RARE DISEASE
Herpes simplex virus encephalitis
Herpes simplex virus encephalitis
Herpes simplex virus encephalitis
Synonyms: HSE, HSV encephalitis, HSVE, Herpes simplex meningo-encephalitis, Herpes simplex neuroinvasion, Herpetic encephalitis
Synonyms: HSE, HSV encephalitis, HSVE, Herpes simplex meningo-encephalitis, Herpes simplex neuroinvasion, Herpetic encephalitis
Synonyms: HSE, HSV encephalitis, HSVE, Herpes simplex meningo-encephalitis, Herpes simplex neuroinvasion, Herpetic encephalitis
Drug discovery
2
drugs
With orphan designations
Overview
Herpes simplex virus encephalitis (HSE), primarily caused by HSV-1, is a life-threatening neurologic infection characterized by fever, altered consciousness, seizures, and focal deficits. Prompt IV acyclovir (10 mg/kg every 8 hours for 14–21 days) reduces mortality from 70–80% to 10–20% [2][9]. Adjunct corticosteroids may mitigate inflammation in severe cases [3][13]. Delays in treatment beyond 48 hours increase mortality and neurocognitive sequelae (30–40% survivors) [1][9]. Autoimmune anti-NMDA receptor encephalitis can occur post-HSE [2].
Burden
Mortality: 7.7% in adults, 6.9% in neonates; survivors face epilepsy (38%), cognitive impairment, or behavioral disorders [4][9][12].
Economic burden: Prolonged ICU stays (median 3–14 days) and high rehabilitation needs [1][14].
Global disparities: LMICs face higher morbidity due to delayed diagnostics and treatment barriers [14].
Therapies
First-line: High-dose IV acyclovir (14–21 days), with CSF-PCR monitoring to guide duration [2][11].
Adjunctive therapies: Corticosteroids (e.g., dexamethasone) for fulminant cases to reduce cerebral edema [3][13].
Supportive care: Seizure management, ICP control, and rehabilitation for residual deficits [6][13].
Categories: rare genetic diseases, rare immunological diseases, rare infectious diseases, rare neurological diseases
Research Papers
1,243 drug discovery papers about Herpes simplex virus encephalitis, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,243 drug discovery papers about Herpes simplex virus encephalitis, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-05-27 | Bispecific antibodies targeting herpes simplex virus glycoproteins B and D.
Herpes simplex viruses (HSV-1 and HSV-2) can be transmitted both orally and sexually and cause lifelong morbidity and, in some cases, meningitis and encephalitis. Although several clinical trials using subunit antigens have been conducted, no vaccine exists. One problem in viral treatment is the emergence of drug resistance through mutations, thereby conferring resistance. Treatment with antibodies targeting multiple epitopes, such as antibody cocktails or bispecific antibodies (BsAbs), should reduce the likelihood of viral escape. We screened pairs of antibodies targeting key functional sites on glycoproteins B (gB) and D (gD), which are crucial for HSV entry. Murine hybridoma cells expressing anti-gD and anti-gB Mabs were sequenced. Recombinant antibodies, mono- and bispecific, were purified from supernatants of 293T transfected cells. From a panel of gD-gB monoclonal antibodies (Mabs), we selected MC2 (anti-gD) and C226 (anti-gB) for the design of BsAbs: MC2/C226sc and a simpler version in which the C226scFv was cloned at the C-terminus of MC2 Fc, which we termed BD Tetra. Notably, both MC2/C226sc and BD Tetra BsAbs simultaneously recognized and bound gB and gD and had a marked synergistic effect on inhibiting cell-cell fusion, virus entry, and plaque formation. Although MC2 is HSV-2 specific, both MC2/C226sc and BD Tetra showed activity against HSV-1. The Fc domains of these two BsAbs were equally effective at binding to mouse Fcγ receptors RI or RIV in vitro. The data presented here demonstrate the generation, characterization, and potential of bispecific antibodies targeting two distinct glycoproteins to enhance neutralization of herpes simplex virus compared with monoclonal antibodies. BsAbs offer a potential avenue for herpes therapeutics, but their design and mechanism of action require careful consideration for optimal efficacy. Engineering different formats of BsAbs will not only enable optimal protective and therapeutic outcomes but also aid in the study of the spatial relationships between key glycoproteins involved in HSV infection. We propose that targeting distinct steps of the fusion cascade will yield a BsAb that is highly effective.
2025-12-17 | A broadly neutralizing antibody confers cross-genus protection against alphaherpesviruses by inhibiting gB-mediated membrane fusion.
The global prevalence and disease burden of alphaherpesviruses infections, including human-infecting viruses such as HSV-1, HSV-2, and VZV, as well as animal-infecting viruses like PRV, BHV, CHV, and FHV, highlight the unmet need for more effective and universal antiviral strategies. However, there has been no significant progress in developing broad-spectrum interventions against herpesvirus. Here we report the identification of a broadly neutralizing antibody against alphaherpesviruses, 16F9, which targets the glycoprotein B (gB) of alphaherpesviruses and offers cross-protection against multiple viruses such as HSV-1, HSV-2, and PRV in mice. 16F9 demonstrated robust therapeutic efficacy in various female mouse models of herpesvirus diseases including PRV-induced viral encephalitis, HSV-1-induced viral encephalitis, viral keratitis, cutaneous herpes, and neonatal herpesvirus infections. High-resolution cryo-electron microscopy structures revealed that 16F9 binds a conserved site of vulnerability on Domain I of gB. The binding of 16F9 disrupts the interaction between pre-gB and gHgL complex, thereby preventing viral membrane fusion and blocking viral infection. This study provides a foundation for advancing antiviral strategies and underscores the potential of gB-targeted interventions for combating herpesvirus infections.
2025-09-01 | Refractory "status dyskineticus" in a child with post-herpes simplex virus 1 N-methyl-D-aspartate receptor encephalitis: a case report.
Herpes simplex virus 1 (HSV-1) encephalitis may result in relapsing neurological symptoms secondary to immune-mediated processes, including anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Refractory status dyskineticus (RSD), a severe subset of status dystonicus, is characterized by a hyperkinetic movement disorder phenotype alongside dystonic features. This critical condition presents substantial challenges in neurocritical care. The present case highlights the importance of prompt intervention and immunotherapy escalation in managing severe movement disorders due to pediatric autoimmune encephalitis. A previously healthy 2-year-old boy was admitted with HSV-1 encephalitis, confirmed by brain MRI and cerebrospinal fluid (CSF) analysis. When initially treated with acyclovir, the patient achieved partial recovery but later developed encephalopathy, vomiting, behavioral regression, and severe dyskinetic movements. Upon transfer to our center, NMDAR antibodies were detected in the CSF, with no evidence of HSV reactivation. Despite first-line immunotherapy with intravenous steroids and immunoglobulins, his condition deteriorated, progressing to status dyskineticus (SD), with dystonia, hyperthermia, and hypercapnia, requiring intensive care management and mechanical ventilation. A treatment escalation regimen including both immunotherapy with rituximab, rapamycin, bortezomib, and multiple symptomatic therapies resulted in gradual improvement and resolution of the movement disorder. This case underscores the crucial role of neurocritical care in managing refractory movement disorders associated with autoimmune encephalitis. Early recognition and immunotherapy escalation are essential to improve outcomes in children with complex, life-threatening neurological conditions. A comprehensive, multidisciplinary approach in the neurocritical care setting is key to achieving recovery and minimizing long-term neurological damage.
2025-08-09 | Clinical phenotype and outcomes in autoimmune encephalitis after herpes simplex virus encephalitis: A systematic review and meta-analysis.
Autoimmune encephalitis after herpes simplex virus encephalitis (HSVE-AE) represents the intersection of central nervous system infection and autoimmunity. Defining the phenotype and the safety and effectiveness of immunotherapy in HSVE-AE would help identify immunotherapy candidates, optimise therapeutic strategies, and improve patient outcomes. We systematically searched Embase, Medline, PubMed, and Web of Science (2007-2024) for cases meeting consensus criteria for AE after confirmed HSVE. Demographics, phenotype, treatment and outcome data were extracted. Dimensionality reduction, network analysis, and multivariate logistic regression was used to explore age- and diagnosis-specific patterns and outcome predictors. From 2259 articles screened, 78 studies (225 patients) were included (median age 7.25 years; 52.9% female). Children (0-12 years) experienced more seizures during HSVE (p=0.003) and movement disorders during AE (p<0.001). Older patients (>12 years) had more headaches during HSVE (p=0.003), and speech dysfunction (p=0.02) and neuropsychiatric symptoms (p=0.02) during AE. HSVE-AE (89.3% N-methyl-D-aspartate receptor-antibody encephalitis [NMDAR-AbE]) differed significantly from a canonical NMDAR-AbE cohort (n=1550) in clinical, paraclinical and outcome domains. Poor outcomes were linked to infant and older adult age, neuropsychiatric symptoms, and AE-phase mRS >4. Rituximab independently predicted better outcomes. Disability improved over time (p<0.001), with adverse event rates comparable to NMDAR-AbE. This meta-analysis defines novel age-specific HSVE-AE features, outcome predictors, and confirms the safety and improved outcomes of HSVE-AE after immunotherapy.
2025-05-21 | Neurological outcomes and disability predictors in paediatric herpes simplex virus encephalitis: a multicentre cohort from French tertiary hospitals.
To identify factors associated with the neurological outcome of HSVE in children. In this retrospective multicentric observational study, clinical, paraclinical data at onset and neurological outcomes at last follow-up of children (≥28 days and <18 years old) with HSVE, were studied. Univariate and multivariate analyses were performed to identify factors associated with neurological outcome. 49 children (mean age of 4.9 ± 5.5 years) were included. At last follow-up of 5.9 ± 3,13 years, 2 children died (4 %) and 37 (76 %) children presented with poor neurological outcome with epilepsy (57 %), intellectual disability (51 %) and language disorders (47 %). Rehabilitation was necessary for 76 % and 59 % had abnormal academic performances. At onset, younger age and seizures were significantly associated to language disorders (p < 0.01), motor disabilities (p = 0.01), and intellectual disabilities (p = 0.01) in univariate analysis. Abnormal MRIs were more frequent in children with neurological sequalae (p = 0.01). Multivariate analyses identified that: (1) epilepsy occurred more frequently in females (p = 0.03), with insular lesions (p = 0.048); (2) language disorders were more common in children who had seizures at onset (p 0.02); (3) motor disorders were more frequent in younger children (p = 0.03) with thalamic lesions (p = 0.04). Our findings indicate that despite decrease in mortality rates, neurological disabilities in children with HSVE still persist at high levels. This underscores the need to enhance HSVE management strategies. Moreover, the identified risk factors associated with poor neurological outcomes can aid in identifying high-risk children, facilitating the implementation of alternative treatment approaches such as immunotherapy or intensive rehabilitation.
small molecules
2026-09-26 | Host Genetic Susceptibility and Antiviral Immunity Shape the Pathogenesis and Outcomes of Herpes Simplex Encephalitis.
