Short-form thymic stromal lymphopoietin (sfTSLP) restricts herpes simplex virus infection of human primary keratinocytes.

Eczema herpeticum (EH) is a disseminated severe herpes simplex virus type 1 (HSV-1) infection that mainly occurs in a subset of patients suffering from atopic dermatitis (AD). EH is complex and multifaceted, involving immunological changes, environmental influences, and genetic aberrations. Certain genetic variants of the thymic stromal lymphopoietin (TSLP) may predispose to develop severe HSV-1-induced eczema. Therefore, we investigated the impact of TSLP on HSV-1 infection. TSLP encodes for two distinct forms: a long-form (lfTSLP), primarily associated with type 2 immunity, and a short-form (sfTSLP) with anti-inflammatory and antimicrobial properties. While sfTSLP reduced HSV-1 infectibility in human primary keratinocytes (HPK), lfTSLP did not. In HPK treated with sfTSLP, HSV-1 gene expression, and replication decreased, while virion binding to cells and targeting of incoming capsids to the nucleus were not diminished compared to untreated cells. sfTSLP caused only minor changes in the expression of innate immunity cytokines, and its inhibition of HSV-1 infection did not require de novo protein synthesis. Time window experiments indicated a different antiviral mechanism than LL-37. sfTSLP showed the strongest antiviral effect when administered to HPK before or after inoculation with HSV-1, and outperformed the inhibitory potential of LL-37 under these conditions. Our data show that sfTSLP has antiviral functions and promotes repression of the HSV-1 infection in HPK.

Recurrent herpes infection showing a new facial phenotype: A case report.

BACKGROUND: Facial herpes is a common form of the herpes simplex virus-1 infection and usually presents as vesicles near the mouth, nose, and periocular sites. In contrast, we observed a new facial symptom of herpes on the entire face without vesicles. CASE SUMMARY: A 33-year-old woman with a history of varicella infection and shingles since an early age presented with sarcoidosis of the entire face and neuralgia without oral lesions. The patient was prescribed antiviral treatment with valacyclovir and acyclovir cream. One day after drug administration, facial skin lesions and neurological pain improved. Herpes simplex without oral blisters can easily be misdiagnosed as pimples upon visual examination in an outpatient clinic. CONCLUSION: As acute herpes simplex is accompanied by neuralgia, prompt diagnosis and prescription are necessary, considering the pathological history and health conditions.

Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis.

INTRODUCTION: Mitophagy, a selective form of autophagy responsible for maintaining mitochondrial homeostasis, regulates the antiviral immune response and acts as viral replication platforms to facilitate infection with various viruses. However, its precise role in herpes simplex virus 1 (HSV-1) infection and herpes simplex encephalitis (HSE) remains largely unknown. OBJECTIVES: We aimed to investigate the regulation of mitophagy by HSV-1 neurotropic infection and its role in viral encephalitis, and to identify small compounds that regulate mitophagy to affect HSV-1 infection. METHODS: The antiviral effects of compounds were investigated by Western blot, RT-PCR and plaque assay. The changes of Parkin (PRKN)-mediated mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation were examined by TEM, RT-qPCR, Western blot and ELISA. The therapeutic effect of taurine or PRKN-overexpression was confirmed in the HSE mouse model by evaluating survival rate, eye damage, neurodegenerative symptoms, immunohistochemistry analysis and histopathology. RESULTS: HSV-1 infection caused the accumulation of damaged mitochondria in neuronal cells and in the brain tissue of HSE mice. Early HSV-1 infection led to mitophagy activation, followed by inhibition in the later viral infection. The HSV-1 proteins ICP34.5 or US11 deregulated the EIF2S1-ATF4 axis to suppress PRKN/Parkin mRNA expression, thereby impeding PRKN-dependent mitophagy. Consequently, inhibition of mitophagy by specific inhibitor midiv-1 promoted HSV-1 infection, whereas mitophagy activation by PRKN overexpression or agonists (CCCP and rotenone) attenuated HSV-1 infection and reduced the NF-κB-mediated neuroinflammation. Moreover, PRKN-overexpressing mice showed enhanced resistance to HSV-1 infection and ameliorated HSE pathogenesis. Furthermore, taurine, a differentially regulated gut microbial metabolite upon HSV-1 infection, acted as a mitophagy activator that transcriptionally promotes PRKN expression to stimulate mitophagy and to limit HSV-1 infection both in vitro and in vivo. CONCLUSION: These results reveal the protective function of mitophagy in HSE pathogenesis and highlight mitophagy activation as a potential antiviral therapeutic strategy for HSV-1-related diseases.

