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.

Prevalence of human herpesvirus in plasma and saliva of cirrhotic patients: A pilot study.

AIMS: The objective of this study was to identify the presence of human herpesvirus (HHV) in the plasma and saliva of hepatic-cirrhosis patients and correlate it with clinical data and laboratory tests. This is a pilot, observational, and cross-sectional study. METHODS AND RESULTS: Specimens of plasma and saliva from 72 cirrhotic individuals were analyzed by means of polymerase chain reaction. The patient population had a mean age of 54.84 years old (SD ± 10) and was 70% males (51/72). Approximately 47% (n = 34) of the patients had leukopenia and HHV was not identified in the plasma specimens. The main species of HHV identified in the saliva were HHV-7 (n = 42, 62%) and Epstein-Barr virus (EBV) (n = 30, 41%). Moreover, there was a significant decrease in the total number of leukocytes and lymphocytes in saliva containing EBV (P = .038 and P = .047, respectively). CONCLUSION: The results show that the presence of EBV in the saliva of cirrhotic patients was correlated with their circulating immune status. It may be possible that the immune dysfunction displayed by the cirrhotic patients plays a role in the shedding of EBV into saliva.

The Eruptive Fevers at Sixes and Sevens.

Sixth Disease (roseola infantum) and its primary causative agent, HHV-6, share names that numerically concur. This article examines and answers the question of whether that correspondence is by design or coincidental by briefly reviewing the history and nomenclature of the HHV viruses and the classic febrile rashes of childhood while highlighting some clinical and microbiologic features of HHV-6 infection.

Alzheimer's disease and herpes viruses: Current events and perspectives.

Alzheimer's disease (AD) is a real and current scientific and societal challenge. Alzheimer's disease is characterised by a neurodegenerative neuroinflammatory process, but the etiopathogenetic mechanisms are still unclear. The possible infectious aetiology and potential involvement of Herpes viruses as triggers for the formation of extracellular deposits of amyloid beta (Aß) peptide (amyloid plaques) and intraneuronal aggregates of hyperphosphorylated and misfold could be a possible explanation. In fact, the possible genetic interference of Herpes viruses with the genome of the host neuronal cell or the stimulation of the infection to a continuous immune response with a consequent chronic inflammation could constitute those mechanisms underlying the development of AD, with possible implications in the understanding and management of the disease. Herpes viruses could be significantly involved in the pathogenesis of AD and in particular, their ability to reactivate in particular conditions such as immunocompromise and immunosenescence, could explain the neurological damage characteristic of AD. Our review aims to evaluate the state of the art of knowledge and perspectives regarding the potential relationship between Herpes viruses and AD, in order to be able to identify the possible etiopathogenetic mechanisms and the possible therapeutic implications.

Association between Pityriasis Rosea (PR) and HHV-6/HHV-7 Infection: Importance of Sample Selection and Diagnostic Techniques.

Recent studies have focused on the role of human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) in PR etiology with varying results. In our study, with the approach that the discrepancy between the results may be related to the different samples and techniques used, we aimed to clarify the etiology by examining tissue and plasma samples using molecular methods and evaluating the results together with serological parameters. Skin biopsies and plasma samples of twenty-five PR patients were tested to detect HHV-6 and HHV-7 DNA using calibrated quantitative real-time polymerase chain reaction (CQ RT-PCR). IgG and IgM antibodies against HHV-6 and HHV-7 were tested by enzyme-linked immunosorbent assay and indirect immunofluorescence. Of the patient group, 64% were positive for HHV-6 IgG without IgM positivity. HHV-6 DNA was present in seven tissue and ten plasma samples. HHV-7 positivity was 100% and 12% for IgG and IgM antibodies, respectively. HHV-7 DNA was detected in four tissue samples and one plasma sample. Patients with HHV-7 DNA-positive plasma and tissue samples had also HHV-7 IgM antibodies. In conclusion, our results seem to support the role of HHV-6/HHV-7 in the etiology of PR. To clarify the etiology of PR and avoid confusion, the collection of different biological materials simultaneously and the usage of CQ RT-PCR as a diagnostic technique are recommended.

Hybrid capture shotgun sequencing detected unexpected viruses in the cerebrospinal fluid of children with acute meningitis and encephalitis.

