Update on human herpesvirus 7 pathogenesis and clinical aspects as a roadmap for future research.

Human herpesvirus 7 (HHV-7) is a common virus that is associated with various human diseases including febrile syndromes, dermatological lesions, neurological defects, and transplant complications. Still, HHV-7 remains one of the least studied members of all human betaherpesviruses. In addition, HHV-7-related research is mostly confined to case reports, while in vitro or in vivo studies unraveling basic virology, transmission mechanisms, and viral pathogenesis are sparse. Here, we discuss HHV-7-related literature linking clinical syndromes to the viral life cycle, epidemiology, and viral immunopathogenesis. Based on our review, we propose a hypothetical model of HHV-7 pathogenesis inside its host. Furthermore, we identify important knowledge gaps and recommendations for future research to better understand HHV-7 diseases and improve therapeutic interventions.

Metagenomic next-generation sequencing of viruses, bacteria, and fungi in the epineurium of the facial nerve with Bell's palsy patients.

Bell's palsy (BP) represents a major cause leading to facial paralysis in the world. The etiology of BP is still unknown, and virology is the prevailing theory. The purpose of this study is to explore the pathogenic microorganisms that may be related to BP, and it is of great significance to study the pathogenesis and treatment of BP. Metagenomic next-generation sequencing (mNGS) detection was performed in the epineurium of the facial nerve of 30 BP patients who underwent facial nerve epineurium decompression. A total of 84 pathogenic microorganisms were detected in 30 clinical samples, including 4 viruses, 10 fungi, and 70 bacteria. The species with the highest detection frequency in virus was human betaherpesvirus 7 (HHV-7). The species with the highest detection frequency in Fungi was Malassezia restricta. The species with the highest detection frequency in Bacteria was Pseudomonas aeruginosa. In this study, mNGS method was firstly used to detect the pathogenic microorganisms in the epineurium of the facial nerve with BP patients. We have for the first time identified HHV-7 and aspergillus in the epineurium of the facial nerve of BP patients. These results suggest that these two pathogenic microorganisms should be considered in the pathogenesis of BP.

Inflammatory Cytokine-Producing Cells and Inflammation Markers in the Synovium of Osteoarthritis Patients Evidenced in Human Herpesvirus 7 Infection.

A direct association between joint inflammation and the progression of osteoarthritis (OA) has been proposed, and synovitis is considered a powerful driver of the disease. Among infections implicated in the development of joint disease, human herpesvirus 7 (HHV-7) infection remains poorly characterized. Therefore, we assessed synovitis in OA patients; determined the occurrence and distribution of the HHV-7 antigen within the synovial membrane of OA-affected subjects; and correlated plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF), interleukin-6 (IL-6), and TNF expressed locally within lesioned synovial tissues with HHV-7 observations, suggesting differences in persistent latent and active infection. Synovial HHV-7, CD4, CD68, and TNF antigens were detected immunohistochemically. The plasma levels of TNF and IL-6 were measured by an enzyme-linked immunosorbent assay. Our findings confirm the presence of persistent HHV-7 infection in 81.5% and reactivation in 20.5% of patients. In 35.2% of patients, virus-specific DNA was extracted from synovial membrane tissue samples. We evidenced the absence of histopathologically detectable synovitis and low-grade changes in the majority of OA patients enrolled in the study, in both HHV-7 PCR+ and HHV-7 PCR‒ groups. The number of synovial CD4-positive cells in the HHV-7 polymerase chain reaction (PCR)+ group was significantly higher than that in the HHV-7 PCR‒ group. CD4- and CD68-positive cells were differently distributed in both HHV-7 PCR+ and HHV-7 PCR‒ groups, as well as in latent and active HHV-7 infection. The number of TNF+ and HHV-7+ lymphocytes, as well as HHV-7+ vascular endothelial cells, was strongly correlated. Vascular endothelial cells, especially in the case of infection reactivation, appeared vulnerable. The balance between virus latency and reactivation is a long-term relationship between the host and infectious agent, and the immune system appears to be involved in displaying overreaction when a shift in the established equilibrium develops.

The role of HHV-6 and HHV-7 infections in the development of fibromyalgia.

