus 6 (HHV6) may be an important pathogen following allogeneic hematopoietic cell transplantation (HCT). We prospectively evaluated weekly HHV6 viremia testing after allogeneic HCT using a quantitative polymerase chain reaction (PCR)-based assay. HHV-6 viremia was detected in 46 of 82 (56%) patients at a median of 23 days post-HCT (range: day + 10 to + 168). More males (65% vs females 39%, P = .03) and recipients of umbilical cord blood (UCB 69% vs unrelated donor [URD], 46% vs sibling donor [20%] grafts, P = 0.01) reactivated HHV-6. Patients with HHV6 viremia had more cytomegalovirus (CMV) reactivation (26% vs 5.5%, P = .01) and unexplained fever and rash (23.9% vs 2.7%, P = .01) compared with patients without HHV6 viremia. High-level HHV6 (≥25,000 copies/mL) versus lower levels were associated with more culture-negative pneumonitis (72.7% vs 22.8%, P = .01). Twenty HHV6-positive patients were treated with foscarnet, ganciclovir, or cidofovir for HHV6 or other coexistent viruses. Within 2 weeks, HHV6 viremia resolved more commonly in treated (65%) than untreated patients (31%), P = .02. Survival at 3 months was similar in treated and untreated patients (90% vs 81%, P = .4). Survival at 3 and 6 months post-HCTwere not affected by HHV6 positivity (3 months HHV6 + 85% vs 78%, P = .46; 6 months HHV6+ 70% vs 72%, P = .89) or by HHV6 level (3-month high level 73% vs 89%, P = .23; 6-month high level 64% vs 71%, P = .54). Neither the occurrence of HHV6, degree of viremia, nor use of antiviral drugs influenced short-term survival after HCT.
PMCID: PMC3285510  PMID: 21549850
Human herpesvirus 6; Allogeneic transplantation; Umbilical cord blood; Foscarnet; Ganciclovir
12.  Novel Marmoset (Callithrix jacchus) Model of Human Herpesvirus 6A and 6B Infections: Immunologic, Virologic and Radiologic Characterization 
PLoS Pathogens  2013;9(1):e1003138.
Human Herpesvirus 6 (HHV-6) is a ubiquitous virus with an estimated seroprevalence of 95% in the adult population. HHV-6 is associated with several neurologic disorders, including multiple sclerosis, an inflammatory demyelinating disease affecting the CNS. Animal models of HHV-6 infection would help clarify its role in human disease but have been slow to develop because rodents lack CD46, the receptor for cellular entry. Therefore, we investigated the effects of HHV-6 infections in a non-human primate, the common marmoset Callithrix jacchus. We inoculated a total of 12 marmosets with HHV-6A and HHV-6B intravenously and HHV-6A intranasally. Animals were monitored for 25 weeks post-inoculation clinically, immunologically and by MRI. Marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms and generated virus-specific antibody responses, while those inoculated intravenously with HHV-6B were asymptomatic and generated comparatively lower antibody responses. Viral DNA was detected at a low frequency in paraffin-embedded CNS tissue of a subset of marmosets inoculated with HHV-6A and HHV-6B intravenously. When different routes of HHV-6A inoculation were compared, intravenous inoculation resulted in virus-specific antibody responses and infrequent detection of viral DNA in the periphery, while intranasal inoculation resulted in negligible virus-specific antibody responses and frequent detection of viral DNA in the periphery. Moreover, marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms, while marmosets inoculated with HHV-6A intranasally were asymptomatic. We demonstrate that a marmoset model of HHV-6 infection can serve to further define the contribution of this ubiquitous virus to human neurologic disorders.
