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The present book presents a comprehensive review of Human Herpesvirus-6 (HHV-6) infects up to 90% of the world's population and can cause potentially life-threatening diseases. Clinicians typically do not search for HHV-6, and if they do, they will find only few laboratories providing the necessary diagnostic tests that can differentiate between active and latent infection. Adding to this problem is that scientists still disagree about whether serological or molecular assays will be the best diagnostic test, yet there is no disagreement about the inadequacy of many of the currently existing assays. Consequently, our knowledge of etiology and pathogenesis of HHV-6 associated diseases can only come from the combined efforts of clinicians, virologists, molecular biologists and pathologists. It is the prime task of this book to summarize the status quo of HHV-6 research and to further stimulate such a collaboration. It will be a valuable reference for both clinical and basic scientists including epidemiologists, virologists, practicing clinicians and infectiologists, pathologists and essentially all scientists entering the field of herpes virus research.

Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer's disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid-β protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1β and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.

The sensor RIG-I detects double-stranded RNA derived from RNA viruses. Although RIG-I is also known to have a role in the antiviral response to DNA viruses, physiological RNA species recognized by RIG-I during infection with a DNA virus are largely unknown. Using next-generation RNA sequencing (RNAseq), we found that host-derived RNAs, most prominently 5S ribosomal RNA pseudogene 141 ( RNA5SP141 ), bound to RIG-I during infection with herpes simplex virus 1 (HSV-1). Infection with HSV-1 induced relocalization of RNA5SP141 from the nucleus to the cytoplasm, and virus-induced shutoff of host protein synthesis downregulated the abundance of RNA5SP141 -interacting proteins, which allowed RNA5SP141 to bind RIG-I and induce the expression of type I interferons. Silencing of RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related virus Epstein-Barr virus (EBV), as well as influenza A virus (IAV). Our findings reveal that antiviral immunity can be triggered by host RNAs that are unshielded following depletion of their respective binding proteins by the virus. RIG-I is a cytosolic RNA sensor. Gack and colleagues show that herpesviruses, duplex DNA viruses, also activate RIG-I by inducing cytoplasmic translocation and unmasking of an endogenous host 5S ribosomal pseudogene RNA, RNA5SP141 .

Viral reactivation occurs frequently in the context of immunodeficiency and immunosuppression after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and can cause severe complications. The aim of this single-center retrospective analysis was to characterize viral infections in the first year after HSCT, to investigate risk factors and to study the impact of viral infections on transplantation outcome. This will facilitate the identification of at-risk patients and the development of new preventive strategies. 107 pediatric allo-HSCT from January 2005 through December 2015 were analyzed for infections with Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), adenovirus (ADV), herpes simplex virus (HSV) and varicella zoster virus (VZV). Viral infections were detected after 68.2% of transplantations. The viruses most commonly encountered were HHV-6 (36/107) and EBV (30/107). Severe viral disease was rare (7/107) and none of the patients died as result of viral reactivation. Important risk factors for viral infections were higher age at HSCT, donor type and occurrence of acute graft-versus-host disease (aGvHD). Especially for EBV, transplant from an unrelated donor and in-vivo T-cell depletion (TCD) had a significant effect on infection rates, whereas for CMV the strongest effect was seen by donor and recipient serostatus with recipient seropositivity most predictive for reactivation. The occurrence of severe aGvHD was associated with EBV and ADV infections. For HSV, the recipient serostatus was identified as prognostic factor for HSV infections, while we found higher age at time of HSCT as risk factor for VZV infections. The overall survival of patients with or without viral infections did not differ significantly. Interestingly, when looking at the 85 patients in our cohort who had received an HSCT for a malignant disease, a tendency towards lower relapse rates was seen in patients affected by viral infections (HR 0.51, 95% CI 0.25 - 1.06, p = 0.072). Viral reactivations are common after pediatric allo-HSCT, though severe complications were rare in our collective. Determining risk factors for viral reactivations may help to identify patients in need of intensified monitoring and to individualize preventive strategies.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with the development of cancer and multiple sclerosis. Unlike other viral families, gammaherpesviruses selectively target B cells to establish chronic infection. Specifically, gammaherpesvirus-driven differentiation of latently infected cells through the germinal center supports chronic infection and seeds viral lymphomagenesis. CD11c B cells are induced by most viral infections and are also observed in aged individuals and autoimmune diseases. Classically, CD11c B cells differentiate via an extrafollicular pathway that does not involve germinal center response, generating antibodies of beneficial (antiviral) or pathogenic (self-reactive) nature. While CD11c B cells are induced during B cell-tropic gammaherpesvirus infection, their role in chronic infection remains poorly defined. Here, we demonstrate that infection of the CD11c B cells, including those expressing germinal center markers, contributes to the overall latent gammaherpesvirus reservoir during natural infection. Both T-bet and T-bet CD11c B cell subsets expanded and underwent germinal center differentiation during chronic gammaherpesvirus infection. Furthermore, B cell-intrinsic T-bet expression attenuated the long-term latent viral reservoir, gammaherpesvirus-driven germinal center responses, and differentiation of self-reactive B cells. In summary, our study for the first time defines CD11c splenic B cells as a reservoir of latent gammaherpesvirus during mucosal chronic infection and reveals an important role of T-bet B cells in controlling long-term infection and gammaherpesvirus-driven pathogenic host processes.IMPORTANCEGammaherpesviruses are ubiquitous pathogens that are associated with cancer and multiple sclerosis. These viruses selectively infect B cells and drive their differentiation through the germinal center response to establish chronic infection. Here, we demonstrate that gammaherpesvirus infection drives expansion and germinal center-based differentiation of CD11c B cells that host the latent viral reservoir. We also show that B-cell-intrinsic T-bet expression is important for control of long-term gammaherpesvirus infection and pathogenesis.