Herpes simplex encephalitis (HSE), predominantly caused by herpes simplex virus type 1 (HSV-1), is the most common sporadic viral encephalitis worldwide and remains life threatening despite antiviral therapy. Although herpes simplex virus (HSV) infection is highly prevalent, only a minority of individuals develop HSE, highlighting the critical contribution of host-specific factors to disease susceptibility. This review summarizes current knowledge regarding HSE epidemiology, antiviral immunity, genetic susceptibility, and therapeutic advances. Underlying inborn errors of immunity fall into three mechanistic groups: impaired innate immune sensing pathways, including Toll-like receptor 3 (TLR3), retinoic-acid-inducible gene-I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), which compromise type I interferon (IFN) production in central nervous system (CNS) resident cells; disrupted neuron intrinsic antiviral mechanisms represented by mutations in specific genes (e.g., DBR1, SNORA31, and GTF3A); and defects in other IFN signaling molecules, including interferon-α/β receptor 1 (IFNAR1) and 2 (IFNAR2), as well as signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2), which further weaken antiviral defenses. These findings underscore cell autonomous antiviral responses within the brain and provide insights into the selective vulnerability to HSE. Emerging therapeutic strategies aim to integrate antiviral treatment with modulation of host immune responses and, potentially, personalized approaches based on genetic profiling. In all, we emphasize the pivotal role of CNS-intrinsic immunity and host genetic factors in shaping disease outcomes. A deeper understanding of the interplay between HSV and host defense mechanisms will facilitate the development of improved diagnostic tools and targeted therapies, ultimately reducing the burden of this devastating disease.
2026-09-26 | A Proof-of-Concept Study for the Efficacy of Dispirotripiperazine PDSTP in a Mouse Model of Herpes Simplex Herpetic Encephalitis.
Herpes simplex encephalitis (HSE) remains a life-threatening disease with high mortality and severe neurological complications, despite acyclovir therapy being limited by delayed diagnosis, drug resistance, and poor blood-brain barrier penetration. New antivirals with different mechanisms of action are urgently needed. We evaluated PDSTP, a novel dispirotripiperazine-based compound targeting host heparan sulfate proteoglycans (HSPGs), in mouse models of HSV-1 encephalitis. This study evaluates the therapeutic and prophylactic potential of PDSTP, an antiviral compound that blocks HSV glycoconjugates on the host cell membrane, using a well-established mouse model of herpes encephalitis. BALB/c mice were infected with HSV-1 strains VR-539 or VR-733 via intraperitoneal (IP) or intranasal (IN) routes. PDSTP was administered orally (PO) or intraperitoneally (IP) at 12.5-80 mg/kg/day, alone or in combination with acyclovir (10-100 mg/kg/day), using a prophylactic-therapeutic regimen (2 h pre-infection, then twice daily for 7 days). Survival, weight loss, mean survival time, and brain viral loads were assessed. PDSTP at 80 mg/kg/day (PO) protected 30-40% of VR-733-infected mice and extended lifespan 1.9-fold (p < 0.05), comparable to acyclovir at 100 mg/kg/day. IP administration was superior to PO. The combination of IP PDSTP (12.5 mg/kg/day) with IP acyclovir (10 mg/kg/day) achieved 100% survival, prevented weight loss, and significantly reduced brain viral titers (p < 0.001) in both infection models. PDSTP demonstrates dose- and strain-dependent activity as monotherapy and enhanced efficacy when combined with acyclovir. The IP combination provided complete protection at low doses, supporting PDSTP as a promising candidate for further development against HSE.
2026-09-22 | EARLY DIAGNOSIS AND TREATMENT PROTOCOLS FOR HERPES ENCEPHALITIS IN PUBLIC HEALTH
Herpes simplex virus encephalitis (HSE) is one of the leading infectious causes of central nervous system disease, characterized by high morbidity and mortality and a significant risk of neurological sequelae despite standardized antiviral treatment. This narrative review aims to compile the main evidence related to early diagnosis, pathophysiology, immunobiology, and current therapeutic approaches to herpes simplex encephalitis, with an emphasis on the pathways of tissue damage and secondary immune-mediated manifestations. The literature search was conducted on the PubMed platform using the search terms “Herpes Simplex Encephalitis” and “Therapeutics,” combined with the Boolean operators “AND” and “OR.” We selected original studies, prospective cohort studies, translational research, and conceptual reviews published in the last five years in English and Portuguese, excluding duplicate publications, studies with methodological weaknesses, and works that fell outside the scope of this study. The evidence indicates that the clinical presentation of HSE can be nonspecific, requiring integration of clinical manifestations, neuroimaging, electroencephalography, and cerebrospinal fluid analysis, with particular emphasis on polymerase chain reaction (PCR) for the detection of HSV DNA. However, laboratory confirmation should never delay the empirical infusion of intravenous acyclovir based on clinical suspicion, since therapeutic latency is directly correlated with a worse functional prognosis. Furthermore, recent data demonstrate that residual morbidity is not exclusively related to viral replication but involves mechanisms of neuroinflammation, alterations in intrinsic cerebral immunity, ferroptosis, and post-herpetic autoimmunity. Translational models reinforce the finding that HSV-1 infection can disrupt neuroepithelial integrity, neuronal activity, and antioxidant mechanisms; in this context, adjunctive immunomodulatory approaches have been shown to provide preclinical neuroprotection. Additionally, the identification of innate defects in cerebral immunity and the recognition of post-herpetic autoimmune encephalitis have expanded our understanding of the clinical and immunological heterogeneity of the disease. Ultimately, the management of herpes simplex encephalitis prioritizes early recognition and immediate administration of acyclovir, while new immunomodulatory strategies remain under investigation. Given the complex host immune response, clinical studies are still needed to establish the safety and efficacy of combination therapies, as well as biomarkers capable of identifying patients at higher risk for neurological damage and autoimmune complications.
2026-09-21 | RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis
Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic viral encephalitis, where uncontrolled viral replication and neuroinflammation drive fatal brain injury. Inherited RIPK3 deficiency predisposes humans to severe disease, but the protective mechanism remains unclear. Using single-cell transcriptomics, genetic knockout models, and analysis of viral replication, interferon production, and cell death across neurons, astrocytes, microglia, and myeloid cells, we show that RIPK3 acts as a cell-type-specific molecular switch. RIPK3 scaffolding promotes interferon response and viral control in multiple central nervous system cell types, while RIPK3-dependent apoptosis limits myeloid accumulation. In contrast, RIPK3 kinase activity in astrocytes triggers necroptosis, leading to neuronal loss and lethal neuroinflammation. Genetic or pharmacological inhibition of RIPK3 kinase suppresses astrocyte necroptosis, enhances IFN responses, preserves brain integrity, and improves survival. These findings suggest that selective modulation of RIPK3 signaling may balance antiviral defense with limitation of neuropathology in HSV-1 encephalitis. HSV-1 encephalitis causes severe brain injury, but the mechanism of immune pathology remains to be explored. The authors here show that RIPK3 drives astrocyte death though benefits viral control in other cell types, further RIPK3 inhibition promotes survival.
2026-09-16 | Computational identification of Ginkgo biloba phytochemicals as dual inhibitors of herpes simplex virus type 1 glycoproteins gB and gD targeting its entry and Alzheimer's disease pathogenesis.
Herpes simplex virus type 1 (HSV-1) causes severe neurological complications such as herpes simplex encephalitis and Alzheimer's disease (AD). Its entry is mediated by glycoproteins gD and gB, which regulate receptor binding and membrane fusion. Targeting these entry glycoproteins represents a promising therapeutic strategy to limit HSV-1 infection and its contribution to AD pathogenesis. Therefore, this study aimed to identify natural dual inhibitors of HSV-1 glycoproteins gB and gD from Ginkgo biloba using an integrated computational approach involving molecular docking, pharmacokinetic, toxicity, and bioactivity profiling, molecular dynamics simulations, and MM-GBSA binding free energy analyses to evaluate binding stability and therapeutic potential. A total of 39 phytochemicals were retrieved from IMPPAT 2.0 and PubChem databases and docked against HSV-1 glycoproteins gB and gD. Pharmacokinetics and toxicity were assessed using admetSAR 3.0, SwissADME, Deep-PK, and pKCSM. Molecular docking revealed several phytochemicals with strong binding affinities to HSV-1 glycoproteins gB and gD, compared to docosanol. Among these, β-sitosterol and ginkgolide A exhibited favorable drug-likeness, acceptable oral bioavailability, no mutagenic and hepatotoxic effects, and biologically active. Molecular dynamic simulation confirmed their greatest binding stability compared to docosanol. MM-GBSA binding free energy analysis further validated their strong and stable interactions within the active sites of HSV-1 glycoproteins gB and gD. These findings identify β-sitosterol and ginkgolide A as promising dual-target inhibitors of HSV-1 glycoproteins gB and gD in context of HSV-1-associated AD pathogenesis. However, experimental validation is required to confirm their antiviral efficacy and potential relevance to AD.
proteins
2026-08-12 | Adjunctive Intravenous Immunoglobulin in Severe Herpes Simplex Encephalitis: A Case Report with a Favorable Outcome
Both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) can cause encephalitis; however, HSV-1 is the most common etiological agent. Herpes simplex encephalitis (HSE) presents with a wide spectrum of clinical manifestations from fever and headaches to acute neurological dysfunctions with seizures. The mortality rate is high even with the right treatment. In this case report we present a 36-year-old female with no comorbidities that presented to the emergency department with a headache and reported olfactory hallucinations. The patient experienced rapid cognitive and neurological deterioration, became stuporous, almost entirely unconscious despite intravenous antiviral therapy. The patient was treated as a ‘last resort’ with intravenous immunoglobulins, and was induced into a coma in the Intensive Care Unit. The patient was extubated a few days later and returned to the neurology ward in a very much improved state where she continued her recovery. At the three-month follow-up the patient exceeded all expectations and was slowly returning to her life before the illness.