Author Summary
The human herpesviruses HHV-6A and HHV-6B are widely distributed in the human population, but also specifically associated with several central nervous system (CNS) diseases. We investigated HHV-6A and HHV-6B infections in the common marmoset, a non-human primate naturally susceptible to infection, unlike rodents. We inoculated marmosets with HHV-6A and HHV-6B intravenously, and with HHV-6A intranasally, to represent a more physiologic route of infection. Following intravenous HHV-6A inoculation, marmosets exhibited clinical symptoms with evidence of spinal cord pathology. Animals inoculated intravenously with HHV-6B were asymptomatic and without detectable CNS pathology. Both groups developed robust anti-viral antibody responses, and we detected viral DNA infrequently in the periphery. By contrast, marmosets inoculated intranasally with HHV-6A were asymptomatic, failed to generate anti-viral antibodies, and we frequently detected viral DNA in the periphery. Interestingly, HHV-6 DNA was detected in brain and spinal cord sections of several intravenously inoculated animals, demonstrating that HHV-6 can gain access to and persist in the CNS. These observations help to define the contributions of ubiquitous herpesviruses to neurologic disease development in a non-human primate. As little is known about the acquisition and host response to HHV-6A, this model may clarify how this virus may trigger or potentiate disease.
PMCID: PMC3561285  PMID: 23382677
13.  Evaluation of a commercial enzyme-linked immunosorbent assay for detection of serum immunoglobulin G response to human herpesvirus 6. 
Journal of Clinical Microbiology  1996;34(3):675-679.
A rapid (60-min) commercially available enzyme-linked immunosorbent assay (ELISA) for the detection of immunoglobulin G (IgG) class antibodies to human herpesvirus 6 (HHV-6) was evaluated. The specificity of the ELISA for HHV-6 was confirmed by absorption studies, with the reactivities of HHV-6-positive sera being unaffected by other herpesviruses (cytomegalovirus, herpes simplex virus, and varicella-zoster virus) or the HSB2 cell line used to culture HHV-6. HHV-6 IgG antibody levels in a panel of 502 serum samples were determined by ELISA and an indirect immunofluorescence assay (IFA). Results obtained by the two methods were in close agreement, suggesting that the ELISA provides a suitable test method for the determination of HHV-6 IgG antibodies in a routine clinical laboratory. Both tests were positive in 398 cases (79%), and both were negative in 71 cases (14%), with a different result obtained by IFA and ELISA in only 33 cases (7%). Furthermore, absorption of sera with HHV-6 prior to assay revealed that the majority of these results were false positive (n = 8) or false negative (n = 23) in the IFA (true positives or negatives in the ELISA). Subsequently, the ELISA showed a sensitivity of 99.76% and a specificity of 98.75%. HHV-6-specific IgG levels were also determined in paired serum samples collected from 49 donors--14 with exanthem subitum (ES), 15 with ES which was complicated with central nervous system involvement, and 20 undergoing bone marrow transplantation--in whom HHV-6 infection had been demonstrated by virus isolation and/or PCR. All patients with ES or central nervous system complications showed an increase in HHV-6-specific IgG, indicating that this ELISA may be a useful aid in the diagnosis of these conditions. Furthermore, 14 of 20 patients undergoing bone marrow transplantation showed an increase in HHV-6-specific IgG levels, possibly reflecting a reactivation of HHV-6 in these patients.
PMCID: PMC228868  PMID: 8904436
14.  Human CD4+ T Cell Response to Human Herpesvirus 6 
Journal of Virology  2012;86(9):4776-4792.
Following primary infection, human herpesvirus 6 (HHV-6) establishes a persistent infection for life. HHV-6 reactivation has been associated with transplant rejection, delayed engraftment, encephalitis, muscular dystrophy, and drug-induced hypersensitivity syndrome. The poor understanding of the targets and outcome of the cellular immune response to HHV-6 makes it difficult to outline the role of HHV-6 in human disease. To fill in this gap, we characterized CD4 T cell responses to HHV-6 using peripheral blood mononuclear cell (PBMC) and T cell lines generated from healthy donors. CD4+ T cells responding to HHV-6 in peripheral blood were observed at frequencies below 0.1% of total T cells but could be expanded easily in vitro. Analysis of cytokines in supernatants of PBMC and T cell cultures challenged with HHV-6 preparations indicated that gamma interferon (IFN-γ) and interleukin-10 (IL-10) were appropriate markers of the HHV-6 cellular response. Eleven CD4+ T cell epitopes, all but one derived from abundant virion components, were identified. The response was highly cross-reactive between HHV-6A and HHV-6B variants. Seven of the CD4+ T cell epitopes do not share significant homologies with other known human pathogens, including the closely related human viruses human herpesvirus 7 (HHV-7) and human cytomegalovirus (HCMV). Major histocompatibility complex (MHC) tetramers generated with these epitopes were able to detect HHV-6-specific T cell populations. These findings provide a window into the immune response to HHV-6 and provide a basis for tracking HHV-6 cellular immune responses.