Disparities in burden of herpes simplex virus type 2 in China: systematic review, meta-analyses, and meta-regressions.

Background: The rising prevalence of herpes simplex type 2 (HSV-2) infection poses a growing global public health challenge. A comprehensive understanding of its epidemiology and burden disparities in China is crucial for informing targeted and effective intervention strategies in the future. Methods: We followed Cochrane and PRISMA guidelines for a systematic review and included publications published in Chinese and English bibliographic systems until March 31st, 2024. We synthesized HSV-2 seroprevalence data across different population types. We used random-effects models for meta-analyses and conducted meta-regression to assess the association between population characteristics and seroprevalence. Results: Overall, 23,999 articles were identified, and 402 publications (1,203,362 participants) that reported the overall seroprevalence rates (858 stratified measures) were included. Pooled HSV-2 seroprevalence among the general population (lower risk) was 7.7% (95% CI: 6.8-8.7%). Compared to the general population, there is a higher risk of HSV-2 prevalence among intermediate-risk populations (14.8%, 95% CI: 11.0-19.1%), and key populations (31.7%, 95% CI: 27.4-36.1%). Female sexual workers (FSWs) have the highest HSV-2 risk (ARR:1.69, 95% CI: 1.61-1.78). We found northeastern regions had a higher HSV-2 seroprevalence than other regions (17.0%, 95% CI: 4.3-35.6%, ARR: 1.38, 95% CI: 1.26-1.50, Northern China as the reference group). This highlighted the disparity by population risk levels and regions. We also found lower HSV-2 prevalence estimates in publications in Chinese bibliographic databases than those in English databases among key populations (such as MSM and HIV-discordant populations). Conclusion: There is a gradient increase in HSV-2 prevalence risk stratification. We also identified region, population, and age disparities and heterogeneities by publication language in the HSV-2 burden. This study provides guidance for future HSV-2 prevention to eliminate disparities of HSV-2 infection and reduce overall HSV-2 burden. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=408108, identifier CRD42023408108.

Elevated cerebrospinal fluid IgG index in herpes simplex encephalitis post-HSV-1 clearance: A preliminary study.

Herpes simplex encephalitis (HSE) is an acute form of encephalitis that can lead to poor neurological outcomes. Although the exact pathogenesis of HSE remains elusive, recent reports suggest a significant role for postinfectious immune-inflammatory processes in the central nervous system (CNS). This study aimed to clarify the association between CNS autoimmune responses and clinical presentation in patients with HSE, focusing on cerebrospinal fluid (CSF) characteristics, particularly the IgG index. We retrospectively analyzed 176 consecutive patients suspected of having aseptic meningitis /encephalitis for chronological changes in CSF findings and clinical presentations. These patients underwent PCR screening for herpesviruses (HV) in their CSF. We identified seven patients positive for herpes simplex virus type 1 (HSV-1), 20 patients positive for varicella-zoster virus, and 17 patients who met the criteria for aseptic meningitis but were PCR-negative for HV. Patients in the HSV-1-positive group exhibited a significant increase in the IgG index at the time of PCR-negative conversion compared with on admission (p = 0.0156), while such a change was not observed in the other two groups. Additionally, all patients in the HSV-1-positive group tested negative for anti-neural autoantibodies in CSF and serum samples collected approximately 3 weeks after onset. This study, therefore, highlights that CSF IgG index elevation occurs even after PCR-confirmed HSV-1 clearance, which might indicate immunopathogenesis that is independent of antibody-mediated mechanisms.