PURPOSE: Investigation of undiagnosed cases of infectious neurological diseases, especially in the paediatric population, remains a challenge. This study aimed to enhance understanding of viruses in CSF from children with clinically diagnosed meningitis and/or encephalitis (M/ME) of unknown aetiology using shotgun sequencing enhanced by hybrid capture (HCSS). METHODS: A single-centre prospective study was conducted at Sant Joan de Déu University Hospital, Barcelona, involving 40 M/ME episodes of unknown aetiology, recruited from May 2021 to July 2022. All participants had previously tested negative with the FilmArray Meningitis/Encephalitis Panel. HCSS was used to detect viral nucleic acid in the patients' CSF. Sequencing was performed on Illumina NovaSeq platform. Raw sequence data were analysed using CZ ID metagenomics and PikaVirus bioinformatics pipelines. RESULTS: Forty episodes of M/ME of unknown aetiology in 39 children were analysed by HCSS. A significant viral detection in 30 CSF samples was obtained, including six parechovirus A, three enterovirus ACD, four polyomavirus 5, three HHV-7, two BKV, one HSV-1, one VZV, two CMV, one EBV, one influenza A virus, one rhinovirus, and 13 HERV-K113 detections. Of these, one sample with BKV, three with HHV-7, one with EBV, and all HERV-K113 were confirmed by specific PCR. The requirement for Intensive Care Unit admission was associated with HCSS detections. CONCLUSION: This study highlights HCSS as a powerful tool for the investigation of undiagnosed cases of M/ME. Data generated must be carefully analysed and reasonable precautions must be taken before establishing association of clinical features with unexpected or novel virus findings.

Encephalitis in the Course of HHV-7 Infection in an Infant.

Most cases of acute infections caused by human herpesvirus 7 (HHV-7) are asymptomatic or very mild. Clinical symptoms disappear spontaneously; however, the infection becomes latent and persists for life with periodic asymptomatic reactivation. Little is known about the virus's ability to cross the blood-brain barrier. Our case of an immunocompetent infant indicates that HHV-7 infection should be considered a cause of neuroinfection, not only in immunocompromised patients but also in the youngest immunocompetent patients.

Vitreous Humor Positive for DNA of Human Herpesvirus 7 in Eye With Ocular Toxoplasmosis.

The aim of this article was to report our findings in a case of infectious uveitis in which the DNAs of both Toxoplasma gondii and human herpesvirus 7 (HHV-7) were detected in the vitreous fluid. A 31-year-old Brazilian man was examined in our hospital with a one-month history of blurred vision (20/40) in the right eye. He had been diagnosed with ocular toxoplasmosis of the right eye at nine years of age and has had repeated relapses. Because of the persistent vitreous opacities and refractoriness to acetylspiramycin and betamethasone, pars plana vitrectomy was performed. Multiplex PCR of the vitreous sample demonstrated the DNAs for both T. gondii and HHV-7. Trimethoprim/sulfamethoxazole with prednisone was prescribed. Six months after the beginning of the therapy, a resolution of the retinochoroiditis was found and the vision recovered to 20/25. Two months later, we performed a pars plana vitrectomy for an epiretinal membrane. The DNAs of both T. gondii and HHV-7 were not detected in the vitreous fluid and the epiretinal membrane. After continued treatment, the best-corrected visual acuity (BCVA) in the right eye improved to 20/16 and the metamorphopsia was reduced. It is inferred from this work that HHV-7 reactivation can activate refractory infectious uveitis in patients with chronic ocular toxoplasmosis.

Characteristics of HHV-7 meningitis: a systematic review.

There are limited data on HHV-7 meningitis and this systematic review used electronic search to gather pieces of evidence regarding its characteristics. Nine articles were included which three were case reports and the rest of the articles were retrospective studies. Altogether, 32 cases were described in the literature that 13 were females and 26 were aged less than 16 years old. The HHV-7 meningitis has been reported in any season, especially in winter. It affected both immunocompetent and immunocompromised individuals and mostly presented with fever and headache, however rash and seizure have also been documented. The CSF analysis in general showed an elevated range of cell count with lymphocytic predominance and normal to slightly elevated protein levels. Thirteen patients did not receive treatment for HHV-7 meningitis and full recovery was gained in the majority of cases after about 10 days. This review summarizes characteristics of HHV-7 meningitis in the literature, and yet epidemiological studies are needed to shed more light which eventually could be helpful for the diagnosis and management of this disease.

Human herpesvirus-7 meningitis in an immunocompetent adult patient: a case report.

Aim: The underlying pathological mechanisms of CNS human herpesvirus-7 (HHV-7) related infections are still unknown, especially among immunocompetent adults. Although HHV-7 meningitis in immunocompetent adults is usually uncommon, serious consideration for possible HHV-7 involvement should be taken when assessing CNS infection of unknown etiology. Case presentation: We report a 53-year-old female who presented for fever and progressive headaches. Cerebrospinal fluid (CSF) analysis was compatible with a viral meningitis. CSF cultures were negative and HHV-7 DNA was the only strain detected in the CSF analysis. The patient died 1 month later following complications and cardiac arrest. Conclusion: HHV-7 CNS infection in immunocompetent patient can be a serious infection. Prompt diagnosis and treatment management are essential for better outcome.

