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Herpes zoster, caused by the reactivation of varicella-zoster virus, typically presents with a unilateral, dermatomal rash. This case report describes a presentation of oral herpes zoster in a 64-year-old female patient. The patient presented with painful mouth ulcers confined to the right half of the posterior two-thirds of the hard palate, not crossing the midline. The diagnosis was based on clinical presentation, and treatment included systemic oral acyclovir and pain management with paracetamol. The patient showed substantial improvement with complete healing of the ulcers. This case highlights the importance of recognizing various presentations of herpes zoster, particularly in the oral cavity. It emphasizes the effectiveness of prompt antiviral therapy and appropriate pain management in treating oral herpes zoster. The report also underscores the potential role of risk factors such as advanced age and chronic conditions in herpes zoster susceptibility. This case contributes to the literature on oral manifestations of herpes zoster and stresses the need for clinical vigilance in diagnosing and managing such cases. Keywords: herpes zoster, varicella-zoster virus, oral lesion, unilateral lesion, clinical diagnosis, acyclovir treatment, antiviral therapy

Background Herpes simplex virus type 1 (HSV-1) is a prevalent lifelong infection that appears to be undergoing an epidemiologic transition in the United States (US). Using an analytical approach, this study aimed to characterize HSV-1 transitioning epidemiology and estimate its epidemiologic indicators, past, present, and future. Methods An age-structured mathematical model was developed to describe HSV-1 transmission through oral and sexual modes of transmission. The model was fitted to the National Health and Nutrition Examination Surveys, 1976–2016 data series. Results HSV-1 seroprevalence was projected to decline from 61.5% in 1970 to 54.8% in 2018, 48.5% in 2050, and 42.0% in 2100. In < 3 decades, seroprevalence declined by > 30% for those aged 0–19 years, but < 5% for those aged > 60. Meanwhile, the number of new infections per year (oral and genital) was persistent at 2,762,000 in 1970, 2,941,000 in 2018, 2,933,000 in 2050, and 2,960,000 in 2100. Of this total, genital acquisitions contributed 252,000 infections in 1970, 410,000 in 2018, 478,000 in 2050, and 440,000 in 2100—a quarter of which are symptomatic with clinical manifestations. For those aged 15–49 years, nearly 25% of incident infections are genital. Most genital acquisitions (> 85%) were due to oral-to-genital transmission through oral sex, as opposed to genital-to-genital transmission through sexual intercourse. Conclusion HSV-1 epidemiology is undergoing a remarkable transition in the US, with less exposure in childhood and more in adulthood, and less oral but more genital acquisition. HSV-1 will persist as a widely prevalent infection, with ever-increasing genital disease burden.

Viral infection is usually studied at the population level by averaging over millions of cells. However, infection at the single-cell level is highly heterogeneous, with most infected cells giving rise to no or few viral progeny while some cells produce thousands. Analysis of Herpes Simplex virus 1 (HSV-1) infection by population-averaged measurements has taught us a lot about the course of viral infection, but has also produced contradictory results, such as the concurrent activation and inhibition of type I interferon signaling during infection. Here, we combine live-cell imaging and single-cell RNA sequencing to characterize viral and host transcriptional heterogeneity during HSV-1 infection of primary human cells. We find extreme variability in the level of viral gene expression among individually infected cells and show that these cells cluster into transcriptionally distinct sub-populations. We find that anti-viral signaling is initiated in a rare group of abortively infected cells, while highly infected cells undergo cellular reprogramming to an embryonic-like transcriptional state. This reprogramming involves the recruitment of β-catenin to the host nucleus and viral replication compartments, and is required for late viral gene expression and progeny production. These findings uncover the transcriptional differences in cells with variable infection outcomes and shed new light on the manipulation of host pathways by HSV-1. Herpes simplex virus 1, or HSV-1, is a virus that infects most of the human population. In many people, the virus stays dormant in nerve cells, but in some individuals, it can ‘wake up’ regularly and cause painful facial lesions known as cold sores. In very few cases, the virus can enter the brain and become life threatening. When HSV-1 encounters a human cell, there are three possible outcomes. The virus can either enter the cell and then replicate uncontrollably, get inside the cell but not multiply, or fail to enter the cell altogether. However, during experiments, researchers do not usually look at individual cells but instead consider whole populations. This makes it hard to understand the exact mechanisms that contribute to a cell resisting or succumbing to the virus. New approaches are now making it possible to study individual cells over time. Here, Drayman et al. harnessed these methods to understand how individual human cells respond to HSV-1. The experiments show that most cells are actually able to resist the infection. Amongst those, a small fraction managed to stop the virus replicating by initiating a built-in ‘antivirus program’. However, a minority of cells did become highly infected, shutting down the signaling process that fends off the virus. In these cells a different set of genes were switched on, making them more similar to the cells found in embryos. In the process, the virus recruited a protein called β-catenin to help with its multiplication. There are efforts to develop drugs to interfere with β-catenin, as this protein is also produced differently in people with cancer. Such drugs, if identified and safe in humans, could potentially serve to treat HSV-1 infections.