Efgartigimod-associated Kaposi's varicelliform eruption and herpetic conjunctivitis in a patient with seropositive ocular myasthenia gravis: a case report and review.

Background: Efgartigimod (Efgartigimod alpha fcab, Vyvgart™) is a pioneering neonatal Fc receptor (FcRn) antagonist for the treatment of severe autoimmune diseases mediated by pathogenic immunoglobulin G (IgG) autoantibodies, including myasthenia gravis (MG). It is a well-tolerated drug with minor side effects, such as headache and upper respiratory (lung) and urinary tract infections. Here, we present a case of Kaposi's varicelliform eruption (KVE) and herpetic conjunctivitis related to efgartigimod in a 60-year-old patient with ocular MG (OMG). Case description: A 60-year-old Chinese male suffered from acetylcholine receptor antibody positive (AChR Ab+) OMG for 8 years. During this period, he underwent first-line treatment with systemic corticosteroids, cyclosporine, cyclophosphamide, and so on, but had poor symptom improvement. On the recommendation of his attending neurologist, he received one cycle of intravenous efgartigimod (10mg/kg, once weekly for 4 weeks). The patient experienced fever, widespread painful blisters, and edema on the face on the third day after his last intravenous infusion. The patient also complained of increased secretions and a foreign body sensation in both eyes. Laboratory tests confirmed infection with herpes simplex virus (HSV). A diagnosis of efgartigimod-associated KVE and herpetic conjunctivitis was made. After intravenous administration (5mg/kg, 3 times a day, every 8 hours) for 10 days, the patient was cured without residual complications. Conclusions: This case is the first report of a patient with KVE and herpetic conjunctivitis related to efgartigimod in PubMed. This is rare and unusual. Clinicians should be alert to the rare symptoms related to efgartigimod.

Overexpression of NLRP12 enhances macrophage immune response and alleviates herpes simplex keratitis.

Introduction: Herpes simplex keratitis (HSK) is a blinding disease caused by corneal infection of Herpes simplex virus type 1 (HSV-1). Effective clearance of HSV-1 from the infected cornea is crucial for HSK management. Macrophages play an important part in the innate immune defense against viral infections. This study investigates the immunomodulatory role of NLRP12 in macrophage immune response during HSV-1 infection. Methods: NLRP12 expression post-infection was assessed in various macrophage cell lines. Overexpression of NLRP12 was achieved by lentiviral transfection, and its effect on HSV-1 replication and immune responses were examined. Mechanistic insights into the role of NLRP12 were explored using immunofluorescence and Western Blot. For in vivo studies, ocular adoptive transfer of NLRP12-overexpressing bone marrow derived macrophages (BMDMs) was performed. HSV-1 viral loads, HSK symptoms, and macrophage-mediated immune responses were investigated. Results: A significant decrease in NLRP12 expression post-infection was observed in various macrophage cell lines. Overexpression of NLRP12 in macrophages reduced HSV-1 replication. Mechanistically, overexpression of NLRP12 triggered early and robust pyroptosis in response to HSV-1 infection, inducing interleukin (IL)-18 production and activating downstream antiviral responses through the JAK-STAT signaling pathway. In vivo, ocular adoptive transfer of NLRP12-overexpressing BMDMs to mouse corneas alleviated HSK damage and reduced HSV-1 viral loads. NLRP12-overexpressing BMDMs improved antiviral responses in the cornea and promoted the maturation of corneal-infiltrating macrophages and dendritic cells. Additionally, NLRP12-overexpressing BMDMs amplified the adaptive immune response in the submandibular draining lymph nodes. Discussion: These findings highlight the role of NLRP12 in macrophage-mediated immune response against HSV-1 infection and suggest its potential for possible immunotherapy for HSK.

Enhanced synergistic antiviral effects of thermally expanded graphite and copper oxide nanosheets in the form of a novel nanocomposite against herpes simplex virus type 1.