We do not fully understand how human herpesvirus-7 (HHV-7) brain infections affect healthy individuals. We share a case of a 53-year-old woman who presented with fever and worsening headaches. In her cerebrospinal fluid analysis, only HHV-7 DNA was found. She received treatment with acyclovir initially and later with ganciclovir for a total of 4 weeks. Unfortunately, the patient passed away 1 month later due to complications and cardiac arrest. We highlight the need for robust guidelines for effectively treating HHV-7 brain infections in healthy individuals.

Anti-N-methyl-D-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes-macrophages, epithelial cells, and central nervous system cells. The pathogenicity of human herpesvirus-7 is unclear. Cases of anti-N-methyl-D-aspartate receptor encephalitis with human herpesvirus-7 present in cerebrospinal fluid have been documented, but the clinical significance of this finding remains unclear. CASE PRESENTATION: An 11-year-old Caucasian boy was admitted to hospital after a generalized tonic-clonic seizure. Generalized tonic seizures repeated three more times during the day of hospitalization. Blood tests showed minor ongoing inflammation, while brain computed tomography yielded normal results. Brain magnetic resonance imaging showed hyperintense focal alterations in both temporal lobes, hippocampi, and at the base of the right frontal lobe. Positive anti-N-methyl-D-aspartate receptor antibodies were found in both serum and cerebrospinal fluid. Positive novel coronavirus 2 (severe acute respiratory syndrome coronavirus 2) immunoglobulin G antibodies were found in serum. Polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 was negative. Furthermore, positive human herpesvirus-7 deoxyribonucleic acid was found in cerebrospinal fluid. The patient was treated with acyclovir, human immunoglobulin, and methylprednisolone. The seizures did not repeat, and no psychiatric symptoms were present. The patient made a full recovery. CONCLUSIONS: We present a pediatric case of anti-N-methyl-D-aspartate receptor encephalitis with atypical clinical presentation. The role of human herpesvirus-7 in neurological disorders remains unclear in immunocompetent patients.

Contribution of carbohydrate-related metabolism in Herpesvirus infections.

Human herpesviruses are enveloped viruses with double-stranded linear DNA genomes highly prevalent in the human population. These viruses are subdivided into three subfamilies, namely alphaherpesvirinae (herpes simplex virus type 1, HSV-1; herpes simplex virus type 2, HSV-2; and varicella-zoster virus, VZV), betaherpesvirinae (human cytomegalovirus, HCMV; human herpesvirus 6, HHV-6; and human herpesvirus 7, HHV-7) and gammaherpesvirinae (Epstein-Barr virus, EBV; and Kaposi's sarcoma-associated herpesvirus, KSHV). Besides encoding numerous molecular determinants to evade the host antiviral responses, these viruses also modulate cellular metabolic processes to promote their replication. Here, we review and discuss existing studies describing an interplay between carbohydrate metabolism and the replication cycle of herpesviruses, altogether highlighting potentially new molecular targets based on these interactions that could be used to block herpesvirus infections.

Hematopoietic stem cells and betaherpesvirus latency.

The human betaherpesviruses including human cytomegalovirus (HCMV), human herpesvirus (HHV)-6a and HHV-6b, and HHV-7 infect and establish latency in CD34+ hematopoietic stem and progenitor cells (HPCs). The diverse repertoire of HPCs in humans and the complex interactions between these viruses and host HPCs regulate the viral lifecycle, including latency. Precise manipulation of host and viral factors contribute to preferential maintenance of the viral genome, increased host cell survival, and specific manipulation of the cellular environment including suppression of neighboring cells and immune control. The dynamic control of these processes by the virus regulate inter- and intra-host signals critical to the establishment of chronic infection. Regulation occurs through direct viral protein interactions and cellular signaling, miRNA regulation, and viral mimics of cellular receptors and ligands, all leading to control of cell proliferation, survival, and differentiation. Hematopoietic stem cells have unique biological properties and the tandem control of virus and host make this a unique environment for chronic herpesvirus infection in the bone marrow. This review highlights the elegant complexities of the betaherpesvirus latency and HPC virus-host interactions.

Meningitis associated with HHV-7 in an Iranian immunocompetent adolescent girl.

