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Herpes simplex viruses (HSV-1 and HSV-2), which can be transmitted both orally and sexually, cause lifelong morbidity and in some cases, meningitis and encephalitis. While both the passive transfer of neutralizing antibodies and placental transfer of anti-HSV monoclonal antibodies (Mabs) have shown therapeutic promise in animal models, clinical trials have yet to identify approved immunotherapeutics for herpes infection. Here, we present strategies for the generation of recombinant bispecific antibodies (BsAbs) that target different domains of glycoprotein D (gD), crucial for HSV entry, that have the potential to outperform the effect of individual Mabs to curb herpes infection. Specifically, we selected three pairs of Mabs from our extensive panel for BsAb design and production based on their binding site and ability to block virus entry. Actual binding of BsAbs to gD and epitope availability on gD after BsAb binding were characterized using surface plasmon resonance (SPR) and inhibition by IgG Fab fragments generated from selected Mabs. While one BsAb exhibited an additive effect similar to that observed using a combination of the Mabs utilized for its generation, two showed antagonistic effects, suggesting that the simultaneous engagement of two epitopes or selective binding to one affected their activity against HSV. One BsAb (DL11/1D3) targeting the binding site for both nectin-1 and HVEM receptors demonstrated synergistic inhibitory activity against HSV, outperforming the effect of the individual antibodies. Recombinant DL11/1D3 antibody variants, in which the size of one or both paratopes was decreased to single chains (scFv-Fc), highlighted differences in potency depending on antibody size and format. We propose that BsAbs to individual glycoproteins offer a potential avenue for herpes therapeutics, but their design, mechanism of action, antibody format, and epitope engagement require careful consideration of structure for optimal efficacy.

Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling pathway, an essential element in the innate antiviral immune responses, has emerged as a key component of innate immune system to modulate type I IFNs production and response by recognizing both exogenous and endogenous DNA. Although some cGAS-STING signaling small molecule agonists have been developed, there are few natural polysaccharides reported to activate cGAS-STING signaling for the treatment of infectious diseases. Here, we reported that Laminaran, a low molecular weight β-glucan storage polysaccharide present in brown algae, potentiates cGAS-STING signaling to promote type I IFNs production and antiviral response. Laminaran enhanced cGAS-STING signaling mediated type I IFNs production and response both in human and murine cells upon HSV-1 infection or DNA mimics stimulation. Importantly, we found that Laminaran markedly inhibited Herpes simplex virus-1 (HSV-1) induced death and inflammatory responses and increased the induction of type I IFNs in C57BL/6J mice. Mechanistically, we found Laminaran inhibited autophagy and suppressed STING autophagic degradation to positively regulate cGAS-STING signaling response. Taken together, we uncovered the function of Laminaran in DNA triggered innate immunity by enhancing cGAS-STING signaling response. Laminaran might be a potential therapeutic candidate for viral infectious diseases., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Oncolytic virotherapy (OVT) aims to disrupt the tumor microenvironment and provide a unique therapeutic approach against solid tumors. Herpes simplex virus type-1 (HSV-1) has shown strong promise for treating various solid tumors and has been approved to treat melanoma and glioma in human patients. Previously, we reported the generation of an engineered HSV-1 vaccine strain VC2, which has shown exceptional promise as an oncolytic and immunotherapeutic virus. In the present work, we engineered VC2 to constitutively express the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene inserted in place of HSV-1 Glycoprotein C (gC). We tested the efficacy of VC2-GMCSF for its ability to generate antitumor response in the 4T1 stage four metastatic breast cancer mouse model. GM-CSF expression enhanced VC2 viral replication and infectious virus production. Tumors formed after 7 days of engraftment in the mammary fat pad of Balb/CJ mice were treated by injecting ~5 × 10 4 plaque forming units (PFU) of VC2/VC2-GMCSF once. Intratumor treatment did not appreciably reduce average primary tumor sizes. However, metastatic foci were significantly reduced in mice lungs treated with VC2-GMCSF compared to VC2 or mock treatment. VC2-GMCSF intratumoral treatment induced a stronger intratumor T cell infiltration but not an increased cytotoxic activity. A significant T cell infiltration was observed in the metastatic areas in VC2-GMCSF treated animals, which was associated with reduced pro-tumor marker PDL1 and VEGF gene expression. These results show that constitutive expression of GM-CSF enhanced the overall efficacy of VC2 for OVT. VC2-GMCSF holds promise as oncolytic and immunotherapeutic virotherapy for breast and other cancers., (© 2025 Wiley Periodicals LLC.)