Herpes simplex virus type 1 (HSV-1) is responsible for a wide range of human infections, including skin and mucosal ulcers, encephalitis, and keratitis. The gold standard for treating HSV-1 infections is acyclovir. However, the use of this drug is associated with several limitations such as toxic reactions and the development of drug-resistant strains. So, there is an urgent need to discover and develop novel and effective agents against this virus. For the first time, this study aimed to investigate the antiviral effects of the Thermally Expanded Graphite (TEG)-copper oxide (CuO) nanocomposite against HSV-1 and compare results with its constituent components. After microwave (MW)-assisted synthesis of TEG and CuO nanosheets as well as MW-CuO/TEG nanocomposite and characterization of all these nanomaterials, an MTT assay was used to determine their cytotoxicity. The quantitative real-time PCR was then used to investigate the effects of these nanomaterials on viral load. Three-hour incubation of HSV-1 with TEG nanosheets (500 µg/mL), MW-CuO nanosheets (15 µg/mL), and MW-CuO/TEG nanocomposite (35 µg/mL) resulted in a decrease in viral load with an inhibition rate of 31.4 %, 49.2 %, and 74.4 %, respectively. The results from the post-treatment assay also showed that TEG nanosheets (600 µg/mL), MW-CuO nanosheets (15 µg/mL), and MW-CuO/TEG nanocomposite (10 µg/mL) led to a remarkable decrease in viral load with an inhibition rate of 56.9 %, 63 %, and 99.9 %, respectively. The combination of TEG and MW-CuO nanosheets together and the formation of a nanocomposite structure display strong synergy in their ability to inhibit HSV-1 infection. MW-CuO/TEG nanocomposites can be considered a suitable candidate for the treatment of HSV-1 infection.

Herpes simplex encephalomyeloradiculitis initially presents with urinary retention.

Herpes simplex virus (HSV) infections necessitate careful management of urinary dysfunction and retention, which are underestimated conditions. Here, we present a rare case of HSV encephalomyeloradiculitis in a 76-year-old man, whose initial symptoms included urinary dysfunction and retention that alone lasted for approximately 1 week. Unlike in meningoencephalitis, high fever and headache were absent; however, the patient subsequently developed cauda equina syndrome and consciousness disturbance. Gadolinium-enhanced spinal MRI suggested enhanced cauda equina at the L2/3 level. Upon admission, he was treated for meningoencephalitis with acyclovir and steroid pulse therapy. Subsequent cerebrospinal fluid analysis result was positive for HSV DNA. A |brain MRI conducted 1 week after admission displayed high-intensity lesions in the white matter of the right temporal lobe, confirming HSV encephalomyeloradiculitis. These treatments were highly effective and gradually improved the patient's condition. He was discharged 1 month after hospitalization, and the urinary catheter was removed 2 weeks later. HSV infections can cause life-threatening encephalomyeloradiculitis. Therefore, both neurologists and urologists must pay attention to their occurrence and characteristics in clinical settings.

The Rab6 post-Golgi secretory pathway contributes to herpes simplex virus 1 (HSV-1) egress.

Herpes simplex virus 1 (HSV-1) is an alpha herpesvirus that infects a majority of the world population. The mechanisms and cellular host factors involved in the intracellular transport and exocytosis of HSV-1 particles are not fully understood. To elucidate these late steps in the replication cycle, we developed a live-cell fluorescence microscopy assay of HSV-1 virion intracellular trafficking and exocytosis. This method allows us to track individual virus particles and identify the precise moment and location of particle exocytosis using a pH-sensitive reporter. We show that HSV-1 uses the host cell's post-Golgi secretory pathway during egress. The small GTPase, Rab6, binds to nascent secretory vesicles at the trans-Golgi network and plays important, but non-essential, roles in vesicle traffic and exocytosis at the plasma membrane, therefore making it a useful marker of the Golgi and post-Golgi secretory pathway. We show that HSV-1 particles colocalize with Rab6a in the region of the Golgi, cotraffic with Rab6a to the cell periphery, and undergo exocytosis from Rab6a vesicles. Consistent with previous reports, we find that HSV-1 particles accumulate at preferential egress sites in infected cells. The secretory pathway mediates this preferential/polarized egress, since Rab6a vesicles accumulate near the plasma membrane similarly in uninfected cells. These data suggest that, following particle envelopment, HSV-1 egress follows a pre-existing cellular secretory pathway to exit infected cells rather than novel, virus-induced mechanisms. IMPORTANCE: Herpes simplex virus 1 (HSV-1) infects a majority of people. It establishes a life-long latent infection and occasionally reactivates, typically causing characteristic oral or genital lesions. Rarely in healthy natural hosts, but more commonly in zoonotic infections and in elderly, newborn, or immunocompromised patients, HSV-1 can cause severe herpes encephalitis. The precise cellular mechanisms used by HSV-1 remain an important area of research. In particular, the egress pathways that newly assembled virus particles use to exit from infected cells are unclear. In this study, we used fluorescence microscopy to visualize individual virus particles exiting from cells and found that HSV-1 particles use the pre-existing cellular secretory pathway.