2026-06-12 | Differential Sensitivity of HSV-1 and PRV to IFN-λ Reveals a Neuron-Specific Antiviral Role for RSAD2.
Alpha herpesviruses (α-HV) initially infect mucosal epithelial cells and subsequently establish lifelong latency in the peripheral nervous system (PNS). Herpes simplex virus-1 (HSV-1), a human pathogen persisting in the majority of the adult population, shares neuroinvasive properties with Pseudorabies virus (PRV), a swine α-HV, commonly used as a model α-HV. Utilizing primary peripheral neuronal cultures, we previously showed that IFN-λ pre-treatment significantly reduced PRV yield. In this paper, we further characterized the early and late neuronal responses to IFN-λ by RNA-seq, and the antiviral potential of this response against HSV-1. Notably, HSV-1 exhibited neuron-specific resistance to IFN-λ mediated antiviral responses both in murine primary neurons and human neuronal cells. An ICP34.5-deficient HSV-1 (Δ34.5) mutant showed IFN-λ sensitivity in neurons, while replicating normally in untreated neurons showing that ICP34.5 is responsible for the neuron specific IFN-λ resistance of HSV-1. Our results further demonstrate that RSAD2 is strongly induced by IFN-λ in neurons, localizing to ER-associated membranes, and effectively restricting α-HV protein synthesis in the absence of ICP34.5. siRNA-mediated RSAD2 knockdown in IFN-λ-primed primary neurons largely restored replication of Δ34.5 HSV-1, highlighting the role of this IFN-λ induced host factor in neuronal infections. Together, neuronal IFN-λ-induced RSAD2 and HSV-1 ICP34.5 define a neuron-specific antagonistic mechanism that collectively determines the replication efficiency of HSV-1 in the PNS.
2025-11-03 | Cerebrolysin treatment in a case of post-herpes simplex encephalitis with neuropsychiatric symptoms.
Herpes simplex encephalitis (HSE) is a severe central nervous system (CNS) infection associated with cognitive decline, psychotic symptoms, and epilepsy. Despite aggressive antiviral and corticosteroid treatments, post-HSE complications remain challenging to manage. We report a case of a 33-year-old female patient with post-HSE neuropsychiatric symptoms who showed significant improvement following Cerebrolysin treatment. The patient was treated with acyclovir and dexamethasone in the acute phase, followed by Cerebrolysin administration in the post-acute phase. This case highlights the potential therapeutic role of Cerebrolysin in managing post-encephalitic cognitive dysfunction, underscoring the need for further studies.
2025-09-16 | Unleashing the Antiviral Potential of Stapled Peptides: A New Frontier in Combating Human Neurotropic Viral Infections.
Neurotropic viral infections continue to pose significant global health challenges, with pathogens such as herpes simplex virus (HSV), varicella-zoster virus, human immunodeficiency virus, poliovirus, enteroviruses, parechovirus, West Nile virus and Japanese encephalitis virus driving the search for more effective therapeutic interventions. Current antiviral strategies, including small molecules and monoclonal antibodies, often face limitations such as drug resistance, narrow spectrum activity and adverse side effects, underscoring the need for alternative approaches. Antiviral peptides are emerging as potential therapeutic agents against these viral infections as entry and fusion inhibitors. However, their clinical development is limited by poor stability, low bioavailability and insufficient cellular penetration. To address these limitations, peptide stapling, a chemical modification that stabilises peptide α-helices through covalent linkage, has emerged as a transformative technique to enhance the therapeutic potential of peptides, especially in antiviral drug development. Stapling techniques, including hydrocarbon staples, lactam bridges and metal-coordination bonds, are explored for their ability to improve peptide stability, bioavailability and target binding affinity. This review examines the application of stapling in the development of antiviral peptides with a focus on stapled peptides targeting viral fusion and entry mechanisms, highlighting their potential against neurotropic viruses such as HSV and influenza. By integrating the structural rigidity conferred by stapling, these constructs promise to overcome delivery barriers and achieve superior antiviral efficacy. This paper underscores the pivotal role of peptide stapling by highlighting recent advancements in antiviral therapeutics and presents a roadmap for future research into multifunctional stapled peptides.
2024-08-14 | Leveraging biotin-based proximity labeling to identify cellular factors governing early alphaherpesvirus infection.
Neurotropic alphaherpesviruses, including herpes simplex virus type 1 and pseudorabies virus, establish a lifelong presence within the peripheral nervous system of their mammalian hosts. Upon entering cells, two conserved tegument proteins, pUL36 and pUL37, traffic DNA-containing capsids to nuclei. These proteins support long-distance retrograde axonal transport and invasion of the nervous system in vivo. To better understand how pUL36 and pUL37 function, recombinant viral particles carrying BioID2 fused to these proteins were produced to biotinylate cellular proteins in their proximity (<10 nm) during infection. Eighty-six high-confidence host proteins were identified by mass spectrometry and subsequently targeted by CRISPR-Cas9 gene editing to assess their contributions to early infection. Proteins were identified that both supported and antagonized infection in immortalized human epithelial cells. The latter included zyxin, a protein that localizes to focal adhesions and regulates actin cytoskeletal dynamics. Zyxin knockout cells were hyper-permissive to infection and could be rescued with even modest expression of GFP-zyxin. These results provide a resource for studies of the virus-cell interface and identify zyxin as a novel deterrent to alphaherpesvirus infection.IMPORTANCENeuroinvasive alphaherpesviruses are highly prevalent with many members found across mammals [e.g., herpes simplex virus type 1 (HSV-1) in humans and pseudorabies virus in pigs]. HSV-1 causes a range of clinical manifestations from cold sores to blindness and encephalitis. There are no vaccines or curative therapies available for HSV-1. A fundamental feature of these viruses is their establishment of lifelong infection of the nervous system in their respective hosts. This outcome is possible due to a potent neuroinvasive property that is coordinated by two proteins: pUL36 and pUL37. In this study, we explore the cellular protein network in proximity to pUL36 and pUL37 during infection and examine the impact of knocking down the expression of these proteins upon infection.
gene therapies
2026-06-01 | Clinical characteristics and prognostic analysis of patients with herpesvirus meningitis/encephalitis based on cerebrospinal fluid mNGS positivity.
Herpes viruses are a major cause of meningitis/encephalitis in adults. However, their individual clinical phenotypes and outcomes remain incompletely delineated. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) offers a powerful tool for precise pathogen identification, facilitating the comparison of distinct herpes virus infections. This retrospective cohort study analyzed 66 patients with CSF-mNGS confirmed herpes virus meningitis/encephalitis at a single center between October 2019 and August 2025. The cohort was stratified into five etiological groups: herpes simplex virus type 1 (HSV-1, n = 10), herpes simplex virus type 2 (HSV-2, n = 5), varicella-zoster virus (VZV, n = 27), Epstein-Barr virus (EBV, n = 15), and human herpesvirus 7 (HHV-7, n = 9). Demographic, clinical, laboratory, and neuroimaging data were collected. Outcomes were assessed using the Glasgow Outcome Scale (GOS) at 3 months post-discharge. Distinct clinical phenotypes were observed. HSV-1 encephalitis typically presented with psychiatric symptoms, seizures, and temporal lobe involvement on MRI. HSV-2 infection manifested primarily as a febrile headache syndrome with minimal brain parenchymal involvement. VZV infection was associated with the most intense CSF inflammatory response (highest WBC and protein), a higher incidence of hypoglycorrhachia (25.9%) and hypochloridia (40.7%), and unique complications like cranial neuritis and vasculopathy. EBV infections occurred in older patients and showed features overlapping with HSV-1. HHV-7 infected a significantly younger population and was strikingly associated with elevated intracranial pressure (ICP ≥ 330 mmH2O in 33.3%). Multivariate analysis identified a longer interval from symptom onset to hospitalization (OR: 1.118, p = 0.025) and an abnormal EEG (OR: 0.066, p < 0.001) as independent predictors of an unfavorable outcome (GOS < 5). Antiviral or steroid therapy was not significantly associated with prognosis in this cohort. CSF-mNGS reveals distinct and clinically significant phenotypic differences among various herpesvirus meningitis/encephalitis. VZV is characterized by a vigorous CSF inflammatory response and vascular complications, while HHV-7 predominantly affects younger adults and is significantly associated with intracranial hypertension. These findings underscore the value of mNGS in enabling pathogen-directed diagnosis and management, moving beyond syndromic approaches.
2026-04-28 | UNC93B1 Gene Therapy for Pediatric HSV Encephalitis
UNC93B1 (Open Targets score 0.37) is critical for TLR3/7/9 trafficking and antiviral immunity. ClinVar reports multiple UNC93B1 variants (e.g., c.1363+18C>G) associated with herpes susceptibility. Gene therapy delivering functional UNC93B1 could restore innate immunity in children with severe HSV encephalitis due to UNC93B1 deficiency.
2026-03-14 | Herpes simplex virus type 2 encephalitis in critically ill adults: A retrospective analysis of EURECA and Herpetics cohort studies.