Human herpes virus-6 (HHV-6) and human herpes virus-7 (HHV-7) are immunomodulating viruses potentially affecting the nervous system. We evaluated the influence of HHV-6 and HHV-7 infections on fibromyalgia (FM) clinical course. Forty-three FM patients and 50 control group participants were enrolled. 39.50% (n = 17) FM patients had light A delta and C nerve fiber damage, 27.91% (n = 12) had severe A delta and C nerve fiber damage. 67.44% (n = 29) FM patients had loss of warm sensation in feet, loss of heat pain sensation, and increased cold pain sensation (34.90%, n = 15 in both findings). HHV-6 and HHV-7 genomic sequences in peripheral blood DNA in 23/43 (51.00%) and 34/43 (75.50%) of samples from FM patients and in 3/50 (6.00%) and 26/50 (52.00%) of samples from the control group individuals were detected. Active HHV-6 (plasma viremia) or HHV-7 infection was revealed only in FM patients (4/23, 17.40% and 4/34, 11.80%, respectively). A statistically significant moderate positive correlation was found between A delta and C nerve fiber damage severity and HHV-6 infection (p < 0.01, r = 0.410). 23/43 patients from the FM group and control group participants HHV-6 and 34/45 HHV-7 did have infection markers. A statistically significant moderate positive correlation was found between A delta and C nerve fiber damage severity and HHV-6 infection (p < 0.01, r = 0.410). No difference was found between detection frequency of persistent HHV-6 and HHV-7 infection between FM patients and the control group. Statistically significant correlation was observed between quantitation of changes in QST thermal modalities and HHV-6 infection. There was no correlation between A delta and C nerve fiber damage and HHV-7 infection.

Reactivation of human herpesviruses 6 and 7 in Kawasaki disease.

Objectives: Kawasaki disease (KD) is one of the most common childhood vasculitides. Some serological studies have suggested an etiological relationship between KD and human herpesvirus (HHV)-6 or HHV-7. However, primary or reactivated HHV-6 and -7 has not been fully investigated in patients with KD. Methods: Twenty-three patients with KD were prospectively enrolled in this study. Peripheral blood was collected in the acute and convalescence phases, and HHV-6 and -7 viral loads were measured by real-time PCR. Results: In the acute phase, HHV-6 and -7 DNA was detected in 7 (30%) patients each, compared to 13 (57%) and 9 (39%) patients in the convalescence phase, respectively. HHV-6 and -7 DNA loads were significantly higher in the convalescence phase than in the acute phase. Significant increases in HHV-6 and -7 DNA loads were not observed in disease control patients. Taking into account HHV-6 and -7 serostatus, reactivation of HHV-6 and -7 was observed in 7 and 9 patients, respectively. KD patients with HHV-6 reactivation showed higher C-reactive protein levels and more frequently required steroid therapies than patients without reactivation. Conclusion: HHV-6 and -7 reactivation is frequent in KD patients. HHV-6 reactivation might exacerbate the severity of KD.

Summary of the 10th International Conference on Human Herpesviruses-6 and -7 (HHV-6A, -6B, and HHV-7).

The 10th International Conference on Human herpesviruses-6 and -7 (HHV-6A, HHV-6B, and HHV-7) was held at the Freie Universität, Berlin, Germany from July 23-26, 2017. It attracted more than 130 basic, translational and clinical scientists from 19 countries. Important new information was presented regarding: the biology of HHV-6A and -6B; the biology and epidemiology of inherited chromosomally integrated HHV-6A and -6B; improved diagnostic tests; animal models for and animal viruses with similarities to HHV-6A, -6B, and -7; established and possible disease associations; and new treatment strategies. Here, we summarize work presented at the meeting that is of particular interest.

The human herpesvirus-7 (HHV-7) U21 immunoevasin subverts NK-mediated cytoxicity through modulation of MICA and MICB.

Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. Many herpesviruses encode gene products devoted to preventing viral antigen presentation as a means of escaping detection by cytotoxic T lymphocytes. The human herpesvirus-7 (HHV-7) U21 gene product, for example, is an immunoevasin that binds to class I major histocompatibility complex molecules and redirects them to the lysosomal compartment. Virus infection can also induce the upregulation of surface ligands that activate NK cells. Accordingly, the herpesviruses have evolved a diverse array of mechanisms to prevent NK cell engagement of NK-activating ligands on virus-infected cells. Here we demonstrate that the HHV-7 U21 gene product interferes with NK recognition. U21 can bind to the NK activating ligand ULBP1 and reroute it to the lysosomal compartment. In addition, U21 downregulates the surface expression of the NK activating ligands MICA and MICB, resulting in a reduction in NK-mediated cytotoxicity. These results suggest that this single viral protein may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands.