Challenges for early diagnosis of neonatal herpes infection in Japan.

Background: This study aimed to analyze the recent prevalence of neonatal herpes simplex virus infection, maternal symptoms in the presence of neonate who has herpes simplex virus infection, and mode of delivery in Japan. Methods: We requested 2.078 obstetrical facilities that are members of the Japan Association of Obstetricians and Gynecologists (JAOG) to provide information on neonatal herpes simplex virus infection involving deliveries at or after 22 weeks of gestation between 2020 and 2022. Of these, 1.371 (66.0%) facilities responded with information that could undergo statistical analysis. Results: There were 10 cases of neonatal herpes simplex virus infection, and the incidence of neonatal herpes simplex virus infection in Japan was about 1 in 1.4 × 105 live births. There were no characteristic maternal findings common to cases of neonatal herpes simplex virus infection. Conclusion: The incidence of neonatal herpes simplex virus infection in Japan was low. We could not identify any characteristic maternal findings common to cases of neonatal herpes simplex virus infection.

HERV-K np9 and HERV-R env: Two endogenous retrovirus products with potential Pathogenic roles in pediatric acute lymphoblastic leukemia.

OBJECTIVES: Human endogenous retroviruses (HERVs) are integral components of the human genome, and their reactivation has been implicated in the pathogenesis of some malignancies. External viral co-infections are suspected to play a role in HERV transactivation. This study aimed to investigate the expression of HERV-K np9 elements and HERV-R env gene in pediatric acute lymphoblastic leukemia (ALL) patients. Additionally, we explored potential correlations between HERV expression and common viral infections prevalent in this group of patients. METHODS: Blood samples were collected from 43 pediatric ALL patients and 48 age- and sex-matched healthy controls. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of HERV-K np9 and HERV-R env, along with herpes simplex virus (HSV), parvovirus B19, and polyomavirus BK. RESULTS: HERV-K np9 and HERV-R env showed significantly higher expression in the peripheral blood of ALL patients compared to healthy controls (p < .001 and p = .003, respectively). HSV positivity was associated with significantly increased HERV-K np9 expression. No significant correlations were observed between other investigated viruses and HERV gene expression. CONCLUSION: The overexpression of HERV-K np9 and HERV-R env in pediatric ALL patients suggest their potential role in leukemogenesis. Our findings also suggest a possible link between HSV infection and HERV reactivation in this population. Future investigations are needed to understand the precise roles of these genes and viral infections in the development of ALL.

Rapid diagnosis of herpes simplex virus 1 and 2 bloodstream infections utilizing a sample-to-answer platform.