BACKGROUND: Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic infectious encephalitis. Although typically associated with benign meningitis, HSV-2 can also cause encephalitis in adults, a condition that remains poorly characterized in intensive care unit (ICU). We aimed to compare the characteristics, management, and outcomes of critically ill adult with HSV-2 and HSV-1 encephalitis. METHODS: We performed a retrospective analysis of adults with herpes simplex encephalitis (HSE) admitted to the ICU in two large multicenter cohorts. Patients were classified according to cerebrospinal fluid (CSF) HSV genotype. The primary endpoint was unfavourable outcome at 3 months, defined as a modified Rankin Scale score 3–6. RESULTS: Among 285 HSE patients, 17 (6%) had HSV-2 encephalitis (age 60 [53–67] years, female sex 58.8%). Although the proportion of immunocompromised status did not differ significantly between groups (29.4% vs 15.4%, p = 0.13), HSV-2 cases had a significantly higher prevalence of HIV infection (17.6 vs 1.5%, p < 0.01), less frequent brain MRI abnormalities (85.7% vs 97.7%, p = 0.01) and similar CSF findings compared to HSV-1 cases. The duration of intravenous acyclovir treatment was shorter for HSV-2 cases (18 [4–21] days) versus 21[20–21] days, p = 0.04). Unfavourable outcome occurred in 9/16 (56.3%) patients with HSV-2 encephalitis and in 175/236 (74.2%) patients with HSV-1 encephalitis (p = 0.25). CONCLUSION: Encephalitis caused by HSV-2 represent a consistent proportion of severe HSE. Clinical presentation and outcomes and broadly comparable to those of HSV-1 cases, underscoring the importance of early recognition and standardized management of encephalitis caused by HSV, regardless of genotype.
2026-02-04 | What are the risks to a 2-week-old fetus from maternal HSV encephalitis?
Maternal HSV encephalitis poses significant risks to a 2-week-old fetus, with potential for severe outcomes including miscarriage and developmental issues, although evidence specific to early gestation is limited.
2025-12-22 | Epidemiology and Prognostic Factors of Herpes Simplex Virus Encephalitis in Japan: A Nationwide Database Study.
Herpes simplex virus encephalitis(HSE) is a rare but life-threatening condition. While the disease has been well characterized in Western countries, large-scale epidemiological data from Japan are lacking. Using the Diagnosis Procedure Combination(DPC) Study Group database, we identified patients hospitalized with HSE between July 2010 and March 2023. Patients were identified using ICD-10 codes. Nationwide incidence was estimated by multiplying the observed case counts by the annual ratio of total discharges in the national MHLW-DPC database to those in the DPC Study Group. We used generalized estimating equations (GEE) to account for clustering within hospitals in multivariable models. In-hospital mortality and functional and neurological outcomes were assessed. Multivariable logistic regression identified prognostic factors. A total of 6,788 patients were identified. The annual incidence of HSE ranged from 5.7 to 8.2 per 100,000 hospitalizations. Overall, in-hospital mortality was 6.0%. Of 6,378 survivors, 2,295 (36.0%) had a Barthel Index score ≤90 and 1,602 (25.1%) had impaired consciousness (Japan Coma Scale ≥1) at discharge. A composite poor outcome (death or impaired consciousness) occurred in 2,012 (29.6%). Older age (especially ≥80 years), impaired consciousness at presentation, and comorbidities such as congestive heart failure, chronic renal disease, malignancy, and underweight status were associated with in-hospital mortality and poor outcomes. This multicenter analysis of HSV encephalitis in Japan showed that HSV encephalitis in Japan was associated with substantial disability among survivors, in addition to non-negligible mortality. Our findings highlight the need for post-acute rehabilitation to reduce the burden of residual disability.
other
2026-07-09 | Glycoprotein G enables HSV-2 neuroinvasion and provides protection as a glycosylated vaccine antigen.
The role of glycoprotein G (gG-2) of herpes simplex virus type 2 (HSV-2) in viral pathogenesis remains poorly understood. gG-2 is cleaved into a secreted form (sgG-2) and a membrane-associated form (mgG-2), but the in vivo function of mgG-2 and the contribution of its glycosylation to immune responses have not been defined. Here, we provide a comprehensive characterization of the N- and O-linked glycosylation profile of mgG-2 and investigate its functional relevance for viral spread and vaccine-induced immunity. Using a mouse genital infection model, we show that an mgG-2-deficient HSV-2 mutant replicates in vaginal epithelial cells but is severely impaired in dissemination to dorsal root ganglia and the central nervous system, identifying mgG-2 as a key determinant of neuronal spread in vivo. In parallel, immunization with recombinant mgG-2 elicited strong humoral and Th1-polarized CD4 + T-cell responses and conferred protection against genital HSV-2 challenge. Importantly, glycosylation of mgG-2 was required for optimal immunogenicity and protection, as deglycosylated variants induced reduced CD4 + T-cell responses and allowed increased viral spread to neuronal tissues. Mechanistically, our findings suggest that glycosylation of mgG-2 modulates antigen recognition and shapes adaptive immune responses that limit viral dissemination after vaccination. Together, these results demonstrate that mgG-2 plays a critical role in HSV-2 pathogenesis and provide a strong rationale for targeting glycosylated mgG-2 in the development of both prophylactic and therapeutic vaccines against HSV-2.
2026-03-27 | Immunogenicity and Efficacy of a Trivalent HSV-2 gC2, gD2, gE2 Nucleoside-Modified mRNA-LNP Vaccine Against HSV-1 Eye Infection and Neuroinvasion in Mice.
Eye infection with herpes simplex virus type 1 (HSV-1) can result in keratitis, a leading cause of corneal blindness. We evaluated whether an experimental vaccine containing HSV-2 immunogens to prevent genital herpes also protects against HSV-1 eye infection and neuroinvasion. Mice were immunized twice, one month apart, with PBS or a nucleoside-modified lipid nanoparticle vaccine containing mRNA encoding for gC2, gD2, and gE2. One month later, 106 plaque forming units (PFU) (10 lethal dose 50, LD50) of the HSV-1 McKrae strain were added to the intact cornea of each eye. The vaccine prevented death and markedly reduced eyelid and attached conjunctival inflammation (blepharoconjunctivitis) and weight loss compared with the PBS group. Tissues from the ocular conjunctiva and eye bulb, olfactory bulb/peduncle, trigeminal ganglia, and brain (brainstem, cerebrum, and cerebellum) were harvested 5 days post-infection from 5 mice each in the PBS and vaccine groups, and from another 10 mice in the vaccine group 7 weeks post-infection. At 5 days, HSV-1 was not detected in any tissue in the vaccine group, while viral titers were positive in 16 of 25 (64%), and HSV-1 DNA was detected in 22 of 25 (88%) individual tissues in the PBS group. Histopathological and immunohistochemical analysis at 5 days post-infection confirmed that the vaccine protected against inflammation; however, some animals experienced breakthrough blepharoconjunctivitis. At 7 weeks, 3 of 10 (30%) mice in the vaccine group had HSV-1 DNA detected in the eyes or trigeminal ganglia tissues, but no animal had HSV-1 DNA detected in brain tissues. The vaccine produced cross-reactive HSV-1 neutralizing antibodies and gD1 IgG binding antibodies, but low or undetectable cross-reactive binding antibodies to gC1 and gE1. Despite occasional mild, localized breakthrough infections, the vaccine provided disease-modifying immunity and was neuroprotective. The results suggest that a single herpes vaccine effective against genital HSV-2 may be neuroprotective against HSV-1 following eye infection.
2026-03-13 | Enucleated cells with Nectin-1 overexpression capture HSV-1 and promote viral elimination for herpes simplex encephalitis therapy.
Herpes simplex encephalitis (HSE) is a life-threatening disease of the central nervous system caused by herpes simplex virus type 1 (HSV-1). Despite being a standard treatment, antiviral acyclovir and its derivatives often face limitations in clinical application due to their side effects and viral drug resistance. Inspired by viral entry through recognition of nectin-1 on the host cell surface, we engineered enucleated mesenchymal stem cells with high nectin-1 expression (eMSCs) to serve as "decoys" for capturing HSV-1. We found that eMSCs competitively captured the virus in the presence of neurons while inhibiting its replication and spread by removing the nucleus in advance. Interestingly, due to the absence of nuclei, eMSCs capturing the virus trigger macrophage efferocytosis through intrinsic apoptosis after approximately 60 h, thereby accelerating existing viral clearance. This is a property lacking in current antiviral drugs, including ACV. In summary, this strategy significantly improved the quality of life of HSE mice.
2026-01-26 | Systematic evaluation of HSV-1 Δ34.5Δ47 as a dual-function platform for attenuated HSV-1 vaccine and heterologous antigen delivery.
Herpes simplex virus type 1 (HSV-1) causes lifelong latent infection and is associated with severe diseases, including herpes simplex encephalitis, neonatal herpes, and no licensed vaccine is currently available for this pathogen. Here, we systematically evaluated an attenuated HSV-1 platform with deletions in ICP34.5 and ICP47 genes (HSV-1 Δ34.5Δ47) for application as a dual-function vaccine. This construct, generated by BAC-galK recombination, showed attenuated replication in vitro. Notably, it elicited robust humoral and cellular immune responses in mice, and provided complete protection against lethal challenge with virulent HSV-1 McKrae strain through both corneal and genital tract infection routes. To assess its utility for heterologous antigen delivery, we engineered a recombinant HSV-1 Δ34.5Δ47-N, which expresses the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein. This recombinant virus retained the protective efficacy against HSV-1 and induced robust N-specific immune responses. Passive serum transfer and in vivo T-cell depletion studies demonstrated that humoral immunity was sufficient to mediate protective immunity against HSV-1 challenge. Safety assessment revealed no detectable viral mRNA or pathological lesions in the brains of immunized animals. These findings support HSV-1 Δ34.5Δ47 as a safe and versatile platform for both HSV-1 prophylaxis and heterologous antigen delivery.
2025-09-28 | Alteration of <i>IFN</i>α and <i>IFN</i>β gene expression by siRNA targeting the <i>Nup98</i> gene during <i>in vitro</i> HSV-1 infection
Herpes simplex virus type 1 (HSV-1) is taxonomically classified as α-herpesvirus and is a complex double-stranded DNA virus. HSV-1 infections are extremely common among human population, with a global prevalence of 65% in persons under 50. In addition to labial and genital lesions, HSV-1-associated diseases include herpetic stromal keratitis, HSV encephalitis, and Alzheimer’s disease. Therefore, adaptive immune response is essential for controlling HSV infection, its reactivation, and complications. Key components of the adaptive immunity include IFNα and IFNβ, which play an important role at the early stages of infection caused by herpesviruses. Increased IFNα expression induces a systemic immune response, by activating NK cells, T lymphocytes, and increasing their migration to the inflammation site, as well as suppression of the viral life cycle by stimulating NK cell cytotoxicity and Th1 cell differentiation. Moreover, the main functions of IFNβ are to induce expression of interferon-stimulating genes (ISGs), whose expression products are able to inhibit viral reproduction cycle at various stages. A wide range of drug therapies and other approaches are currently used to treat herpes infections. Over time, however, an increased incidence of HSV-1 infection is observed in general population. In view of the current trends, it is necessary to search for new approaches aimed at reducing the incidence of HSV-1 infection and its complications. A promising approach may include usage of RNA interference effect, which underlies the action of potential new-generation antiherpetic drugs. RNA interference is a targeted inhibition of mRNA translation which entails disruption of subsequent protein biosynthesis. During its reproduction, HSV-1 imports viral DNA through the nuclear pore complex (NPC), located at the nuclear membrane. The NPC consists of nucleoporin proteins (Nup98, Nup205, NXF1 and others). Therefore, disruption of NPC structure resulting from miRNA-mediated inhibition of nucleoporin protein formation may hypothetically lead to a decreased HSV-1 reproduction.
antibodies
2026-05-27 | Bispecific antibodies targeting herpes simplex virus glycoproteins B and D.