Relationship between beta-herpesviruses reactivation and development of complications after autologous peripheral blood stem cell transplantation.

The relationship between beta-herpesviruses reactivation and the development of complications after autologous peripheral blood stem cell transplantation was investigated. Viral genomic sequences were detected by the polymerase chain reaction, virus-specific antibodies by ELISA, and human herpesvirus (HHV)-6 variants by restriction endonuclease analysis. Virus reactivation, serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, soluble IL-2 receptor (sIL-2R), IL-2, and IL-4 were compared with clinical features in 44 patients before and after transplantation. Anti-CMV and anti-HHV-6 antibodies were found in 70.5% and 81.8% of patients, respectively. The frequency of plasma viremia was significantly higher in patients after transplantation (41% vs. 11.4%). Reactivation of more than one virus was identified in 55.6% of patients and reactivation of HHV-7 alone in 44.4%. In cases of concurrent infection, HHV-7 was reactivated before HHV-6, and both HHV-6 and HHV-7 were reactivated before CMV. There was a significant increase in HHV-6 load in peripheral blood leukocytes DNA during viremia. In all cases HHV-6B variant was detected. Complications after transplantation occurred in 27.3% of patients and virus reactivation was detected in all patients with complications. The significant increases in the rate of HHV-6 and HHV-7 reactivation and in serum levels of TNF-α, IL-1ß, and sIL-2R, as well as aggravated immunosuppression, suggest that both viruses were involved in the complications after autologous peripheral blood stem cell transplantation, via their immunomodulatory activity. The kinetics of reactivation suggests a potential role of HHV-7 as a co-factor of HHV-6 reactivation, and of both HHV-6 and HHV-7 as co-factors of CMV reactivation.

Human herpesvirus 7 u21 downregulates classical and nonclassical class I major histocompatibility complex molecules from the cell surface.

Herpesviruses have evolved numerous strategies to evade detection by the immune system. Notably, most of the herpesviruses interfere with viral antigen presentation to cytotoxic T lymphocytes (CTLs) by removing class I major histocompatibility complex (MHC) molecules from the infected cell surface. Clearly, since the herpesviruses have evolved an extensive array of mechanisms to remove class I MHC molecules from the cell surface, this strategy serves them well. However, class I MHC molecules often serve as inhibitory ligands for NK cells, so viral downregulation of all class I MHC molecules should leave the infected cell open to NK cell attack. Some viruses solve this problem by selectively downregulating certain class I MHC products, leaving other class I products at the cell surface to serve as inhibitory NK cell ligands. Here, we show that human herpesvirus 7 (HHV-7) U21 binds to and downregulates all of the human class I MHC gene products, as well as the murine class I molecule H-2K(b). HHV-7-infected cells must therefore possess other means of escaping NK cell detection.

Emerging viruses in transplantation.

PURPOSE OF REVIEW: Several viruses have recently gained importance for the transplant recipient. The purpose of this review is to give an update on emerging viruses in transplantation. RECENT FINDINGS: BK virus-associated nephropathy (BKVAN) causes graft loss after kidney transplantation. Immunosuppression lowering strategies have now been shown to have benefit in decreasing the incidence of BKVAN. Guidelines for screening, prevention, and therapy have also been developed. Another polyomavirus, JC virus, is a cause of progressive multifocal leukoencephalopathy and has also gained prominence due to the increasing use of monoclonal antibodies in transplant recipients. The significance of human herpesvirus-6 and -7 continues to be debated in the literature, and new data is available on their association with clinical disease. Finally, newly discovered respiratory viruses, such as human metapneumovirus, bocavirus, KI and WU viruses, have also been described in transplant recipients. Human metapneumovirus appears to cause significant respiratory disease whereas the significance of bocavirus, KI and WU viruses in transplant recipients remains uncertain. SUMMARY: Viral infections, such as polyomaviruses, human herpesvirus-6 and -7 and respiratory viruses, are emerging as causes of significant disease in transplantation. Antiviral options for these viruses are limited, and decreasing immunosuppression is the cornerstone of therapy.