Background Oncolytic viruses preferentially replicate in tumors as compared to normal tissue and promote immunogenic cell death and induction of host systemic anti-tumor immunity. HSV-1 was chosen for further development as an oncolytic immunotherapy in this study as it is highly lytic, infects human tumor cells broadly, kills mainly by necrosis and is a potent activator of both innate and adaptive immunity. HSV-1 also has a large capacity for the insertion of additional, potentially therapeutic, exogenous genes. Finally, HSV-1 has a proven safety and efficacy profile in patients with cancer, talimogene laherparepvec (T-VEC), an oncolytic HSV-1 which expresses GM-CSF, being the only oncolytic immunotherapy approach that has received FDA approval. As the clinical efficacy of oncolytic immunotherapy has been shown to be further enhanced by combination with immune checkpoint inhibitors, developing improved oncolytic platforms which can synergize with other existing immunotherapies is a high priority. In this study we sought to further optimize HSV-1 based oncolytic immunotherapy through multiple approaches to maximize: (i) the extent of tumor cell killing, augmenting the release of tumor antigens and danger-associated molecular pattern (DAMP) factors; (ii) the immunogenicity of tumor cell death; and (iii) the resulting systemic anti-tumor immune response. Methods To sample the wide diversity amongst clinical strains of HSV-1, twenty nine new clinical strains isolated from cold sores from otherwise healthy volunteers were screened across a panel of human tumor cell lines to identify the strain with the most potent tumor cell killing ability, which was then used for further development. Following deletion of the genes encoding ICP34.5 and ICP47 to provide tumor selectivity, the extent of cell killing and the immunogenicity of cell death was enhanced through insertion of a gene encoding a truncated, constitutively highly fusogenic form of the envelope glycoprotein of gibbon ape leukemia virus (GALV-GP-R − ). A number of further armed derivatives of this virus were then constructed intended to further enhance the anti-tumor immune response which was generated following fusion-enhanced, oncolytic virus replication-mediated cell death. These viruses expressed GMCSF, an anti-CTLA-4 antibody-like molecule, CD40L, OX40L and/or 4-1BB, each of which is expected to act predominantly at the site and time of immune response initiation. Expression of these proteins was confirmed by ELISA and/or western blotting. Immunogenic cell death was assessed by measuring the levels of HMGB1 and ATP from cell free supernatants from treated cells, and by measuring the surface expression of calreticulin. GALV-GP-R − mediated cell to cell fusion and killing was tested in a range of tumor cell lines in vitro. Finally, the in vivo therapeutic potential of these viruses was tested using human A549 (lung cancer) and MDA-MB-231(breast cancer) tumor nude mouse xenograft models and systemic anti-tumor effects tested using dual flank syngeneic 4434 (melanoma), A20 (lymphoma) mouse tumor models alone and in combination with a murine anti-PD1 antibody, and 9 L (gliosarcoma) tumors in rats. Results The twenty nine clinical strains of HSV-1 isolated and tested demonstrated a broad range of tumor cell killing abilities allowing the most potent strain to be identified which was then used for further development. Oncolytic ability was demonstrated to be further augmented by the expression of GALV-GP-R − in a range of tumor cell lines in vitro and in mouse xenograft models in nude mice. The expression of GALV-GP-R − was also demonstrated to lead to enhanced immunogenic cell death in vitro as confirmed by the increased release of HMGB1 and ATP and increased levels of calreticulin on the cell surface. Experiments using the rat 9 L syngeneic tumor model demonstrated that GALV-GP-R − expression increased abscopal uninjected (anenestic) tumor responses and data using mouse 4434 tumors demonstrated that virus treatment increased CD8+ T cell levels both in the injected and uninjected tumor, and also led to increased expression of PD-L1. A combination study using varying doses of a virus expressing GALV-GP-R − and mGM-CSF and an anti-murine PD1 antibody showed enhanced anti-tumor effects with the combination which was most evident at low virus doses, and also lead to immunological memory. Finally, treatment of mice with derivatives of this virus which additionally expressed anti-mCTLA-4, mCD40L, m4-1BBL, or mOX40L demonstrated enhanced activity, particularly in uninjected tumors. Conclusion The new HSV-1 based platform described provides a potent and versatile approach to developing new oncolytic immunotherapies for clinical use. Each of the modifications employed was demonstrated to aid in optimizing the potential of the virus to both directly kill tumors and to lead to systemic therapeutic benefit. For clinical use, these viruses are expected to be most effective in combination with other anti-cancer agents, in particular PD1/L1-targeted immune checkpoint blockade. The first virus from this program (expressing GALV-GP-R − and hGM-CSF) has entered clinical development alone and in combination with anti-PD1 therapy in a number of tumor types (NCT03767348).