Herpes simplex viruses (HSV-1 and HSV-2) can be transmitted both orally and sexually and cause lifelong morbidity and, in some cases, meningitis and encephalitis. Although several clinical trials using subunit antigens have been conducted, no vaccine exists. One problem in viral treatment is the emergence of drug resistance through mutations, thereby conferring resistance. Treatment with antibodies targeting multiple epitopes, such as antibody cocktails or bispecific antibodies (BsAbs), should reduce the likelihood of viral escape. We screened pairs of antibodies targeting key functional sites on glycoproteins B (gB) and D (gD), which are crucial for HSV entry. Murine hybridoma cells expressing anti-gD and anti-gB Mabs were sequenced. Recombinant antibodies, mono- and bispecific, were purified from supernatants of 293T transfected cells. From a panel of gD-gB monoclonal antibodies (Mabs), we selected MC2 (anti-gD) and C226 (anti-gB) for the design of BsAbs: MC2/C226sc and a simpler version in which the C226scFv was cloned at the C-terminus of MC2 Fc, which we termed BD Tetra. Notably, both MC2/C226sc and BD Tetra BsAbs simultaneously recognized and bound gB and gD and had a marked synergistic effect on inhibiting cell-cell fusion, virus entry, and plaque formation. Although MC2 is HSV-2 specific, both MC2/C226sc and BD Tetra showed activity against HSV-1. The Fc domains of these two BsAbs were equally effective at binding to mouse Fcγ receptors RI or RIV in vitro. The data presented here demonstrate the generation, characterization, and potential of bispecific antibodies targeting two distinct glycoproteins to enhance neutralization of herpes simplex virus compared with monoclonal antibodies. BsAbs offer a potential avenue for herpes therapeutics, but their design and mechanism of action require careful consideration for optimal efficacy. Engineering different formats of BsAbs will not only enable optimal protective and therapeutic outcomes but also aid in the study of the spatial relationships between key glycoproteins involved in HSV infection. We propose that targeting distinct steps of the fusion cascade will yield a BsAb that is highly effective.
2025-12-17 | A broadly neutralizing antibody confers cross-genus protection against alphaherpesviruses by inhibiting gB-mediated membrane fusion.
The global prevalence and disease burden of alphaherpesviruses infections, including human-infecting viruses such as HSV-1, HSV-2, and VZV, as well as animal-infecting viruses like PRV, BHV, CHV, and FHV, highlight the unmet need for more effective and universal antiviral strategies. However, there has been no significant progress in developing broad-spectrum interventions against herpesvirus. Here we report the identification of a broadly neutralizing antibody against alphaherpesviruses, 16F9, which targets the glycoprotein B (gB) of alphaherpesviruses and offers cross-protection against multiple viruses such as HSV-1, HSV-2, and PRV in mice. 16F9 demonstrated robust therapeutic efficacy in various female mouse models of herpesvirus diseases including PRV-induced viral encephalitis, HSV-1-induced viral encephalitis, viral keratitis, cutaneous herpes, and neonatal herpesvirus infections. High-resolution cryo-electron microscopy structures revealed that 16F9 binds a conserved site of vulnerability on Domain I of gB. The binding of 16F9 disrupts the interaction between pre-gB and gHgL complex, thereby preventing viral membrane fusion and blocking viral infection. This study provides a foundation for advancing antiviral strategies and underscores the potential of gB-targeted interventions for combating herpesvirus infections.
2025-09-01 | Refractory "status dyskineticus" in a child with post-herpes simplex virus 1 N-methyl-D-aspartate receptor encephalitis: a case report.
Herpes simplex virus 1 (HSV-1) encephalitis may result in relapsing neurological symptoms secondary to immune-mediated processes, including anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Refractory status dyskineticus (RSD), a severe subset of status dystonicus, is characterized by a hyperkinetic movement disorder phenotype alongside dystonic features. This critical condition presents substantial challenges in neurocritical care. The present case highlights the importance of prompt intervention and immunotherapy escalation in managing severe movement disorders due to pediatric autoimmune encephalitis. A previously healthy 2-year-old boy was admitted with HSV-1 encephalitis, confirmed by brain MRI and cerebrospinal fluid (CSF) analysis. When initially treated with acyclovir, the patient achieved partial recovery but later developed encephalopathy, vomiting, behavioral regression, and severe dyskinetic movements. Upon transfer to our center, NMDAR antibodies were detected in the CSF, with no evidence of HSV reactivation. Despite first-line immunotherapy with intravenous steroids and immunoglobulins, his condition deteriorated, progressing to status dyskineticus (SD), with dystonia, hyperthermia, and hypercapnia, requiring intensive care management and mechanical ventilation. A treatment escalation regimen including both immunotherapy with rituximab, rapamycin, bortezomib, and multiple symptomatic therapies resulted in gradual improvement and resolution of the movement disorder. This case underscores the crucial role of neurocritical care in managing refractory movement disorders associated with autoimmune encephalitis. Early recognition and immunotherapy escalation are essential to improve outcomes in children with complex, life-threatening neurological conditions. A comprehensive, multidisciplinary approach in the neurocritical care setting is key to achieving recovery and minimizing long-term neurological damage.
2025-08-09 | Clinical phenotype and outcomes in autoimmune encephalitis after herpes simplex virus encephalitis: A systematic review and meta-analysis.
Autoimmune encephalitis after herpes simplex virus encephalitis (HSVE-AE) represents the intersection of central nervous system infection and autoimmunity. Defining the phenotype and the safety and effectiveness of immunotherapy in HSVE-AE would help identify immunotherapy candidates, optimise therapeutic strategies, and improve patient outcomes. We systematically searched Embase, Medline, PubMed, and Web of Science (2007-2024) for cases meeting consensus criteria for AE after confirmed HSVE. Demographics, phenotype, treatment and outcome data were extracted. Dimensionality reduction, network analysis, and multivariate logistic regression was used to explore age- and diagnosis-specific patterns and outcome predictors. From 2259 articles screened, 78 studies (225 patients) were included (median age 7.25 years; 52.9% female). Children (0-12 years) experienced more seizures during HSVE (p=0.003) and movement disorders during AE (p<0.001). Older patients (>12 years) had more headaches during HSVE (p=0.003), and speech dysfunction (p=0.02) and neuropsychiatric symptoms (p=0.02) during AE. HSVE-AE (89.3% N-methyl-D-aspartate receptor-antibody encephalitis [NMDAR-AbE]) differed significantly from a canonical NMDAR-AbE cohort (n=1550) in clinical, paraclinical and outcome domains. Poor outcomes were linked to infant and older adult age, neuropsychiatric symptoms, and AE-phase mRS >4. Rituximab independently predicted better outcomes. Disability improved over time (p<0.001), with adverse event rates comparable to NMDAR-AbE. This meta-analysis defines novel age-specific HSVE-AE features, outcome predictors, and confirms the safety and improved outcomes of HSVE-AE after immunotherapy.
2025-05-21 | Neurological outcomes and disability predictors in paediatric herpes simplex virus encephalitis: a multicentre cohort from French tertiary hospitals.
To identify factors associated with the neurological outcome of HSVE in children. In this retrospective multicentric observational study, clinical, paraclinical data at onset and neurological outcomes at last follow-up of children (≥28 days and <18 years old) with HSVE, were studied. Univariate and multivariate analyses were performed to identify factors associated with neurological outcome. 49 children (mean age of 4.9 ± 5.5 years) were included. At last follow-up of 5.9 ± 3,13 years, 2 children died (4 %) and 37 (76 %) children presented with poor neurological outcome with epilepsy (57 %), intellectual disability (51 %) and language disorders (47 %). Rehabilitation was necessary for 76 % and 59 % had abnormal academic performances. At onset, younger age and seizures were significantly associated to language disorders (p < 0.01), motor disabilities (p = 0.01), and intellectual disabilities (p = 0.01) in univariate analysis. Abnormal MRIs were more frequent in children with neurological sequalae (p = 0.01). Multivariate analyses identified that: (1) epilepsy occurred more frequently in females (p = 0.03), with insular lesions (p = 0.048); (2) language disorders were more common in children who had seizures at onset (p 0.02); (3) motor disorders were more frequent in younger children (p = 0.03) with thalamic lesions (p = 0.04). Our findings indicate that despite decrease in mortality rates, neurological disabilities in children with HSVE still persist at high levels. This underscores the need to enhance HSVE management strategies. Moreover, the identified risk factors associated with poor neurological outcomes can aid in identifying high-risk children, facilitating the implementation of alternative treatment approaches such as immunotherapy or intensive rehabilitation.
small molecules
2026-09-26 | Host Genetic Susceptibility and Antiviral Immunity Shape the Pathogenesis and Outcomes of Herpes Simplex Encephalitis.