The recurrent herpes simplex virus-1 (HSV-1) infection of the cornea can cause the development of herpes stromal keratitis (HSK). This chronic immunoinflammatory condition is a major cause of infection-induced vision loss. The previous episodes of HSK increase the risk of future recurrences in the same cornea. However, not all HSV-1 infected corneas that shed infectious virus at the ocular surface develop HSK, suggesting that corneal HSV-1 infection may cause an establishment of protective immunity in HSV-1 infected corneas. However, upon recurrent corneal HSV-1 infection, the established protective immunity can get compromised, resulting in the development of HSK. In this study, we compared the quantity and quality of tissue-resident memory T (T RM ) cells in HSV-1 infected corneas that did or did not develop HSK. Our results showed the predominance of T RM cell in the epithelium than in stroma of HSV-1 infected corneas. Furthermore, HSV-1 infected non-HSK corneas exhibited more CD4 and CD8 T RM cells than HSK corneas. The T RM cells in non-HSK than in HSK corneas were more effective in clearing the infectious virus upon secondary corneal HSV-1 infection. Our results demonstrate the differential quantity and quality of T RM cells in HSV-1 infected corneas that did or did not develop HSK., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Histone deacetylase HDAC6 has been implicated in regulating antiviral innate immunity. However, its precise function in response to DNA virus infection remains elusive. Herein, we find that HDAC6 deficiency promotes the activation of cGAS-STING signaling and type I interferon (IFN) production, both in vitro and in vivo, resulting in a decrease in HSV-1 infection. Mechanistically, HDAC6 deacetylates tripartite motif protein 56 (TRIM56) at K110 in mice, thereby impairing the monoubiquitination cGAS and its DNA binding ability. Overexpression of TRIM56 K110Q protects mice against HSV-1 infection. Notably, different amino acids at position 110 of TRIM56 in human and mouse cause species-specific IFN responses. Further, we show that during early stages of HSV-1 infection, the viral protein US3 phosphorylates HDAC6 to inhibit the cGAS-mediated antiviral response. Our results suggest that HDAC6 inhibits cGAS activation through TRIM56 deacetylation in a species-specific manner., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Messenger RNA vaccines lack specificity for dendritic cells (DCs)-the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid-nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines., Competing Interests: Competing interests: Y.C. is a co-founder and advisor of BDGENE Therapeutics. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Approximately 2% of HerpeSelect herpes simples virus type 2 (HSV-2) IgG enzyme immunoassay (screen assay) sera-positive samples do not confirm using an HSV-2 IgG inhibition assay. Of these, roughly 1.33% are confirmed negative, and a small proportion (0.2%) are indeterminate due to inhibition observed with HSV-1 and HSV-2 lysate. The objective of this study was to assess the relationship between HSV-1 IgG serostatus and HSV-2 IgG confirmation results using the HSV-2 IgG inhibition assay., Methods: This study included consecutive HSV-2 IgG screen-positive specimens regardless of index value. Specimens were also tested for HSV-1 IgG. The HSV-2 IgG confirmation results from the inhibition assay were evaluated to assess the relationship between inhibition results and HSV-1 serostatus., Results: Of the 21,006 positive HSV-2 IgG specimens, 13,237 (63%) were also positive for HSV-1 IgG. The proportion of HSV-1 IgG-positive samples among inhibition-indeterminate samples (33 to 40 [83%]) was higher than among inhibition-negative (167 of 279 [60%]) and inhibition-positive (13,041 of 20,691 [63%]) samples. Among HSV-1 IgG-positive samples, the median HSV-1 IgG index was also significantly higher for the inhibition-indeterminate group (median, 48.8) than for the inhibition-negative (median, 30.7) and inhibition-positive groups (median, 31.2; P = 0.00013 and P = 3.1e - 05, respectively)., Conclusion: These findings suggest that HSV-2 IgG inhibition-indeterminate, but not inhibition-negative, results are associated with higher index values of HSV-1 IgG. Further studies are needed to understand other factors associated with inhibition-indeterminate results., Competing Interests: Conflict of Interest and Sources of Funding: T.M.S., S.R., and E.M.M. are employees of Quest Diagnostics. There were no external sources of funding for this study., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Background: Uveitis, characterized by intraocular inflammation, poses significant clinical challenges, often leading to vision impairment or blindness. Herpes Simplex Virus type 1 (HSV-1) is a major cause of virus-induced uveitis. This study aims to design a novel multi-epitope vaccine targeting HSV-1 glycoproteins B, C, D, H, and L using an immuno-informatics approach, which are essential for viral entry and pathogenesis., Methods: The study identified epitopes for CD8+ T cells, CD4+ T cells, and B cells within the target glycoproteins. These epitopes were systematically evaluated for conservancy, immunogenicity, non-allergenicity, non-glycosylated regions, and binding affinities. A multi-epitope construct was designed, incorporating these epitopes along with an adjuvant, a PADRE sequence, and suitable linkers. In-silico immune simulations were performed to evaluate the vaccine's potential to activate both innate and adaptive immune responses. Molecular docking simulations assessed the binding interactions between the multi-epitope vaccine and Toll-like receptor (TLR-9)., Results: The selected epitopes demonstrated high conservancy, immunogenicity, and non-allergenicity. The multi-epitope construct effectively activated cytokine production, immunoglobulin secretion, and T cell responses in in-silico immune simulations. Molecular docking simulations showed strong binding interactions between the vaccine and TLR-9, suggesting enhanced antigen presentation capabilities., Conclusion: This comprehensive immuno-informatics approach provides a precision immunotherapy strategy for uveitis by leveraging computational modeling and predictive analytics to design a multi-epitope vaccine for HSV-1. The in-silico results indicate the vaccine's potential efficacy in activating immune responses. Future experimental validation and clinical studies are necessary to confirm the safety and efficacy of this proposed vaccine in managing uveitis and preserving vision., Competing Interests: Author ZC was employed by Mentor Graphics Technology Shenzhen CO. LTD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Cao, Cao, Han and Shan.)