PMCID: PMC3347333  PMID: 22357271
15.  Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain and Ireland 
Archives of Disease in Childhood  2005;90(6):619-623.
Background: Primary human herpesvirus-6 and -7 (HHV-6/-7) infections cause febrile illness sometimes complicated by convulsions and rarely encephalopathy.
Aims: To explore the extent of such HHV-6 and -7 induced disease in young children.
Methods: In a three year prospective study in Britain and Ireland, 205 children (2–35 months old) hospitalised with suspected encephalitis and/or severe illness with fever and convulsions were reported via the British Paediatric Surveillance Unit network. Blood samples were tested for primary HHV-6 and -7 infections.
Results: 26/156 (17%) of children aged 2–23 months had primary infection (11 HHV-6; 13 HHV-7; two with both viruses) coinciding with the acute illness; this was much higher than the about three cases expected by chance. All 26 were pyrexial; 25 had convulsions (18 status epilepticus), 11 requiring ventilation. Median hospital stay was 7.5 days. For HHV-6 primary infection the median age was 53 weeks (range 42–94) and the distribution differed from that of uninfected children; for HHV-7, the median was 60 weeks (range 17–102) and the distribution did not differ for the uninfected. Fewer (5/15) children with primary HHV-7 infection had previously been infected with HHV-6 than expected.
Conclusions: Primary HHV-6 and HHV-7 infections accounted for a significant proportion of cases in those <2 years old of severe illness with fever and convulsions requiring hospital admission; each virus contributed equally. Predisposing factors are age for HHV-6 and no previous infection with HHV-6 for HHV-7. Children with such neurological disease should be investigated for primary HHV-6/-7 infections, especially in rare cases coinciding by chance with immunisation to exclude misdiagnosis as vaccine reactions.
PMCID: PMC1720457  PMID: 15908629
16.  Copy Numbers of Telomeric Repeat Sequences of Human Herpesvirus 6B in Clinical Isolates: Possibility of Mixed Infections 
Journal of Clinical Microbiology  2014;52(2):419-424.
In order to determine whether mixed infections of human herpesvirus 6B (HHV-6B) occur in immunocompetent and immunocompromised individuals, we examined the copy numbers of telomeric repeat sequences (TRS) of clinical isolates. In clinical isolates obtained from patients with exanthem subitum caused by primary HHV-6B infection, PCR products with HHV-6B TRS ranging between 400 and 800 bp were amplified. PCR products of various sizes were amplified in four clinical isolates from drug-induced hypersensitivity syndrome (DIHS) patients and 15 isolates from hematopoietic stem cell transplant (HSCT) recipients with HHV-6B reactivation. Based on the sequence analysis of the PCR products, the copy numbers of TRS in DIHS and HSCT patients were between 42 and 82 and 22 and >90, respectively. For two of the HSCT recipients, HHV-6B TRS PCR products of different sizes were detected in several isolates from each patient, which suggests mixed HHV-6B infections. In two of the posttransplant HHV-6B encephalitis patients, the sizes of the TRS nested PCR products amplified from the reactivated virus detected in the central nervous system differed from those of the virus detected in initial isolates from peripheral blood mononuclear cells. Taken together, these results suggest that PCR analysis of TRS copy number is a reliable tool for the discrimination of HHV-6B clinical isolates. Additionally, mixed HHV-6B infections occurred in HSCT recipients, and in some cases, compartmentalization of the HHV-6B strains to the central nervous system versus the blood compartment occurred in posttransplant HHV-6B encephalitis patients.