Herpes simplex encephalitis (HSE), predominantly caused by herpes simplex virus type 1 (HSV-1), is the most common sporadic viral encephalitis worldwide and remains life threatening despite antiviral therapy. Although herpes simplex virus (HSV) infection is highly prevalent, only a minority of individuals develop HSE, highlighting the critical contribution of host-specific factors to disease susceptibility. This review summarizes current knowledge regarding HSE epidemiology, antiviral immunity, genetic susceptibility, and therapeutic advances. Underlying inborn errors of immunity fall into three mechanistic groups: impaired innate immune sensing pathways, including Toll-like receptor 3 (TLR3), retinoic-acid-inducible gene-I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), which compromise type I interferon (IFN) production in central nervous system (CNS) resident cells; disrupted neuron intrinsic antiviral mechanisms represented by mutations in specific genes (e.g., DBR1, SNORA31, and GTF3A); and defects in other IFN signaling molecules, including interferon-α/β receptor 1 (IFNAR1) and 2 (IFNAR2), as well as signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2), which further weaken antiviral defenses. These findings underscore cell autonomous antiviral responses within the brain and provide insights into the selective vulnerability to HSE. Emerging therapeutic strategies aim to integrate antiviral treatment with modulation of host immune responses and, potentially, personalized approaches based on genetic profiling. In all, we emphasize the pivotal role of CNS-intrinsic immunity and host genetic factors in shaping disease outcomes. A deeper understanding of the interplay between HSV and host defense mechanisms will facilitate the development of improved diagnostic tools and targeted therapies, ultimately reducing the burden of this devastating disease.
2026-09-26 | A Proof-of-Concept Study for the Efficacy of Dispirotripiperazine PDSTP in a Mouse Model of Herpes Simplex Herpetic Encephalitis.
Herpes simplex encephalitis (HSE) remains a life-threatening disease with high mortality and severe neurological complications, despite acyclovir therapy being limited by delayed diagnosis, drug resistance, and poor blood-brain barrier penetration. New antivirals with different mechanisms of action are urgently needed. We evaluated PDSTP, a novel dispirotripiperazine-based compound targeting host heparan sulfate proteoglycans (HSPGs), in mouse models of HSV-1 encephalitis. This study evaluates the therapeutic and prophylactic potential of PDSTP, an antiviral compound that blocks HSV glycoconjugates on the host cell membrane, using a well-established mouse model of herpes encephalitis. BALB/c mice were infected with HSV-1 strains VR-539 or VR-733 via intraperitoneal (IP) or intranasal (IN) routes. PDSTP was administered orally (PO) or intraperitoneally (IP) at 12.5-80 mg/kg/day, alone or in combination with acyclovir (10-100 mg/kg/day), using a prophylactic-therapeutic regimen (2 h pre-infection, then twice daily for 7 days). Survival, weight loss, mean survival time, and brain viral loads were assessed. PDSTP at 80 mg/kg/day (PO) protected 30-40% of VR-733-infected mice and extended lifespan 1.9-fold (p < 0.05), comparable to acyclovir at 100 mg/kg/day. IP administration was superior to PO. The combination of IP PDSTP (12.5 mg/kg/day) with IP acyclovir (10 mg/kg/day) achieved 100% survival, prevented weight loss, and significantly reduced brain viral titers (p < 0.001) in both infection models. PDSTP demonstrates dose- and strain-dependent activity as monotherapy and enhanced efficacy when combined with acyclovir. The IP combination provided complete protection at low doses, supporting PDSTP as a promising candidate for further development against HSE.
2026-09-22 | EARLY DIAGNOSIS AND TREATMENT PROTOCOLS FOR HERPES ENCEPHALITIS IN PUBLIC HEALTH
Herpes simplex virus encephalitis (HSE) is one of the leading infectious causes of central nervous system disease, characterized by high morbidity and mortality and a significant risk of neurological sequelae despite standardized antiviral treatment. This narrative review aims to compile the main evidence related to early diagnosis, pathophysiology, immunobiology, and current therapeutic approaches to herpes simplex encephalitis, with an emphasis on the pathways of tissue damage and secondary immune-mediated manifestations. The literature search was conducted on the PubMed platform using the search terms “Herpes Simplex Encephalitis” and “Therapeutics,” combined with the Boolean operators “AND” and “OR.” We selected original studies, prospective cohort studies, translational research, and conceptual reviews published in the last five years in English and Portuguese, excluding duplicate publications, studies with methodological weaknesses, and works that fell outside the scope of this study. The evidence indicates that the clinical presentation of HSE can be nonspecific, requiring integration of clinical manifestations, neuroimaging, electroencephalography, and cerebrospinal fluid analysis, with particular emphasis on polymerase chain reaction (PCR) for the detection of HSV DNA. However, laboratory confirmation should never delay the empirical infusion of intravenous acyclovir based on clinical suspicion, since therapeutic latency is directly correlated with a worse functional prognosis. Furthermore, recent data demonstrate that residual morbidity is not exclusively related to viral replication but involves mechanisms of neuroinflammation, alterations in intrinsic cerebral immunity, ferroptosis, and post-herpetic autoimmunity. Translational models reinforce the finding that HSV-1 infection can disrupt neuroepithelial integrity, neuronal activity, and antioxidant mechanisms; in this context, adjunctive immunomodulatory approaches have been shown to provide preclinical neuroprotection. Additionally, the identification of innate defects in cerebral immunity and the recognition of post-herpetic autoimmune encephalitis have expanded our understanding of the clinical and immunological heterogeneity of the disease. Ultimately, the management of herpes simplex encephalitis prioritizes early recognition and immediate administration of acyclovir, while new immunomodulatory strategies remain under investigation. Given the complex host immune response, clinical studies are still needed to establish the safety and efficacy of combination therapies, as well as biomarkers capable of identifying patients at higher risk for neurological damage and autoimmune complications.
2026-09-21 | RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis
Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic viral encephalitis, where uncontrolled viral replication and neuroinflammation drive fatal brain injury. Inherited RIPK3 deficiency predisposes humans to severe disease, but the protective mechanism remains unclear. Using single-cell transcriptomics, genetic knockout models, and analysis of viral replication, interferon production, and cell death across neurons, astrocytes, microglia, and myeloid cells, we show that RIPK3 acts as a cell-type-specific molecular switch. RIPK3 scaffolding promotes interferon response and viral control in multiple central nervous system cell types, while RIPK3-dependent apoptosis limits myeloid accumulation. In contrast, RIPK3 kinase activity in astrocytes triggers necroptosis, leading to neuronal loss and lethal neuroinflammation. Genetic or pharmacological inhibition of RIPK3 kinase suppresses astrocyte necroptosis, enhances IFN responses, preserves brain integrity, and improves survival. These findings suggest that selective modulation of RIPK3 signaling may balance antiviral defense with limitation of neuropathology in HSV-1 encephalitis. HSV-1 encephalitis causes severe brain injury, but the mechanism of immune pathology remains to be explored. The authors here show that RIPK3 drives astrocyte death though benefits viral control in other cell types, further RIPK3 inhibition promotes survival.
2026-09-16 | Computational identification of Ginkgo biloba phytochemicals as dual inhibitors of herpes simplex virus type 1 glycoproteins gB and gD targeting its entry and Alzheimer's disease pathogenesis.
Herpes simplex virus type 1 (HSV-1) causes severe neurological complications such as herpes simplex encephalitis and Alzheimer's disease (AD). Its entry is mediated by glycoproteins gD and gB, which regulate receptor binding and membrane fusion. Targeting these entry glycoproteins represents a promising therapeutic strategy to limit HSV-1 infection and its contribution to AD pathogenesis. Therefore, this study aimed to identify natural dual inhibitors of HSV-1 glycoproteins gB and gD from Ginkgo biloba using an integrated computational approach involving molecular docking, pharmacokinetic, toxicity, and bioactivity profiling, molecular dynamics simulations, and MM-GBSA binding free energy analyses to evaluate binding stability and therapeutic potential. A total of 39 phytochemicals were retrieved from IMPPAT 2.0 and PubChem databases and docked against HSV-1 glycoproteins gB and gD. Pharmacokinetics and toxicity were assessed using admetSAR 3.0, SwissADME, Deep-PK, and pKCSM. Molecular docking revealed several phytochemicals with strong binding affinities to HSV-1 glycoproteins gB and gD, compared to docosanol. Among these, β-sitosterol and ginkgolide A exhibited favorable drug-likeness, acceptable oral bioavailability, no mutagenic and hepatotoxic effects, and biologically active. Molecular dynamic simulation confirmed their greatest binding stability compared to docosanol. MM-GBSA binding free energy analysis further validated their strong and stable interactions within the active sites of HSV-1 glycoproteins gB and gD. These findings identify β-sitosterol and ginkgolide A as promising dual-target inhibitors of HSV-1 glycoproteins gB and gD in context of HSV-1-associated AD pathogenesis. However, experimental validation is required to confirm their antiviral efficacy and potential relevance to AD.
proteins
2026-08-12 | Adjunctive Intravenous Immunoglobulin in Severe Herpes Simplex Encephalitis: A Case Report with a Favorable Outcome
Both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) can cause encephalitis; however, HSV-1 is the most common etiological agent. Herpes simplex encephalitis (HSE) presents with a wide spectrum of clinical manifestations from fever and headaches to acute neurological dysfunctions with seizures. The mortality rate is high even with the right treatment. In this case report we present a 36-year-old female with no comorbidities that presented to the emergency department with a headache and reported olfactory hallucinations. The patient experienced rapid cognitive and neurological deterioration, became stuporous, almost entirely unconscious despite intravenous antiviral therapy. The patient was treated as a ‘last resort’ with intravenous immunoglobulins, and was induced into a coma in the Intensive Care Unit. The patient was extubated a few days later and returned to the neurology ward in a very much improved state where she continued her recovery. At the three-month follow-up the patient exceeded all expectations and was slowly returning to her life before the illness.
2026-06-12 | Differential Sensitivity of HSV-1 and PRV to IFN-λ Reveals a Neuron-Specific Antiviral Role for RSAD2.