There is limited literature regarding meningitis associated with HHV-7. This article reports an immunocompetent adolescent girl who developed fever, headache, and meningism which CSF molecular analysis with PCR was positive only for HHV-7. Interestingly, persistent cavum septum pellucidum and cavum vergae were observed on brain magnetic resonance imaging. The patient received antibiotics, dexamethasone, and acyclovir and then she gained full recovery. HHV-7 is a rare and yet possible pathogen in patients with meningitis, and this is the first described case report from Iran.

Syndrome of Transient Headache and Neurologic Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): HHV-7 Finding in Cerebrospinal Fluid Challenges Diagnostic Criteria.

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a rare, self-limiting condition with severe headaches combined with neurological symptoms. However, evidence-based recommendations on diagnostics and treatments are unavailable due to the condition's rarity and unknown pathophysiology. A young man experiencing severe headache attacks fulfilled the HaNDL diagnostic criteria according to the third edition of the International Classification of Headache Disorders (ICHD-3). We present the dynamics of cerebrospinal fluid (CSF) biomarkers related to low human herpesvirus 7 (HHV-7) load and anti-inflammatory treatment outcomes. Low HHV-7 load may be an immunological trigger of HaNDL, such that elevated levels of CSF- chemokine (C-X-C motif) ligand 13 open a new way to interpret the role of B cells in HaNDL pathogenesis. We discuss the diagnostic challenge of HaNDL, according to the ICHD-3, in the case of pathogen presence at low load in CSF.

Frequency evaluation and molecular characterization of HHV-6 and HHV-7 among children under 5 years with fever and skin rash.

Skin rash is one of the most common complications during childhood. Viral agents play an essential role in the development of such symptoms. Present study aims to determine the prevalence and genetic variability of Human Herpesvirus 6 and 7 (HHV-6 and HHV-7) infections and their subtypes in children under 5 years of age with skin rash and negative for rubella and measles. We used serum and throat swap samples from 196 children with skin rash and fever. ELISA and IFA tests were performed to detect antibodies against HHV6/7. Sequencing was performed using Sanger sequencing, and BioEdit and MEGA10 software were used for sequence analysis. According to the results, 66% and 40% of cases were positive for HHV-6 IgM and HHV-7 IgM, respectively. According to the molecular analysis, HHV-6 Nested-PCR was positive in 18% of cases, however, HHV-7 Nested-PCR was positive in 7.7% of cases. On the other hand, HHV-6 IgG and HHV-7 IgG were positive in 91% and 55% of study cases, respectively. For HHV-6, we found some genetic variabilities resulting in antigenic changes compared to reference strains. HHV-7 isolates showed no genetic differentiation and had a stable gene sequence. Based on the results, the detection of some cases of HHV6/7 primary infection and the presence of specific symptoms of roseola in the study population needs continuous evaluation of HHV6/7 frequency and distribution, also genetic variabilities of HHV6. This can pave the way for investigating HHV6 immune evasion and vaccine research and studying the relationship between viral genetic variations and other factors like disease severity. Furthermore, it is necessary to determine the relation between HHV6 genetic changes and latent infection to be considered in possible future vaccines and antiviral drug development.

The persistent viral infections in the development and severity of myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disease with an unexplained aetiology in which viral infections are possible trigger factors. The aim of this study was to determine the involvement of human herpesvirus (HHV)-6A/B, HHV-7, and parvovirus B19 (B19V) in the etiopathogenesis of ME/CFS. METHODS: 200 patients with clinically diagnosed ME/CFS and 150 apparently healthy individuals were enrolled in this study. Single-round, nested, and quantitative real-time polymerase chain reactions (PCR) were used to detect the presence and load of HHV-6A/B, HHV-7, and B19V. HHV-6A and HHV-6B were distinguished by PCR and restriction analysis. Immunoenzymatic assays were applied to estimate the presence of virus-specific antibodies and the level of cytokines. RESULTS: HHV-6A/B, HHV-7, and B19V specific antibodies were detected among patients and healthy individuals in 92.1% and 76.7%, 84.6% and 93.8%, and 78% and 67.4% of cases. HHV-6B had 99% of HHV-6 positive patients. Latent HHV-6A/B, HHV-7, and B19V infection/co-infection was observed in 51.5% of the patients and 76.7% of the healthy individuals, whereas active-45% of the ME/CFS patients and 8.7% of healthy individuals. HHV-6A/B load in patients with a persistent infection/co-infection in a latent and active phase was 262 and 653.2 copies/106 cells, whereas HHV-7 load was 166.5 and 248.5 copies/106 cells, and B19V-96.8 and 250.8 copies/106 cells, respectively. ME/CFS patients with persistent infection in an active phase had a higher level of pro-inflammatory cytokines (interleukin(IL)-6, tumor necrosis factor-alpha(TNF-α) and IL-12) and anti-inflammatory (IL-10) than with a persistent infection in a latent phase. A significant difference was revealed in the levels of TNF-α, IL-12, and IL-10 among the patient groups without infection, with latent infection/co-infection, active single, double and triple co-infection. The levels of TNF-α, IL-12, and IL-10 are significantly higher in patients with severe compared with a moderate course of ME/CFS. CONCLUSIONS: Significantly more persistent HHV-6A/B, HHV-7, and B19V infection/co-infection in an active phase with a higher viral load and elevated levels of pro- and anti-inflammatory cytokines among patients with ME/CFS than healthy individuals indicate the importance of these infections/co-infections in ME/CFS development. The presence of these infections/co-infections influences the ME/CFS clinical course severity.