[Human herpesvirus-6 and human herpesvirus-7 (HHV-6, HHV-7)].

human herpesvirus 6 (HHV-6) is the major causative agent of exanthem subitum which is one of popular diseases in infant, and establishes latent infections in adults of more than 90%. Recently, the encephalitis caused by reactivated- HHV-6 has been shown in patients after transplantation. In addition, the relationship HHV-6 and drug-induced hypersensitivity syndrome has also been reported. human herpesvirus 7 (HHV-7) was isolated from the stimulated-peripheral blood lymphocytes of a healthy individual, and also causes exanthema subitum. Both viruses are related viruses which belong to betaherpesvirus subfamily, and replicate and produce progeny viruses in T cells.

Three Adolescents With Primary Human Herpesvirus 7 Infection During a Measles Outbreak.

During local small measles outbreak in Japan, 3 adolescents with febrile skin rash suspected as having measles were diagnosed with primary human herpesvirus (HHV)-7 infection. Primary HHV-7 infection can cause exanthem subitum in not only young children but also adolescents. HHV-7 should be considered as a possible causative agent for adolescent febrile skin rash during the measles outbreak.

Pitiryasis Lichenoides et Varioliformis Aacuta Associated With Human Herpesvirus 7. / Pitiriasis liquenoide y varioliforme aguda asociada al virus herpes humano tipo 7.

Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica represent 2 ends of a disease spectrum of unknown etiology. Herein we describe 2 cases of pityriasis lichenoides et varioliformis acuta, in which human herpesvirus 7 DNA was detected in skin samples by polymerase chain reaction methodology, an association not previously described. This report may support the involvement of viral infection in the etiopathogeny of this disease.

Lichen planus remission is associated with a decrease of human herpes virus type 7 protein expression in plasmacytoid dendritic cells.

The cause of lichen planus is still unknown. Previously we showed human herpes virus 7 (HHV-7) DNA and proteins in lesional lichen planus skin, and significantly less in non-lesional lichen planus, psoriasis or healthy skin. Remarkably, lesional lichen planus skin was infiltrated with plasmacytoid dendritic cells. If HHV-7 is associated with lichen planus, then HHV-7 replication would reduce upon lichen planus remission. HHV-7 DNA detection was performed by nested PCR and HHV-7 protein by immunohistochemistry on lesional skin biopsies from lichen planus patients before treatment and after remission. Biopsies were obtained from lichen planus lesions before treatment (n = 18 patients) and after remission (n = 13). Before treatment 61% biopsies contained HHV-7 DNA versus 8% after remission (P = 0.01). HHV-7-protein positive cell numbers diminished significantly after remission in both dermis and epidermis. Expression of HHV-7 was mainly detected in BDCA-2 positive plasmacytoid dendritic cells rather than CD-3 positive lymphocytes. HHV-7 replicates in plasmacytoid dendritic cells in lesional lichen planus skin and diminishes after remission. This study further supports our hypothesis that HHV-7 is associated with lichen planus pathogenesis.

Molecular biology and clinical associations of Roseoloviruses human herpesvirus 6 and human herpesvirus 7.

Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) are members of the Roseolovirus genus within the Betaherpesvirinae subfamily. HHV-6 and HHV-7 primary infection occurs in early childhood and causes short febrile diseases, sometimes associated with cutaneous rash (exanthem subitum). Both HHV-6 and HHV-7 are highly prevalent in the healthy population, establish latency in macrophages and T-lymphocytes, are frequently shed in saliva of healthy donors, and the pathogenic potential of reactivated virus ranges from asymptomatic infection to severe diseases in transplant recipients. These features have contributed to the notion that HHV-6 and HHV-7 are more or less "harmless" viruses. Consequently, the medical and scientific interest originally prompted by their discovery has been gradually waning. The aim of this review is to provide a short update of the current knowledge on these viruses, and to suggest that the medical importance of Roseoloviruses should not be understimated.

Remission associated with human herpesvirus infection in west syndrome.

Generally, West syndrome is an intractable epileptic syndrome in infancy, although spontaneous remission has been reported in some cases. An immunologic response to infection might be one of the factors involved in the remission of West syndrome, but the mechanisms remain unknown. On the other hand, exanthema subitum is a common disease occurring in infancy with the characteristics of fever and rash. Two kinds of human herpesvirus, 6 and 7, have been isolated as causal agents of exanthema subitum. We experienced one symptomatic case and three cryptogenic cases of West syndrome that showed spontaneous remission. In the symptomatic case, the subject showed a temporary remission; however, in the other cases, the remissions were long term. In the present study, we report the patients' improvement and electroencephalographic (EEG) findings. In all of our cases, hypsarrythmia disappeared on the EEG findings, the human herpesvirus 6 IgG antibodies increased in all four cases, and the herpesvirus 7 IgG antibodies increased in two cases. We postulate that the remission of the four cases proceeded from infection by exanthema subitum. The changes in serum antibody values suggest that the spontaneous remission of West syndrome was related to human herpesvirus 6 and 7 infections.