PMCID: PMC3911338  PMID: 24478470
17.  Cord-blood hematopoietic stem-cell transplantation confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis 
Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem-cell transplantation (HSCT); its most severe manifestation is the syndrome of post-transplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1,344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1,243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in CSF specimens in addition to symptoms and studies indicating limbic encephalitis. 19 (1.4%) cases of HHV6-PALE were identified during this study; 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (p<0.001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio (aHR) 20.0; 95% confidence interval (CI), 7.3–55.0; p<0.001), time-dependent acute graft-versus-host disease grades II-IV (aHR 7.5; 95% CI, 2.8–19.8; p<0.001), and adult-mismatched donor (aHR 4.3; 95% CI, 1.1–17.3; p=0.04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV6-PALE and greater morbidity from this disease.
PMCID: PMC3816521  PMID: 22564265
Clinical research; adult; infectious diseases
18.  A prospective seroepidemiological study of human herpesvirus-8 infection and the risk of multiple myeloma 
British Journal of Cancer  2001;84(1):122-125.
Presence of the Human Herpesvirus 8 (HHV8) genome has been reported in the bone marrow of multiple myeloma (MM) patients. So far, serological studies of HHV8 and MM have been inconsistent but have not included prospective epidemiological studies. We evaluated whether HHV8 infection is associated with increased risk for MM in a prospective population-based study of 39 000 Finnish subjects who donated serum samples in the period 1968–72. Serum samples from 47 subjects who developed MM during a 23-year follow-up and 224 age, area of residence and sex-matched subjects who remained healthy over a similar follow-up period were evaluated for HHV8 antibodies at enrolment, as assayed both with an immunofluorescence assay (IFA) for lytic and latent HHV8 antigens and by Western blot (WB) with three recombinant HHV8 proteins (ORFs 65, 73 and K8.1A). HHV8 seropositivity for at least one HHV8 protein on WB was found in 7% of the Finnish population and was not associated with the risk of developing MM (Relative Risk (RR) = 0.89, Confidence Interval (CI): 0.25–3.25). HHV8 seropositivity for lytic and latent antigens in the IFA was found in 16% and 0.4% of the Finnish population and tended to associate with risk of MM (RR = 2.02, CI: 0.94–4.33 and RR = 10.00, CI: 0.91–110.29, respectively). In conclusion, no statistically significant evidence for an association between HHV8 infection and the risk of future MM was found. © 2001 Cancer Research Campaign
PMCID: PMC2363613  PMID: 11139326
epidemiology; tumour virology; nested case-control study
19.  Multicentric Castleman's disease and Kaposi's sarcoma in a cyclosporin treated, HIV-1 negative patient: case report 
Multicentric Castleman's disease (MCD) is a rare disease, but is more frequent in AIDS patients. MCD has only been reported twice before in patients receiving immunosuppressive therapy after renal transplantation, and never in patients receiving immunosuppressive therapy without transplantation. About half of the cases of MCD are human herpesvirus 8 (HHV8) – related, in contrast to Kaposi's sarcoma, a more common complication arising after immunosuppression, where the virus is found in virtually all cases.
Case presentation
We report a HIV-1 negative, non-transplant patient who developed HHV8-associated multicentric Castleman's disease and Kaposi's sarcoma after 17 years of immunosuppressive treatment with cyclosporin A for a minimal change nephropathy. Chemotherapy with liposomal doxorubicin resolved both symptoms of multicentric Castleman's disease and Kaposi's sarcoma in this patient. A concomitant decline in the HHV8 viral load in serum/plasma, as determined by a quantitative real-time PCR assay, was observed.
Multicentric Castleman's disease can be a complication of cyclosporin A treatment. Both multicentric Castleman's disease and Kaposi's sarcoma in this patient were responsive to liposomal doxorubicin, the treatment of choice for Kaposi's sarcoma at the moment, again suggesting a common mechanism linking both disorders, at least for HHV8-positive multicentric Castleman's disease and Kaposi's sarcoma.
HHV8 viral load measurements can be used to monitor effectiveness of therapy.
PMCID: PMC317306  PMID: 14670091
20.  Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes 
Journal of Virology  2005;79(15):9439-9448.
Though first described as a lymphotropic virus, human herpesvirus 6 (HHV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra- and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra- and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HHV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes.