Alpha herpesviruses (α-HV) initially infect mucosal epithelial cells and subsequently establish lifelong latency in the peripheral nervous system (PNS). Herpes simplex virus-1 (HSV-1), a human pathogen persisting in the majority of the adult population, shares neuroinvasive properties with Pseudorabies virus (PRV), a swine α-HV, commonly used as a model α-HV. Utilizing primary peripheral neuronal cultures, we previously showed that IFN-λ pre-treatment significantly reduced PRV yield. In this paper, we further characterized the early and late neuronal responses to IFN-λ by RNA-seq, and the antiviral potential of this response against HSV-1. Notably, HSV-1 exhibited neuron-specific resistance to IFN-λ mediated antiviral responses both in murine primary neurons and human neuronal cells. An ICP34.5-deficient HSV-1 (Δ34.5) mutant showed IFN-λ sensitivity in neurons, while replicating normally in untreated neurons showing that ICP34.5 is responsible for the neuron specific IFN-λ resistance of HSV-1. Our results further demonstrate that RSAD2 is strongly induced by IFN-λ in neurons, localizing to ER-associated membranes, and effectively restricting α-HV protein synthesis in the absence of ICP34.5. siRNA-mediated RSAD2 knockdown in IFN-λ-primed primary neurons largely restored replication of Δ34.5 HSV-1, highlighting the role of this IFN-λ induced host factor in neuronal infections. Together, neuronal IFN-λ-induced RSAD2 and HSV-1 ICP34.5 define a neuron-specific antagonistic mechanism that collectively determines the replication efficiency of HSV-1 in the PNS.
2025-11-03 | Cerebrolysin treatment in a case of post-herpes simplex encephalitis with neuropsychiatric symptoms.
Herpes simplex encephalitis (HSE) is a severe central nervous system (CNS) infection associated with cognitive decline, psychotic symptoms, and epilepsy. Despite aggressive antiviral and corticosteroid treatments, post-HSE complications remain challenging to manage. We report a case of a 33-year-old female patient with post-HSE neuropsychiatric symptoms who showed significant improvement following Cerebrolysin treatment. The patient was treated with acyclovir and dexamethasone in the acute phase, followed by Cerebrolysin administration in the post-acute phase. This case highlights the potential therapeutic role of Cerebrolysin in managing post-encephalitic cognitive dysfunction, underscoring the need for further studies.
2025-09-16 | Unleashing the Antiviral Potential of Stapled Peptides: A New Frontier in Combating Human Neurotropic Viral Infections.
Neurotropic viral infections continue to pose significant global health challenges, with pathogens such as herpes simplex virus (HSV), varicella-zoster virus, human immunodeficiency virus, poliovirus, enteroviruses, parechovirus, West Nile virus and Japanese encephalitis virus driving the search for more effective therapeutic interventions. Current antiviral strategies, including small molecules and monoclonal antibodies, often face limitations such as drug resistance, narrow spectrum activity and adverse side effects, underscoring the need for alternative approaches. Antiviral peptides are emerging as potential therapeutic agents against these viral infections as entry and fusion inhibitors. However, their clinical development is limited by poor stability, low bioavailability and insufficient cellular penetration. To address these limitations, peptide stapling, a chemical modification that stabilises peptide α-helices through covalent linkage, has emerged as a transformative technique to enhance the therapeutic potential of peptides, especially in antiviral drug development. Stapling techniques, including hydrocarbon staples, lactam bridges and metal-coordination bonds, are explored for their ability to improve peptide stability, bioavailability and target binding affinity. This review examines the application of stapling in the development of antiviral peptides with a focus on stapled peptides targeting viral fusion and entry mechanisms, highlighting their potential against neurotropic viruses such as HSV and influenza. By integrating the structural rigidity conferred by stapling, these constructs promise to overcome delivery barriers and achieve superior antiviral efficacy. This paper underscores the pivotal role of peptide stapling by highlighting recent advancements in antiviral therapeutics and presents a roadmap for future research into multifunctional stapled peptides.
2024-08-14 | Leveraging biotin-based proximity labeling to identify cellular factors governing early alphaherpesvirus infection.
Neurotropic alphaherpesviruses, including herpes simplex virus type 1 and pseudorabies virus, establish a lifelong presence within the peripheral nervous system of their mammalian hosts. Upon entering cells, two conserved tegument proteins, pUL36 and pUL37, traffic DNA-containing capsids to nuclei. These proteins support long-distance retrograde axonal transport and invasion of the nervous system in vivo. To better understand how pUL36 and pUL37 function, recombinant viral particles carrying BioID2 fused to these proteins were produced to biotinylate cellular proteins in their proximity (<10 nm) during infection. Eighty-six high-confidence host proteins were identified by mass spectrometry and subsequently targeted by CRISPR-Cas9 gene editing to assess their contributions to early infection. Proteins were identified that both supported and antagonized infection in immortalized human epithelial cells. The latter included zyxin, a protein that localizes to focal adhesions and regulates actin cytoskeletal dynamics. Zyxin knockout cells were hyper-permissive to infection and could be rescued with even modest expression of GFP-zyxin. These results provide a resource for studies of the virus-cell interface and identify zyxin as a novel deterrent to alphaherpesvirus infection.IMPORTANCENeuroinvasive alphaherpesviruses are highly prevalent with many members found across mammals [e.g., herpes simplex virus type 1 (HSV-1) in humans and pseudorabies virus in pigs]. HSV-1 causes a range of clinical manifestations from cold sores to blindness and encephalitis. There are no vaccines or curative therapies available for HSV-1. A fundamental feature of these viruses is their establishment of lifelong infection of the nervous system in their respective hosts. This outcome is possible due to a potent neuroinvasive property that is coordinated by two proteins: pUL36 and pUL37. In this study, we explore the cellular protein network in proximity to pUL36 and pUL37 during infection and examine the impact of knocking down the expression of these proteins upon infection.
gene therapies
2026-06-01 | Clinical characteristics and prognostic analysis of patients with herpesvirus meningitis/encephalitis based on cerebrospinal fluid mNGS positivity.
Herpes viruses are a major cause of meningitis/encephalitis in adults. However, their individual clinical phenotypes and outcomes remain incompletely delineated. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) offers a powerful tool for precise pathogen identification, facilitating the comparison of distinct herpes virus infections. This retrospective cohort study analyzed 66 patients with CSF-mNGS confirmed herpes virus meningitis/encephalitis at a single center between October 2019 and August 2025. The cohort was stratified into five etiological groups: herpes simplex virus type 1 (HSV-1, n = 10), herpes simplex virus type 2 (HSV-2, n = 5), varicella-zoster virus (VZV, n = 27), Epstein-Barr virus (EBV, n = 15), and human herpesvirus 7 (HHV-7, n = 9). Demographic, clinical, laboratory, and neuroimaging data were collected. Outcomes were assessed using the Glasgow Outcome Scale (GOS) at 3 months post-discharge. Distinct clinical phenotypes were observed. HSV-1 encephalitis typically presented with psychiatric symptoms, seizures, and temporal lobe involvement on MRI. HSV-2 infection manifested primarily as a febrile headache syndrome with minimal brain parenchymal involvement. VZV infection was associated with the most intense CSF inflammatory response (highest WBC and protein), a higher incidence of hypoglycorrhachia (25.9%) and hypochloridia (40.7%), and unique complications like cranial neuritis and vasculopathy. EBV infections occurred in older patients and showed features overlapping with HSV-1. HHV-7 infected a significantly younger population and was strikingly associated with elevated intracranial pressure (ICP ≥ 330 mmH2O in 33.3%). Multivariate analysis identified a longer interval from symptom onset to hospitalization (OR: 1.118, p = 0.025) and an abnormal EEG (OR: 0.066, p < 0.001) as independent predictors of an unfavorable outcome (GOS < 5). Antiviral or steroid therapy was not significantly associated with prognosis in this cohort. CSF-mNGS reveals distinct and clinically significant phenotypic differences among various herpesvirus meningitis/encephalitis. VZV is characterized by a vigorous CSF inflammatory response and vascular complications, while HHV-7 predominantly affects younger adults and is significantly associated with intracranial hypertension. These findings underscore the value of mNGS in enabling pathogen-directed diagnosis and management, moving beyond syndromic approaches.
2026-04-28 | UNC93B1 Gene Therapy for Pediatric HSV Encephalitis
UNC93B1 (Open Targets score 0.37) is critical for TLR3/7/9 trafficking and antiviral immunity. ClinVar reports multiple UNC93B1 variants (e.g., c.1363+18C>G) associated with herpes susceptibility. Gene therapy delivering functional UNC93B1 could restore innate immunity in children with severe HSV encephalitis due to UNC93B1 deficiency.
2026-03-14 | Herpes simplex virus type 2 encephalitis in critically ill adults: A retrospective analysis of EURECA and Herpetics cohort studies.
BACKGROUND: Herpes simplex virus type 1 (HSV-1) is the leading cause of sporadic infectious encephalitis. Although typically associated with benign meningitis, HSV-2 can also cause encephalitis in adults, a condition that remains poorly characterized in intensive care unit (ICU). We aimed to compare the characteristics, management, and outcomes of critically ill adult with HSV-2 and HSV-1 encephalitis. METHODS: We performed a retrospective analysis of adults with herpes simplex encephalitis (HSE) admitted to the ICU in two large multicenter cohorts. Patients were classified according to cerebrospinal fluid (CSF) HSV genotype. The primary endpoint was unfavourable outcome at 3 months, defined as a modified Rankin Scale score 3–6. RESULTS: Among 285 HSE patients, 17 (6%) had HSV-2 encephalitis (age 60 [53–67] years, female sex 58.8%). Although the proportion of immunocompromised status did not differ significantly between groups (29.4% vs 15.4%, p = 0.13), HSV-2 cases had a significantly higher prevalence of HIV infection (17.6 vs 1.5%, p < 0.01), less frequent brain MRI abnormalities (85.7% vs 97.7%, p = 0.01) and similar CSF findings compared to HSV-1 cases. The duration of intravenous acyclovir treatment was shorter for HSV-2 cases (18 [4–21] days) versus 21[20–21] days, p = 0.04). Unfavourable outcome occurred in 9/16 (56.3%) patients with HSV-2 encephalitis and in 175/236 (74.2%) patients with HSV-1 encephalitis (p = 0.25). CONCLUSION: Encephalitis caused by HSV-2 represent a consistent proportion of severe HSE. Clinical presentation and outcomes and broadly comparable to those of HSV-1 cases, underscoring the importance of early recognition and standardized management of encephalitis caused by HSV, regardless of genotype.
2026-02-04 | What are the risks to a 2-week-old fetus from maternal HSV encephalitis?
Maternal HSV encephalitis poses significant risks to a 2-week-old fetus, with potential for severe outcomes including miscarriage and developmental issues, although evidence specific to early gestation is limited.
