Human herpesviruses 6 and 7 (HHV-6 and HHV-7) are prevalent lymphotropic viruses that infect more than 80% of children at infancy or during early childhood. Infection ranges from asymptomatic to severe disease. HHV-6B causes exanthem subitum. The virus can be recovered from peripheral blood mononuclear cells during the acute phase of exanthem subitum, but the host remains latently infected throughout life. In immunocompromised patients undergoing kidney, liver, or bone marrow transplantation latent HHV-6B is reactivated, at times causing severe or fatal disease. Here, we describe the establishment of an in vitro system for reactivation of HHV-6B and HHV-7 from latency. HHV-7 is reactivated from latently infected peripheral blood mononuclear cells by T-cell activation. HHV-6B could not be reactivated under similar conditions; however, the latent HHV-6B could be recovered after the cells were infected with HHV-7. Once reactivated, the HHV-6B genomes became prominent and the HHV-7 disappeared. We conclude that HHV-7 can provide a transacting function(s) mediating HHV-6 reactivating from latency. Understanding the activation process is critical for the development of treatments to control the activation of latent viruses so as to avoid these sometimes life threatening infections in transplant recipients.

The presence and distribution of human herpesvirus 6 (HHV-6) variants was investigated by polymerase chain reaction in samples from healthy donors and biopsies from non-Hodgkin's lymphomas and Hodgkin's disease. HHV-6 DNA was present in peripheral blood lymphocytes of 17% of healthy donors, variant B three times more frequently than A. HHV-6 was not present in 35 non-Hodgkin's lymphomas of B cell origin and was in only 1 of 10 non-Hodgkin's lymphomas in AIDS patients. HHV-6 DNA was present in 29% of Hodgkin's disease samples; variant B was more frequent than A. Epstein-Barr virus DNA was detected in 38% of Hodgkin's disease biopsies and did not correlate with HHV-6. Thus, the two HHV-6 variants are differently distributed in the healthy population, and the virus probably has no direct role in the development of B cell non-Hodgkin's lymphoma. The detection of HHV-6 DNA in about one-third of Hodgkin's disease biopsies suggests that HHV-6 might be associated with a subset of this disorder.

The assay for detecting IgM neutralizing (NT) antibody activity to human herpesvirus-6 (HHV-6) was developed by using pretreatment of blood sample with staphylococcal protein A. The activity was mostly present in IgM fractions of serum but not in IgA fractions separated by ultracentrifugation. The assay was used for seroepidemiological studies for HHV-6 infection. In primary HHV-6 infection, IgM NT antibodies appeared 5 to 7 days after onset of exanthem subitum, reached maximum titers at 2 to 3 weeks, and tended to decline to undetectable levels after 2 months. In contrast, reactivation of HHV-6 observed in organ transplants showed somewhat greater degree of IgM NT antibody responses that persisted for 2 to 3 months and became undetectable 5 to 6 months after transplantation. The level and persistence of NT antibody titers measured by the conventional method was generally greater than those of the IgM titers. The prevalence of the IgM NT antibodies was examined in healthy individuals. The antibody was first detected at 4 to 7 months of age (5%), reached maximum level at 8 to 11 months (40%), and was detectable by 4 to 6 years (17%). A few (4 to 5%) of adolescents and adults were positive for the antibody.

Human herpesvirus-6 (HHV-6), a mature T-cell lymphotropic virus, is a newly recognized member of the herpes virus family and shares limited homology with human cytomegalovirus. HHV-6 has been identified as the etiologic agent of the childhood illness exanthem subitum (roseola infantum). Widespread acquisition of this virus has been demonstrated to occur early in childhood, with fever as the most consistent manifestation of primary infection. Reactivation of latent infection has been postulated and may be associated with lymphoproliferative disorders or other diseases of immune function.

Human herpesvirus 6 (HHV-6) has been reported to be associated with multiple sclerosis (MS) and Guillain-Barré syndrome (GBS).We analyzed cell-free HHV-6 DNA as an indication of active infection in the peripheral blood and cerebrospinal fluid (CSF) of Swedish patients with GBS, patients with chronic inflammatory demyelinating polyradiculoneuropathy, treatment-naïve patients with possible MS, interferon-β treated MS patients [with or without neutralizing antibodies (NAbs)], and control patients with headache.One of 14 GBS patients and one of eight patients with chronic inflammatory demyelinating polyradiculoneuropathy were positive for HHV-6 DNA in serum. Of the 27 treatment-naïve possible MS patients, two were positive in plasma and one in CSF. HHV-6 DNA was detected in the serum of three of 79 NAb+ patients and one of 102 NAb-interferon-β treated MS patients. HHV-6 DNA could not be detected in the plasma or CSF of any of the 33 controls, although the differences were not statistically significant.Our results do not suggest active HHV-6 infection to be a common phenomenon in any of the patient groups studied.Copyright © 2013. Published by Elsevier B.V.

Primary human herpesvirus-6 (HHV-6) infection is a common cause of acute sporadic encephalopathy in Japanese children. Occasionally, HHV-6 is not detected in the cerebrospinal fluid (CSF) of patients with encephalopathy, for example, in those with focal viral encephalitis, such as herpes simplex viral encephalitis. This indicates that HHV-6 encephalopathy is caused by an indirect mechanism, although this is not fully understood. HHV-6 DNA, cytokines (interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12 p70, tumor necrosis factor-alpha, interferon-gamma), and matrix metalloproteinase-9 were quantitated in both the CSF and serum of 13 patients with HHV-6 encephalopathy during the acute phase of the disease. HHV-6 DNA was detected in the CSF of seven patients with HHV-6 encephalopathy. The viral DNA concentration was significantly higher in serum than in CSF (mean 1.64 x 10(4) vs. 5.70 x 10(1) copies/ml; P = 0.003). The lack or low level of viral DNA in the CSF samples suggests that direct invasion of the central nervous system by HHV-6 is not the main cause of encephalopathy. Additionally, the IL-10 concentration was significantly higher in serum than in CSF (P < 0.001), whereas there was no significant difference in IL-6 levels between the CSF and serum samples. Interestingly, the IL-8 concentration was significantly higher in CSF than in serum (P = 0.038). The distribution of these cytokines differed between CSF and serum. The high CSF concentration of IL-8 could play an important role in the pathogenesis of encephalopathy.(c) 2010 Wiley-Liss, Inc.

Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Of the two human herpesvirus 6 (HHV-6) species, human herpesvirus 6B (HHV-6B) encephalitis is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Guidelines for the management of HHV-6 infections in patients with hematologic malignancies or post-transplant were prepared a decade ago but there have been no other guidelines since then despite significant advances in the understanding of HHV-6 encephalitis, its therapy, and other aspects of HHV-6 disease in this patient population. Revised guidelines prepared at the 2017 European Conference on Infections in Leukaemia covering diagnosis, preventative strategies and management of HHV-6 disease are now presented.Copyright© 2019 Ferrata Storti Foundation.