PMCID: PMC1181567  PMID: 16014907
21.  Diagnostic Assays for Active Infection with Human Herpesvirus 6 (HHV-6) 
Human herpesvirus 6 (HHV-6) causes ubiquitous infection in early childhood with lifelong latency or persistence. Reactivation of HHV-6 has been associated with multiple diseases including encephalitis. Chromosomal integration of HHV-6 also occurs. Previous studies have suggested that the detection of HHV-6 DNA in plasma is an accurate marker of active viral replication.
We sought to determine whether PCR assays on plasma could correctly differentiate between primary HHV-6 infection, chromosomal integration of HHV-6 and latent HHV-6 infection.
Study Design
We performed qualitative PCR, real-time quantitative PCR (RQ-PCR), and reverse-transcriptase PCR (RT-PCR) assays on samples of peripheral and cord blood mononuclear cells, as well as plasma, from groups of subjects with well defined HHV-6 infection, including subjects with chromosomally integrated HHV-6.
Results and Conclusions
The detection of HHV-6 DNA in plasma was 92% sensitive compared to viral isolation for the identification of primary infection with HHV-6. All plasma samples from infants with chromosomally integrated HHV-6 had HHV-6 DNA detectable in plasma while only 5.6% were positive by RT-PCR. The specificity of plasma PCR for active replication of HHV-6 was 84% compared to viral culture while the specificity of RT-PCR was 98%. Our results demonstrate that qualitative or quantitative PCR of plasma is insufficient to distinguish between active viral replication and chromosomal integration with HHV-6. We found a higher specificity of RT-PCR performed on PBMC samples compared to PCR or RQ-PCR performed on plasma when evaluating samples for active HHV-6 replication.
PMCID: PMC2855742  PMID: 20211581
Human herpesvirus 6; chromosomally integrated HHV-6 (CI-HHV-6); polymerase chain reaction; real time quantitative polymerase chain reaction (RQ-PCR); reverse transcriptase polymerase chain reaction (RT-PCR)
22.  Infection of primary human fetal astrocytes by human herpesvirus 6. 
Journal of Virology  1996;70(2):1296-1300.
Human herpesvirus 6 (HHV-6) is a lymphotropic betaherpesvirus which productively infects human CD4+ T cells and monocytes. HHV-6 is the etiologic agent for exanthem subitum (roseola), and it is well-known that central nervous system complications occur frequently during the course of HHV-6-associated disease. In addition, HHV-6 has been associated with encephalitis or encephalopathy. However, very little is known about its tropism for neural cells. There are reports that HHV-6 may infect some glial cell lines, but whether it can infect any primary neural cells is not known. Our studies show that both HHV-6A (GS) and HHV-6B (Z-29) can infect highly purified primary fetal astrocytes in vitro. Infected cells showed cytopathic effects, forming giant syncytia. In dual immunofluorescence assays, the infected cells were detected by antibodies against the HHV-6 p41 nuclear antigen and glial fibrillary acidic protein, indicating that the infected cells are indeed astrocytes. PCR and Northern (RNA) blot analyses also confirmed that the astrocytes are infected by HHV-6. The progeny virus did not alter its host range and could reinfect T cells as well as primary astrocytes. These findings suggest that infection of primary human astrocytes may play a role in the neuropathogenesis of HHV-6.
PMCID: PMC189947  PMID: 8551599
23.  Human Herpesvirus-6A/B Binds to Spermatozoa Acrosome and Is the Most Prevalent Herpesvirus in Semen from Sperm Donors 
PLoS ONE  2012;7(11):e48810.