2025-12-22 | Epidemiology and Prognostic Factors of Herpes Simplex Virus Encephalitis in Japan: A Nationwide Database Study.
Herpes simplex virus encephalitis(HSE) is a rare but life-threatening condition. While the disease has been well characterized in Western countries, large-scale epidemiological data from Japan are lacking. Using the Diagnosis Procedure Combination(DPC) Study Group database, we identified patients hospitalized with HSE between July 2010 and March 2023. Patients were identified using ICD-10 codes. Nationwide incidence was estimated by multiplying the observed case counts by the annual ratio of total discharges in the national MHLW-DPC database to those in the DPC Study Group. We used generalized estimating equations (GEE) to account for clustering within hospitals in multivariable models. In-hospital mortality and functional and neurological outcomes were assessed. Multivariable logistic regression identified prognostic factors. A total of 6,788 patients were identified. The annual incidence of HSE ranged from 5.7 to 8.2 per 100,000 hospitalizations. Overall, in-hospital mortality was 6.0%. Of 6,378 survivors, 2,295 (36.0%) had a Barthel Index score ≤90 and 1,602 (25.1%) had impaired consciousness (Japan Coma Scale ≥1) at discharge. A composite poor outcome (death or impaired consciousness) occurred in 2,012 (29.6%). Older age (especially ≥80 years), impaired consciousness at presentation, and comorbidities such as congestive heart failure, chronic renal disease, malignancy, and underweight status were associated with in-hospital mortality and poor outcomes. This multicenter analysis of HSV encephalitis in Japan showed that HSV encephalitis in Japan was associated with substantial disability among survivors, in addition to non-negligible mortality. Our findings highlight the need for post-acute rehabilitation to reduce the burden of residual disability.
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2026-07-09 | Glycoprotein G enables HSV-2 neuroinvasion and provides protection as a glycosylated vaccine antigen.
The role of glycoprotein G (gG-2) of herpes simplex virus type 2 (HSV-2) in viral pathogenesis remains poorly understood. gG-2 is cleaved into a secreted form (sgG-2) and a membrane-associated form (mgG-2), but the in vivo function of mgG-2 and the contribution of its glycosylation to immune responses have not been defined. Here, we provide a comprehensive characterization of the N- and O-linked glycosylation profile of mgG-2 and investigate its functional relevance for viral spread and vaccine-induced immunity. Using a mouse genital infection model, we show that an mgG-2-deficient HSV-2 mutant replicates in vaginal epithelial cells but is severely impaired in dissemination to dorsal root ganglia and the central nervous system, identifying mgG-2 as a key determinant of neuronal spread in vivo. In parallel, immunization with recombinant mgG-2 elicited strong humoral and Th1-polarized CD4 + T-cell responses and conferred protection against genital HSV-2 challenge. Importantly, glycosylation of mgG-2 was required for optimal immunogenicity and protection, as deglycosylated variants induced reduced CD4 + T-cell responses and allowed increased viral spread to neuronal tissues. Mechanistically, our findings suggest that glycosylation of mgG-2 modulates antigen recognition and shapes adaptive immune responses that limit viral dissemination after vaccination. Together, these results demonstrate that mgG-2 plays a critical role in HSV-2 pathogenesis and provide a strong rationale for targeting glycosylated mgG-2 in the development of both prophylactic and therapeutic vaccines against HSV-2.
2026-03-27 | Immunogenicity and Efficacy of a Trivalent HSV-2 gC2, gD2, gE2 Nucleoside-Modified mRNA-LNP Vaccine Against HSV-1 Eye Infection and Neuroinvasion in Mice.
Eye infection with herpes simplex virus type 1 (HSV-1) can result in keratitis, a leading cause of corneal blindness. We evaluated whether an experimental vaccine containing HSV-2 immunogens to prevent genital herpes also protects against HSV-1 eye infection and neuroinvasion. Mice were immunized twice, one month apart, with PBS or a nucleoside-modified lipid nanoparticle vaccine containing mRNA encoding for gC2, gD2, and gE2. One month later, 106 plaque forming units (PFU) (10 lethal dose 50, LD50) of the HSV-1 McKrae strain were added to the intact cornea of each eye. The vaccine prevented death and markedly reduced eyelid and attached conjunctival inflammation (blepharoconjunctivitis) and weight loss compared with the PBS group. Tissues from the ocular conjunctiva and eye bulb, olfactory bulb/peduncle, trigeminal ganglia, and brain (brainstem, cerebrum, and cerebellum) were harvested 5 days post-infection from 5 mice each in the PBS and vaccine groups, and from another 10 mice in the vaccine group 7 weeks post-infection. At 5 days, HSV-1 was not detected in any tissue in the vaccine group, while viral titers were positive in 16 of 25 (64%), and HSV-1 DNA was detected in 22 of 25 (88%) individual tissues in the PBS group. Histopathological and immunohistochemical analysis at 5 days post-infection confirmed that the vaccine protected against inflammation; however, some animals experienced breakthrough blepharoconjunctivitis. At 7 weeks, 3 of 10 (30%) mice in the vaccine group had HSV-1 DNA detected in the eyes or trigeminal ganglia tissues, but no animal had HSV-1 DNA detected in brain tissues. The vaccine produced cross-reactive HSV-1 neutralizing antibodies and gD1 IgG binding antibodies, but low or undetectable cross-reactive binding antibodies to gC1 and gE1. Despite occasional mild, localized breakthrough infections, the vaccine provided disease-modifying immunity and was neuroprotective. The results suggest that a single herpes vaccine effective against genital HSV-2 may be neuroprotective against HSV-1 following eye infection.
2026-03-13 | Enucleated cells with Nectin-1 overexpression capture HSV-1 and promote viral elimination for herpes simplex encephalitis therapy.
Herpes simplex encephalitis (HSE) is a life-threatening disease of the central nervous system caused by herpes simplex virus type 1 (HSV-1). Despite being a standard treatment, antiviral acyclovir and its derivatives often face limitations in clinical application due to their side effects and viral drug resistance. Inspired by viral entry through recognition of nectin-1 on the host cell surface, we engineered enucleated mesenchymal stem cells with high nectin-1 expression (eMSCs) to serve as "decoys" for capturing HSV-1. We found that eMSCs competitively captured the virus in the presence of neurons while inhibiting its replication and spread by removing the nucleus in advance. Interestingly, due to the absence of nuclei, eMSCs capturing the virus trigger macrophage efferocytosis through intrinsic apoptosis after approximately 60 h, thereby accelerating existing viral clearance. This is a property lacking in current antiviral drugs, including ACV. In summary, this strategy significantly improved the quality of life of HSE mice.
2026-01-26 | Systematic evaluation of HSV-1 Δ34.5Δ47 as a dual-function platform for attenuated HSV-1 vaccine and heterologous antigen delivery.
Herpes simplex virus type 1 (HSV-1) causes lifelong latent infection and is associated with severe diseases, including herpes simplex encephalitis, neonatal herpes, and no licensed vaccine is currently available for this pathogen. Here, we systematically evaluated an attenuated HSV-1 platform with deletions in ICP34.5 and ICP47 genes (HSV-1 Δ34.5Δ47) for application as a dual-function vaccine. This construct, generated by BAC-galK recombination, showed attenuated replication in vitro. Notably, it elicited robust humoral and cellular immune responses in mice, and provided complete protection against lethal challenge with virulent HSV-1 McKrae strain through both corneal and genital tract infection routes. To assess its utility for heterologous antigen delivery, we engineered a recombinant HSV-1 Δ34.5Δ47-N, which expresses the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein. This recombinant virus retained the protective efficacy against HSV-1 and induced robust N-specific immune responses. Passive serum transfer and in vivo T-cell depletion studies demonstrated that humoral immunity was sufficient to mediate protective immunity against HSV-1 challenge. Safety assessment revealed no detectable viral mRNA or pathological lesions in the brains of immunized animals. These findings support HSV-1 Δ34.5Δ47 as a safe and versatile platform for both HSV-1 prophylaxis and heterologous antigen delivery.
2025-09-28 | Alteration of <i>IFN</i>α and <i>IFN</i>β gene expression by siRNA targeting the <i>Nup98</i> gene during <i>in vitro</i> HSV-1 infection
Herpes simplex virus type 1 (HSV-1) is taxonomically classified as α-herpesvirus and is a complex double-stranded DNA virus. HSV-1 infections are extremely common among human population, with a global prevalence of 65% in persons under 50. In addition to labial and genital lesions, HSV-1-associated diseases include herpetic stromal keratitis, HSV encephalitis, and Alzheimer’s disease. Therefore, adaptive immune response is essential for controlling HSV infection, its reactivation, and complications. Key components of the adaptive immunity include IFNα and IFNβ, which play an important role at the early stages of infection caused by herpesviruses. Increased IFNα expression induces a systemic immune response, by activating NK cells, T lymphocytes, and increasing their migration to the inflammation site, as well as suppression of the viral life cycle by stimulating NK cell cytotoxicity and Th1 cell differentiation. Moreover, the main functions of IFNβ are to induce expression of interferon-stimulating genes (ISGs), whose expression products are able to inhibit viral reproduction cycle at various stages. A wide range of drug therapies and other approaches are currently used to treat herpes infections. Over time, however, an increased incidence of HSV-1 infection is observed in general population. In view of the current trends, it is necessary to search for new approaches aimed at reducing the incidence of HSV-1 infection and its complications. A promising approach may include usage of RNA interference effect, which underlies the action of potential new-generation antiherpetic drugs. RNA interference is a targeted inhibition of mRNA translation which entails disruption of subsequent protein biosynthesis. During its reproduction, HSV-1 imports viral DNA through the nuclear pore complex (NPC), located at the nuclear membrane. The NPC consists of nucleoporin proteins (Nup98, Nup205, NXF1 and others). Therefore, disruption of NPC structure resulting from miRNA-mediated inhibition of nucleoporin protein formation may hypothetically lead to a decreased HSV-1 reproduction.
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Drug Discovery Landscape
2 orphan drug designations for Herpes simplex virus encephalitis.
2 orphan drug designations for Herpes simplex virus encephalitis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
granzyme B associated peptide | peptides | FDA | — | BioJENC, LLC. |
PR-225 (redox-acyclovir) | small molecules | FDA | — | Pharmos |
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