About the Authors: Oren Kobiler * E-mail: okobiler@tauex.tau.ac.il Affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel ORCID logo http://orcid.org/0000-0001-9914-3770 Matthew D. Weitzman Affiliations Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, Division of Protective Immunity, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America ORCID logo http://orcid.org/0000-0001-9713-167X Introduction Amplification of viral genomes is key to successful infection and spread. Herpesviruses are considered ancient viruses that have coevolved with their hosts for a long time, generating complex virus–host interactions [1]. Because HSV replicates in the nucleus, interactions at sites of viral replication determine outcomes of infection, and interactions between viral genomes and the complex nuclear environment contribute to efficient infection. Because intergenomic recombination is a common phenomenon during HSV-1 coinfection and considered a major driving force of evolution in these viruses [27], the limited mixing of DNA raises questions about where recombination occurs. Viral research has provided insights into many fundamental host mechanisms. Because viral replication is a rapid event that dramatically alters nuclear architecture, understanding mechanisms involved in RC formation, maintenance, and interactions will shed further light on structural processes and regulation within the mammalian nucleus.

Cold sores are nasolabial blisters caused by herpes simplex virus (HSV) infections. Novel therapies demonstrating simultaneously antiviral activity and improved wound healing are warranted. The aim of this study was to investigate the efficacy of medical-grade honey (MGH) for treating HSV-induced cold sores. A crossover trial was performed in patients with recurrent cold sores (n = 29). The majority (65.6%) of these patients experience four or more episodes per year, thus forming a valid self-control group. In this study, patients applied an MGH-based formulation (L-Mesitran Soft) on their cold sore at the onset of symptoms (62.1%) or appearing of blister (37.9%) and compared it to their conventional treatments. After complete healing, patients filled in a questionnaire evaluating healing, pain, and itching. The average absolute healing time was 72.4% slower with conventional treatment (10.0 days) compared to MGH (5.8 days). After MGH treatment, 86.2% of all patients experienced faster objective healing (6.9% similar and 6.9% slower) and the subjective healing score was higher in 79.3% of the patients (20.7% similar). If the patients normally experience pain and itching during their cold sores, these levels were lower with MGH therapy compared to conventional treatment in 72.7% and 71.4% of the patients, respectively. Moreover, 100% of the patients prefer MGH treatment over conventional treatment and will use it again on future cold sores. MGH is a promising alternative treatment for cold sores, likely by combining both increased antiviral and wound healing activities while alleviating pain and itching.