An analysis of all known human herpesviruses has not previously been reported on sperm from normal donors. Using an array-based detection method, we determined the cross-sectional frequency of human herpesviruses in semen from 198 Danish sperm donors. Fifty-five of the donors had at least one ejaculate that was positive for one or more human herpesvirus. Of these 27.3% (n = 15) had a double herpesvirus infection. If corrected for the presence of multiple ejaculates from some donors, the adjusted frequency of herpesviruses in semen was 27.2% with HSV-1 in 0.4%; HSV-2 in 0.1%; EBV in 6.3%; HCMV in 2.7%; HHV-6A/B in 13.5%; HHV-7 in 4.2%, whereas none of the samples had detectable VZV or HHV-8. Subsequently, we examined longitudinally data on ejaculates from 11 herpesvirus-positive donors. Serial analyses revealed that a donor who tested positive for herpesvirus at one time point did not necessarily remain positive over time. For the most frequently found herpesvirus, HHV-6A/B, we examined its association with sperm. For HHV-6A/B PCR-positive semen samples, HHV-6A/B could be detected on the sperm by flow cytometry. Conversely, PCR-negative semen samples were negative by flow cytometry. HHV-6B was shown to associate with sperm within minutes in a concentration dependent manner. Confocal microscopy demonstrated that HHV-6B associated with the sperm head, but only to sperm with an intact acrosome. Taken together, our data suggest that HHV-6A/B could be transported to the uterus via binding to the sperm acrosome. Moreover, we find a 10 times higher frequency of HHV-7 in semen from healthy individuals than previously detected. Further research is required to determine the potential risk of using herpesvirus-positive donor semen. Longitudinally analyses of ejaculate series indicate that implementation of quarantine for a donor shown to shed a herpesvirus is not a tenable solution.
PMCID: PMC3492232  PMID: 23144982
24.  HHV-6 Reactivation and Associated Sequelae after Hematopoietic Cell Transplantation 
Human herpesvirus 6 (HHV-6) reactivation has been associated with acute graft-versus-host-disease (aGVHD), cytomegalovirus (CMV) reactivation, and mortality after allogeneic hematopoietic cell transplantation (HCT), but previous studies have yielded inconsistent results. We performed a large prospective study of allogeneic HCT recipients in order to more definitively define the relationships between HHV-6 and these important outcomes.
Plasma specimens were collected prospectively from 315 allogeneic HCT recipients and tested for HHV-6 DNA at baseline and twice-weekly for 12 weeks. Cox proportional hazards models were used to evaluate the time-dependent associations between HHV-6 reactivation and the targeted outcomes.
HHV-6 was detected in 111 (35%) of 315 patients at a median of 20 days after HCT. HHV-6 reactivation was associated with subsequent CMV reactivation [adjusted hazard ratio (aHR) 1.9, 95% confidence interval (CI) 1.3-2.8, p=0.002]. High-level HHV-6 (>1,000 HHV-6 DNA copies/mL) was associated with subsequent grades II-IV aGVHD (aHR 2.4, 95% CI 1.60-3.6), p<0.001). High-level HHV-6 reactivation was also associated with non-relapse mortality (aHR 2.7, 95% CI 1.2-6.3, p=0.02).
HHV-6 reactivation was independently and quantitatively associated with increased risk of subsequent CMV reactivation, aGVHD, and mortality after HCT. A randomized antiviral trial is warranted to establish causality between HHV-6 and these endpoints and to determine if reducing HHV-6 reactivation will improve outcome after HCT.
PMCID: PMC3439599  PMID: 22641196
25.  Human Herpesvirus 6-A, 6-B and 7 in Vitreous Fluid Samples 
Journal of medical virology  2010;82(6):996-999.
Human herpesvirus 6 and 7 (HHV-6, HHV-7) have been associated with several neurologic syndromes and have been detected in nervous tissue from healthy persons; however, only two cases of HHV-6A have been reported to be associated with intraocular inflammatory disease. Vitreous fluid was tested from 101 patients, including 69 samples from patients with ocular inflammation including CMV retinitis, idiopathic retinitis, iritis, and vitritis, for HHV-6A, HHV-6B, and HHV-7 DNA by PCR. HHV-6A DNA (4,950 copies per ml) was detected in vitreous fluid from one patient with CMV retinitis, HHV-6B DNA (10,140 copies per ml) was detected in vitreous fluid from one patient with idiopathic ocular inflammation in the absence of CMV DNA, and HHV-7 was not detected any of the vitreous samples. HHV-6A, HHV-6B, and HHV-7 DNA are detectable in less than 2% of vitreous samples in patients with ocular inflammation.
PMCID: PMC2938775  PMID: 20419813
HHV-6A; HHV-6B; HHV-7; retinitis; iritis; vitritis

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