Characterization of the HHV-6B U20 Immunoevasin.

Roseoloviruses (human herpesvirus 6A [HHV-6A], -6B, and -7) infect >90% of the human population during early childhood and are thought to remain latent or persistent throughout the life of the host. As such, these viruses are among the most pervasive and stealthy of all viruses; they must necessarily excel at escaping immune detection throughout the life of the host, and yet, very little is known about how these viruses so successfully escape host defenses. Here, we characterize the expression, trafficking, and posttranslational modifications of the HHV6B U20 gene product, which is encoded within a block of genes unique to the roseoloviruses. HHV-6B U20 trafficked slowly through the secretory system, receiving several posttranslational modifications to its N-linked glycans, indicative of surface-expressed glycoproteins, and eventually reaching the cell surface before being internalized. Interestingly, U20 is also phosphorylated on at least one Ser, Thr, or Tyr residue. These results provide a framework to understand the role(s) of U20 in evading host defenses. IMPORTANCE The roseolovirus U20 proteins are virus-encoded integral membrane glycoproteins possessing class I major histocompatibility complex (MHC)-like folds. Surprisingly, although U20 proteins from HHV-6A and -6B share 92% identity, recent studies ascribe different functions to HHV6A U20 and HHV6B U20. HHV6A U20 was shown to downregulate NKG2D ligands, while HHV6B U20 was shown to inhibit tumor necrosis factor alpha (TNF-α)-induced apoptosis during nonproductive infection with HHV6B (E. Kofod-Olsen, K. Ross-Hansen, M. H. Schleimann, D. K. Jensen, et al., J Virol 86:11483-11492, 2012, https://doi.org/10.1128/jvi.00847-12; A. E. Chaouat, B. Seliger, O. Mandelboim, D. Schmiedel, Front Immunol 12:714799, 2021, https://doi.org/10.3389/fimmu.2021.714799). Here, we have performed cell biological and biochemical characterization of the trafficking, glycosylation, and posttranslational modifications occurring on HHV6B U20.

Human herpesvirus 7 encephalitis in an immunocompetent adult and a literature review.

BACKGROUND: Human herpesvirus 7 (HHV-7) is a common virus that infects children early and is accompanied by lifelong latency in cells, which is easy to reactivate in immunodeficient adults, but the underlying pathological mechanism is uncertain in immunocompetent adults without peculiar past medical history. Even though the clinical manifestation of the encephalitis caused by HHV-7 is uncommon in immunocompetent adults, the HHV-7 infection should not be neglected for encephalitis for unknown reasons. CASE PRESENTATION: We reported here a case of HHV-7 encephalitis with epileptic seizures. While the brain computer tomography was standard, electroencephalography displayed slow waves in the temporal and bilateral frontal areas, then HHV-7 DNA was detected in the metagenomic next-generation sequencing of cerebrospinal fluid. Fortunately, the patient recovered after treatment and was discharged 2 months later. We also collected the related cases and explored a better way to illuminate the underlying mechanism. CONCLUSION: The case indicates clinicians should memorize HHV-7 as an unusual etiology of encephalitis to make an early diagnosis and therapy.

Development of a PCR assay for the detection of human herpes virus type 7.

A PCR assay has been developed to identify the DNA of the human herpes virus type 7. The search and selection of conserved regions was carried out by comparing the whole genome nucleotide sequences of HHV-7. A fragment duplicated in the HHV-7 genomes was chosen as a target for amplification. The performance of the assay was tested on a synthetic matrix and clinical samples. The developed assay has high sensitivity and specificity and showed good efficiency in detecting HHV-7 DNA in clinical samples.