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.

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.

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.

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.

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.

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.

Delayed primary HHV-7 infection and neurologic disease.

BACKGROUND: Primary human herpesvirus 7 (HHV-7) infection occurs almost universally during the first 5 years of life and is rarely accompanied by central nervous system (CNS) symptoms such as febrile seizures. The present retrospective study investigated the role of primary HHV-7 infection in CNS disease in children, including adolescents. METHODS: The study included all children who had neurologic disease aged younger than 18 years seen at the Hospital for Sick Children, Toronto, Canada, between April 1, 1998 and December 31, 2011, whose cerebrospinal fluid (CSF) was found by polymerase chain reaction to contain HHV-7 DNA. Where sera were available, HHV-7 IgG antibody titers and avidity were measured to differentiate primary from past infection. RESULTS: HHV-7 DNA was detected in the CSF of 57 (1.9%) of the 2972 children tested. In 3 adolescents primary HHV-7 infection (low avidity IgG) was confirmed as the cause of neurologic disease, 2 who had encephalitis and 1 who had Guillain-Barré syndrome. Eighteen children had possible HHV-7 disease (no alternative cause identified and indeterminate antibody result or serum not available), 7 encephalitis, 8 meningitis, and 3 demyelinating disorders. HHV-7 disease was excluded in 36 children on the basis of past infection (high IgG avidity) and/or an alternative cause. CONCLUSIONS: Primary HHV-7 infection delayed into adolescence can cause serious neurologic disease. HHV-7 DNA in CSF alone is insufficient to prove an etiologic association. Combining CSF polymerase chain reaction with serology is essential to prove primary infection when investigating HHV-7 CNS disease.

Possible interference of human beta-herpesviruses-6 and -7 in gastrointestinal cancer development.

AIM: The high incidence of gastrointestinal cancer combined with high mortality from the disease if diagnosed at a late stage, signifies the need for better diagnostic, prognostic and predictive tools. Human beta-herpesviruses have been suggested as possible cofactors in the development of gastrointestinal cancer. METHODS: Sixty five patients with gastrointestinal cancer before surgery and without any treatment were enrolled in this study and divided into two groups depending on lymphocytes' count: I group (n = 35) -- lymphocytes > 1400x10(6)/L and II group (n = 30) -- lymphocytes < 1400x10(6)/L. Nested polymerase chain reaction was used to detect latent and active stage of persistent human herpesvirus-6 and -7 infection, laser flow cytometry with monoclonal antibodies -- to determine immunological parameters. RESULTS: Activation of herpesvirus-6 and -7 was more frequently observed in the patients' group with lymphopenia (HHV-6 1/1 (100%), HHV-7 4/8 (50%) and HHV-6 + HHV-7 6/9 (66%); p < 0.05). Cellular immune parameters were analysed in immunocompromised II group's patients dependently on beta-herpevirus infection. Although number of leukocytes was higher in patients with active HHV-6/-7 infection (p = 0.01), number of lymphocytes CD3(+), CD4(+), CD8(+) and CD38(+) in patients with active HHV-6/-7 infection tended to decrease (p < 0.0001, P = 0.0002, p = 0.0001 and p < 0.0001, respectively). However, number of CD19(+) had tendency to increase (p = 0.03). CONCLUSION: Activation of herpesvirus-6 and -7 may lead to decrease of lymphocytes total count and develop immunosuppression in patients with gastrointestinal cancer.

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 herpesviruses 6, 7, and 8 from a dermatologic perspective.

Human herpesviruses (HHVs) have frequently been suspected as etiologic agents or cofactors in cutaneous disease. However, clearly established associations are rare. Investigations into an etiologic association between HHVs and cutaneous disease are complicated by the ubiquity and nearly universal prevalence of some herpesviruses. This article summarizes the associations between cutaneous disease and HHV-6, HHV-7, and HHV-8. In addition to a personal library of references, the PubMed database of biomedical literature was searched using the following Medical Subject Heading terms: HHV-6, HHV-7, and HHV-8, each in conjunction with cutaneous manifestations, virology, epidemiology, dermatopathology, and therapeutics, between 1998 and March 2011. Free-text searches with known or suspected disease associations were added for broader coverage. The results have been summarized to provide a practical review for the physician likely to encounter cutaneous diseases.

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.

Cutaneous infections caused by Herpesviridae: a review.

The herpes family of viruses accounts for a significant proportion of human cutaneous disease. Although most episodes of viral infection can be diagnosed clinically, a small subset of these outbreaks will require biopsy for histologic interpretation and diagnosis. Most herpesviruses cause characteristic architectural and cytologic changes in the context of active infection, whereas the effects of some will not manifest until the future as malignant disease. Other infections may go unnoticed secondary to a lack of specific histologic findings. Because herpesviruses cause such a wide spectrum of cutaneous conditions, it is prudent that pathologists be aware of the varied clinical and histopathologic presentations so that these infections will not persist undiagnosed. Additionally, methods of virus detection will briefly be reviewed.

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 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.