Background Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its immunosuppressive tumor microenvironment (TME). Oncolytic herpes simplex virus type 1 (oHSV1) offers dual mechanisms of tumor lysis and immune activation, yet the optimal cytokine payloads for TNBC remain undefined. Methods We developed a CRISPR/Cas9-mediated platform for high-efficiency oHSV1 engineering, replacing the ICP47 locus with murine IFN-γ, GM-CSF, or IL-15Rα/IL-15 fusion protein (IL15Fu). Constructs were validated for cytokine secretion, MHC modulation, and cytotoxicity in 4T1 TNBC and a panel of human cancer cell lines. Antitumor efficacy and immune remodeling were evaluated in a syngeneic 4T1 model using RNA sequencing and flow cytometry. Results The CRISPR platform achieved 62.5–71.4% homologous recombination efficiency, enabling rapid virus construction. In vitro, OV-IFNG exhibited upregulated MHC I/II expression and potent cytotoxicity, while OV-GMCSF attenuated oncolysis in subsets of breast cancer cell lines. In the 4T1 model, OV-IL15Fu modestly improved tumor control and extended survival without apparent toxicity, while OV-IFNG induced early mortality associated with systemic toxicity. Transcriptomic profiling revealed divergent immune modulation: OV-IL15Fu enriched T cell/NK cytotoxicity pathways, OV-IFNG amplified cytokine/chemokine signaling, and OV-GMCSF paradoxically enhanced myeloid recruitment while inhibiting MHC-II pathways. Flow cytometry confirmed functional differences in immune activation: OV-IL15Fu expanding cytotoxic lymphocytes (CD8⁺ T/NK cells), OV-IFNG preferentially promote Th1 polarization and innate immune activation, and OV-GMCSF failed to activate T cells despite myeloid infiltration. Conclusions Our findings underscore the need for rational cytokine selection in oHSV1-based immunotherapy. While IFN-γ increased immunogenic markers, its systemic toxicity and myeloid effects may limit benefit. GM-CSF exacerbated immune suppression in this context, whereas IL15Fu showed favorable immunostimulatory properties without detectable toxicity. These data support IL15Fu as a contextually promising payload for further evaluation in TNBC-targeted oncolytic virotherapy.

Orolabial herpes simplex virus type 1 (HSV-1) infection has a wide spectrum of severity in immunocompetent persons. To study the role of viral genotype and host immunity, we characterized oral HSV-1 shedding rates and host cellular response, and genotyped viral strains, in monozygotic (MZ) and dizygotic (DZ) twins. A total of 29 MZ and 22 DZ HSV-1-seropositive twin pairs were evaluated for oral HSV-1 shedding for 60 days. HSV-1 strains from twins were genotyped as identical or different. CD4+ T-cell responses to HSV-1 proteins were studied. The median per person oral HSV shedding rate was 9% of days that a swab was obtained (mean, 10.2% of days). A positive correlation between shedding rates was observed within all twin pairs, and in the MZ and DZ twins. In twin subsets with sufficient HSV-1 DNA to genotype, 15 had the same strain and 14 had different strains. Viral shedding rates were correlated for those with the same but not different strains. The median number of HSV-1 open reading frames recognized per person was 16. The agreement in the CD4+ T-cell response to specific HSV-1 open reading frames was greater between MZ twins than between unrelated persons (P = .002). Viral strain characteristics likely contribute to oral HSV-1 shedding rates.

Herpes zoster, caused by the reactivation of varicella-zoster virus, typically presents with a unilateral, dermatomal rash. This case report describes a presentation of oral herpes zoster in a 64-year-old female patient. The patient presented with painful mouth ulcers confined to the right half of the posterior two-thirds of the hard palate, not crossing the midline. The diagnosis was based on clinical presentation, and treatment included systemic oral acyclovir and pain management with paracetamol. The patient showed substantial improvement with complete healing of the ulcers. This case highlights the importance of recognizing various presentations of herpes zoster, particularly in the oral cavity. It emphasizes the effectiveness of prompt antiviral therapy and appropriate pain management in treating oral herpes zoster. The report also underscores the potential role of risk factors such as advanced age and chronic conditions in herpes zoster susceptibility. This case contributes to the literature on oral manifestations of herpes zoster and stresses the need for clinical vigilance in diagnosing and managing such cases.

Herpes simplex virus type 1 (HSV-1) is a lifelong pathogen characterized by asymptomatic latent infection in the trigeminal ganglia (TG), with periodic outbreaks of cold sores caused by virus reactivation in the TG and subsequent replication in the oral mucosa. While antiviral therapies can provide relief from cold sores, they are unable to eliminate HSV-1. We provide experimental results that highlight non-thermal plasma (NTP) as a new alternative therapy for HSV-1 infection that would resolve cold sores faster and reduce the establishment of latent infection in the TG. Additionally, this study is the first to explore the use of NTP as a therapy that can both treat and prevent human viral infections. The antiviral effect of NTP was investigated using an in vitro model of HSV-1 epithelial infection that involved the application of NTP from two separate devices to cell-free HSV-1, HSV-1-infected cells, and uninfected cells. It was found that NTP reduced the infectivity of cell-free HSV-1, reduced viral replication in HSV-1-infected cells, and diminished the susceptibility of uninfected cells to HSV-1 infection. This triad of antiviral mechanisms of action suggests the potential of NTP as a therapeutic agent effective against HSV-1 infection.