Pediatric Hemorrhagic Brainstem Encephalitis Associated With HHV-7 Infection.

BACKGROUND: Human herpesviruses-6 and -7 have been associated with febrile seizures and with encephalitis, the latter predominantly in immunocompromised individuals. Acute hemorrhagic encephalitis is frequently a fatal disease that can occur in the setting of viral infection or can be a postinfectious phenomenon, often with no cause identified. Although hemorrhagic encephalitis has been reported with human herpesvirus-6 infection, only one individual, an immunocompromised child, has been documented with human herpesvirus-7 infection. The role of immunosuppression is not well-established in the management of this rare condition. PATIENT DESCRIPTION: We present an 11-year-old boy with hemorrhagic brainstem encephalitis who underwent extensive infectious and autoimmune testing, positive only for human herpesvirus-7 in the cerebrospinal fluid. The patient recovered after treatment with intravenous immunoglobulin, high-dose steroids, and plasma exchange. CONCLUSION: This is the first report of hemorrhagic brainstem encephalitis with human herpesvirus-7 in a previously healthy individual, adding to existing reports of late-onset human herpesvirus-7 infection associated with encephalitis in children. It also underscores that aggressive immunosuppression may be used early in the course of this disorder and may be beneficial for recovery.

Association between Herpesviruses and Chronic Periodontitis: A Meta-Analysis Based on Case-Control Studies.

OBJECTIVE: Numerous studies have investigated the associations between herpesviruses and chronic periodontitis; however, the results remain controversial. To derive a more precise estimation, a meta-analysis on all available studies was performed to identify the association between herpesviruses and chronic periodontitis. METHODS: A computerized literature search was conducted in December 2014 to identify eligible case-control studies from the PUBMED and EMBASE databases according to inclusion and exclusion criteria. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were used to assess the association between herpesviruses and risk of chronic periodontitis. A fixed or random effects model was determined based on a heterogeneity test. Sensitivity analysis was conducted to investigate stability and reliability. Publication bias was investigated using the Begg rank correlation test and Egger's funnel plot. RESULTS: Ten eligible studies were included to investigate the association between Epstein-Barr virus (EBV) and chronic periodontitis. The results showed that EBV has a significant association with chronic periodontitis compared with periodontally healthy group (OR = 5.74, 95% CI = 2.53-13.00, P<0.001). The association between human cytomegalovirus (HCMV) and chronic periodontitis was analyzed in 10 studies. The pooled result showed that HCMV also has a significant association with chronic periodontitis (OR = 3.59, 95% CI = 1.41-9.16, P = 0.007). Similar results were found in the sensitivity analyses. No significant publication bias was observed. Two eligible studies were included to investigate the association between herpes simplex virus (HSV) and chronic periodontitis risk. The association between HSV and chronic periodontitis was inconclusive (OR = 2.81 95% CI = 0.95-8.27, P = 0.06). Only one included study investigated the association between human herpesvirus 7 (HHV-7) and chronic periodontitis risk (OR = 1.00, 95% CI = 0.21-4.86). CONCLUSION: The findings of this meta-analysis suggest that two members of the herpesvirus family, EBV and HCMV, are significantly associated with chronic periodontitis. There is insufficient evidence to support associations between HSV, HHV-7 and chronic periodontitis.

HHV-6, 7 and their related diseases.

Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) are relatively recently discovered beta-herpesvirus. They are prevalent in the human population. Primary infection of HHV-6 has been associated with exanthem subitum and febrile illness. Little information is known about the clinical characteristics of primary infection with HHV-7, although some cases of exanthem subitum have been linked to it. HHV-6 has been recently recognized as an opportunistic pathogen in patients with HIV infection and in transplant recipients. The techniques now available to detect these two viruses remain limited, though putative roles for HHV-6 and HHV-7 in several diseases linked to viral infection have been reported. This report reviews the current knowledge of HHV-6 and HHV-7 biology and their pathogenesis.