Bloodstream HSV-1 and HSV-2 infections can cause devastating outcomes with high morbidity and mortality, especially in neonates or immunocompromised individuals. Proper patient management for herpes simplex virus (HSV) bloodstream infections is time-sensitive and requires a rapid, accurate, and definitive diagnosis. The absence of the U.S. Food and Drug Administration (FDA)-approved molecular assays for HSV detection in blood, coupled with a lack of consensus on the optimal sample type, underscores the unmet need for improved diagnostics. We prospectively compared the cycle threshold values in paired samples including whole blood (WB), plasma, serum, and peripheral blood mononuclear cells (PBMCs) from patients with bloodstream HSV infections. This analysis employed a modified use of the FDA-cleared Simplexa HSV-1 & 2 Direct assay. The clinical performance in serum was assessed by comparing the results of 247 remnant specimens on this sample-to-answer platform to established laboratory-developed tests in a blinded fashion. Serum samples exhibited significantly lower cycle thresholds than whole blood samples [2.6 cycle threshold (Ct) bias, P < 0.001]. The modified Simplexa assay demonstrated 100% positive percent agreement for the detection of HSV-1 and HSV-2 DNA in serum samples and yielded an overall agreement of 95% (95% CI, 0.92 to 0.97), with a κ statistic of 0.75 (95% CI, 0.62 to 0.86) compared to the composite reference method. Discordance rates were 5.20% for HSV-1 and 0.81% for HSV-2. This investigation demonstrates that serum is an optimal specimen type for HSV detection when compared to several blood compartments. Serum offers a promising sample type for rapid and accurate diagnosis of HSV bloodstream infections using the modified Simplexa assay. IMPORTANCE: Rapid, accurate, and definitive diagnosis of herpes simplex virus (HSV) infections is crucial in clinical settings for patient management. The absence of FDA-authorized molecular assays for HSV-1/2 detection in blood, coupled with a lack of consensus on the optimal sample type, underscores the need for improved diagnostic methods. Furthermore, rapid diagnosis of HSV bloodstream infections enables timely administration of antiviral treatment, influences patient management decisions for those at high risk, and can contribute to shorter hospital stays, thereby reducing healthcare costs.

A Rare Presentation of a Periorbital Herpes Simplex Virus Pseudotumor in an Immunocompromised Patient.

Herpes simplex virus (HSV) frequently affects the ocular and genital regions, especially in immunocompromised individuals. On rare occasions, HSV infections can present as pseudotumors. These pseudotumors may mimic cancerous growths, condylomas, or hypertrophic lesions rather than the characteristic small ulcerations. The development of pseudotumors due to HSV is particularly uncommon, especially in the facial region. This atypical presentation poses significant diagnostic challenges and may potentially lead to erroneous identification as a cancerous growth. This case report details a 53-year-old African American man with human immunodeficiency virus (HIV) (noncompliant with antiretroviral therapy) presenting with a purulent ocular pseudotumor secondary to HSV infection, along with a review of the literature surrounding HSV pseudotumors.

Type 2 herpes simplex virus-induced anti-N-methyl-D-aspartate receptor encephalitis responsive to immunoglobulin monotherapy.

Herpes simplex virus-2 encephalitis (HSV2E) in immunocompetent adults is exceptionally rare, and the subsequent onset of autoimmune encephalitis after HSV2E is even less common. This report presents the inaugural Chinese case of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) induced by HSV2E, confirmed via metagenomic next-generation sequencing (mNGS). The patient demonstrated a favorable response to intravenous immunoglobulin (IVIG) monotherapy. This case emphasizes the importance of considering autoimmune encephalitis in patients exhibiting new or recurrent neurological symptoms after HSV2E recovery. Comprehensive mNGS and neuronal antibody testing are essential for timely diagnosis. Moreover, IVIG monotherapy can serve as an effective treatment for NMDARE induced by HSV2, providing a viable alternative, particularly when steroid therapy is contraindicated.

The role of herpes simplex virus infection in the etiology of head and neck cancer-a Mendelian randomization study.