Assessing the epidemiological association between herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections in the United States, and characterizing the trends in the standardized HSV-1 and HSV-2 antibody prevalences (seroprevalences), 1999-2016. Source of data was the cross-sectional and nationally-representative biennial surveys of the National Health and Nutrition Examination Survey (NHANES). All nine NHANES rounds for 1999-2016 were included in analysis. Datasets of these rounds were combined and analyzed accounting for survey design and applying weighting procedures. Logistic regressions were used to identify associations with seropositivity. Sensitivity analyses were conducted. Odds of HSV-1 infection declined by 2.84% (95% CI: 1.70%-4.00%) annually among men, and by 2.22% (95% CI: 1.23%-3.21%) among women. Declines were highest at younger ages. Odds of HSV-2 infection declined by 2.23% (95% CI: 0.71%-3.82%) annually among men, and by 2.89% (95% CI: 1.57%-4.28%) among women. Odds ratio of the association between HSV-2 and HSV-1 seropositivity was 0.71 (95% CI: 0.60-0.84) for men and 0.81 (95% CI: 0.72-0.91) for women, after adjustment for age, ethnicity, and year. HSV-1 and HSV-2 seroprevalences showed a strong declining trend for at least two decades, for both sexes and for the different ethnicities, possibly reflecting improvements in hygiene and living conditions (for HSV-1), and safer sexual behavior (for HSV-2). HSV-1 seroprevalence declines are most pronounced among young individuals. There is evidence for cross protection between the two infections, suggestive of HSV-1 seropositivity being partially protective against HSV-2 infection.

Viral fusogens merge viral and cell membranes during cell penetration. Their ectodomains drive fusion by undergoing large-scale refolding, but little is known about the functionally important regions located within or near the membrane. Here we report the crystal structure of full-length glycoprotein B (gB), the fusogen from herpes simplex virus, complemented by electron spin resonance measurements. The membrane-proximal (MPR), transmembrane (TMD), and cytoplasmic (CTD) domains form a uniquely folded trimeric pedestal beneath the ectodomain, which balances dynamic flexibility with extensive, stabilizing membrane interactions. The postfusion conformation of the ectodomain suggests that the CTD likewise adopted the postfusion form. However, hyperfusogenic mutations, which destabilize the prefusion state of gB, target key interfaces and structural motifs that reinforce the observed CTD structure. Thus, a similar CTD structure must stabilize gB in its prefusion state. Our data suggest a model for how this dynamic, membrane-dependent ‘clamp’ controls the fusogenic refolding of gB.

Gillet and colleagues find that infection with a gammaherpesvirus confers strong and lasting protection against airway allergy through the replacement of lung-resident alveolar macrophages with recruited regulatory monocytes of bone marrow origin. The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the T H 2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.

Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are ubiquitous betaherpesviruses that infects humans within the first years of life and establishes latency in various cell types. Both viruses can integrate their genomes into telomeres of host chromosomes in latently infected cells. The molecular mechanism of viral integration remains elusive. Intriguingly, HHV-6A, HHV-6B and several other herpesviruses harbor arrays of telomeric repeats (TMR) identical to human telomere sequences at the ends of their genomes. The HHV-6A and HHV-6B genomes harbor two TMR arrays, the perfect TMR (pTMR) and the imperfect TMR (impTMR). To determine if the TMR are involved in virus integration, we deleted both pTMR and impTMR in the HHV-6A genome. Upon reconstitution, the TMR mutant virus replicated comparable to wild type (wt) virus, indicating that the TMR are not essential for HHV-6A replication. To assess the integration properties of the recombinant viruses, we established an in vitro integration system that allows assessment of integration efficiency and genome maintenance in latently infected cells. Integration of HHV-6A was severely impaired in the absence of the TMR and the virus genome was lost rapidly, suggesting that integration is crucial for the maintenance of the virus genome. Individual deletion of the pTMR and impTMR revealed that the pTMR play the major role in HHV-6A integration, whereas the impTMR only make a minor contribution, allowing us to establish a model for HHV-6A integration. Taken together, our data shows that the HHV-6A TMR are dispensable for virus replication, but are crucial for integration and maintenance of the virus genome in latently infected cells.

Herpes simplex virus (HSV) is a prevalent and persistent human pathogen belonging to the family Herpesviridae and classified as an alpha-herpesvirus. It comprises two distinct types, HSV-1 and HSV-2, which together infect a significant portion of the global population and pose substantial public health challenges. HSV-1 is typically associated with oral herpes, while HSV-2 primarily causes genital herpes; both are characterized by recurrent lesions, latent infection, and mucocutaneous discomfort. Conventional antiviral drugs such as acyclovir and its derivatives are limited by drug resistance, potential toxicity, and their inability to eradicate latent viral reservoirs. These limitations have prompted increasing interest in alternative therapeutic strategies. Phenolic acids and tannins, plant-derived polyphenolic compounds, have attracted considerable attention due to their potent antiviral properties against various viruses, including HSV. This review summarizes current research on phenolic acids and tannins as promising natural antivirals against HSV, with a focus on their mechanisms of action and efficacy in disrupting multiple stages of the HSV life cycle.