Introduction: Head and neck cancer (HNC) is a complex disease, and multiple risk factors can lead to its progression. Observational studies indicated that herpes simplex virus (HSV) may be correlated with the risk of HNC. However, the causal effects and direction between them were still unclear. Methods: This study utilized a Mendelian randomization (MR) approach for causality assessment between HSV infection and Head and neck cancer based on the latest public health data and Genome-Wide Association Study (GWAS) data. The causal effects were estimated using IVW, weighted median, and MR-Egger. A reverse MR analysis was subsequently performed. Cochrans Q test, MR-Egger intercept test, leave one out analysis, and the funnel plot were all used in sensitivity analyses. Results: Genetically predicted higher level of HSV-1 IgG was causally related to HNC (OR=1.0019, 95%CI=1.0003-1.0036, p=0.0186, IVW) and oral and oropharyngeal cancer (OR=1.0018, 95%CI=1.0004-1.0033, p=0.0105, IVW). The reverse MR analysis did not demonstrate a reverse causal relationship between HSV and HNC. However, HSV-2 infection was not causally related to HNC data and oropharyngeal cancer data. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy. Conclusion: Collectively, a significant association was noted between HSV infection and increased risk of HNC, providing valuable insights into the etiology of this malignancy. Further in-depth study is needed to validate these findings and elucidate the underpinning mechanisms.

UL56 Is Essential for Herpes Simplex Virus-1 Virulence In Vivo but Is Dispensable for Induction of Host-Protective Immunity.

Herpes simplex virus-1 (HSV-1) is common and can cause significant disease in humans. Unfortunately, efforts to develop effective vaccines against HSV-1 have so far failed. A detailed understanding of how the virus infects its host and how the host mounts potent immune responses against the virus may inform new vaccine approaches. Here, using a zosteriform mouse model, we examined how the HSV-1 gene UL56 affects the ability of the virus to cause morbidity and generate protective immunity. A UL56 deletion mutant, ΔUL56, was derived from the wild-type HSV-1 strain SC16, alongside a revertant strain in which UL56 was reintroduced in ΔUL56. In vitro, the three virus strains replicated in a similar manner; however, in vivo, only the wild type and the revertant strains caused shingles-like skin lesions and death. Mice previously infected with ΔUL56 became resistant to a lethal challenge with the wild-type SC16. The protective immunity induced by ΔUL56 was independent of IL-1, IL-33, and IL-36 signaling through IL-1RAP. Both skin and intramuscular ΔUL56 inoculation generated protective immunity against a lethal SC16 challenge. After 6 months, female mice remained resistant to infection, while male mice exhibited signs of declining protection. Our data demonstrate that UL56 is important for the ability of HSV-1 to spread within the infected host and that a ∆UL56 strain elicits an effective immune response against HSV-1 despite this loss of virulence. These findings may guide further HSV-1 vaccine development.

A review of HSV pathogenesis, vaccine development, and advanced applications.

Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons.

Targeting Peptidylarginine Deiminase 3 to Efficiently Suppress Herpes Simplex Virus Type 2 Infection.

Protein expression is regulated through multiple mechanisms, including post-translational modifications (PTMs), which can alter protein structure, stability, localization, and function. Among these, citrullination stands out due to its ability to convert arginine residues into citrulline, altering protein charge and mass. This modification is catalyzed by calcium-dependent protein arginine deiminases (PADs), enzymes implicated in various inflammatory diseases. We have recently shown that human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) exploit these enzymes to enhance their replication capabilities. Although the role of PADs in HCMV and HSV-1 infections is well documented, their involvement in HSV-2 infection has not yet been thoroughly investigated. Here, we demonstrate that HSV-2 manipulates the overall protein citrullination profile by activating three PAD isoforms: PAD2, PAD3, and PAD4. However, as previously observed during HSV-1 infection, PAD3 is the most significantly upregulated isoform, both at the mRNA and protein levels. Consistently, we demonstrate that inhibiting PAD3, either through the specific inhibitor CAY10727 or via CRISPR/Cas9-mediated gene silencing, markedly reduces HSV-2 replication and viral protein expression. Lastly, we show that CAY10727 displays an IC50 value of 0.3 µM, which is extremely close to what was previously observed for HSV-1. Overall, our findings highlight the crucial role of PAD3 in the life cycle of HSV-2 and suggest that the targeted inhibition of PAD3 may represent a promising approach for treating HSV-2 infections, especially in cases resistant to existing antiviral therapies.