Tau aggregates around HSV-1 in the brain, but is this pathological, part of an immune response, or both?

Aerobic glycolysis is a hallmark of many viral infections, leading to substantial accumulation of lactate. However, the regulatory roles of lactate during viral infections remain poorly understood. Here, we report that human cytomegalovirus (HCMV) infection leverages lactate to induce widespread protein lactylation and promote viral spread. We establish that lactyllysine is enriched in intrinsically disordered regions, regulating viral protein condensates and immune signaling transduction. Dynamic lactylation of immune factors suppresses immunity, a feature we show to be shared for HCMV and herpes simplex virus 1 infections, through regulation of RNA binding protein 14 and interferon-γ-inducible protein 16 (IFI16). K90 lactylation of the viral DNA sensor IFI16 inhibits recruitment of the DNA damage response kinase DNA-PK, preventing IFI16-driven virus gene repression and cytokine induction. Together, we characterize global protein lactylation dynamics during virus infection, finding that virus-induced lactate contributes to its immune evasion through direct inhibition of immune signaling pathways.

Infection by human herpes simplex virus type 1 and type 2 (HSV-1/2) is common globally though with wide regional variability. Seroepidemiology of HSV-1/2 infections is of utmost importance in formulating control strategies, but there is a paucity of data from many regions of India. This study aimed to determine the prevalence of anti-HSV-1/2 antibodies in Uttarakhand and adjoining areas and to study its pattern and distribution in different subgroups. Serum samples from 322 cases were subjected to ELISA test to check for the presence of anti-HSV-1/2 IgG and IgM antibodies. Sociodemographic and clinical information were extracted from medical records. The association of seropositivity and associated factors was analyzed using Fisher's exact test. The overall HSV-1/2 seropositivity was observed to be 46.0% (95% confidence interval [CI]: 40.5-51.4). Total IgM and IgG were found in 6.2% (95% CI: 3.6-8.8) and 45.3% (95% CI: 38.1-48.9) cases, respectively. No significant difference between seropositivity of males and females was observed (45.7% in males versus 46.2% in females; p value: 0.928). Seroprevalence increased with age in both genders but was more pronounced in males ( p value: <0.001), while 50.6% of women in the reproductive age group (18-30 years) were found to be seropositive. Females from Uttarakhand, compared to adjoining states ( p value: 0.041) and both men and women residing in hilly terrain compared to plains ( p value: 0.018; p value: 0.030), showed significantly lower prevalence, while urban-dwelling men showed higher seropositivity ( p value: 0.048). Thus, HSV-1/2 seroprevalence is lower in this region, especially in young, rural, and hill dwellers, indicating majority are vulnerable to acquiring new infections. More awareness among high-risk groups and implementation of targeted public health policies can help control the disease burden., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Sangeeta Deka et al. The Scientific World Journal published by John Wiley & Sons Ltd.)

Phenazine biosynthesis-like domain-containing protein (PBLD) and Cedrelone have been identified as tumor suppressors. However, their roles in virus infection remain unclear. Here, we demonstrate that PBLD upregulates the type I interferon (IFN-I) response through activating NF-kappaB (NF-κB) signaling pathway to resist viral infection in cells and mice. Mechanistically, PBLD activates NF-κB signaling pathway during viral infection via blocking tripartite motif containing 21 (TRIM21)-mediated phosphorylated inhibitory kappa B kinase beta (IKKβ) degradation. Furthermore, we show Cedrelone inhibits viral replication by increasing the PBLD protein expression and subsequently activating NF-κB-mediated IFN-I response. Furthermore, the therapeutic potential of Cedrelone lies in its ability to enhance antiviral immunity in primary macrophages and to promote survival and reduce lung tissue damage in HSV-1-infected mice in a PBLD-dependent manner. Consequently, our findings provide a potential combination model that targets PBLD for Cedrelone antiviral drug therapy, potentially paving the way for the development of broad-spectrum antiviral agents., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder typically detected in childhood. Although ADHD has been demonstrated to have a strong genetic component, environmental risk factors, such as maternal infections during pregnancy, may also play a role. We therefore measured the immunological response to 5 abundant microorganisms (Toxoplasmosis Gondii, cytomegalovirus (CMV), Herpes Simplex Virus 1, Epstein Barr Virus and mycoplasma pneumoniae) in newborn heel prick samples of 1679 ADHD cases and 2948 matching controls as part of the iPSYCH Danish case-cohort study. We found an association between high anti-CMV (OR 1.30, 95 % CI [1.09,1.55], p = 0.015) and anti-mycoplasma (OR 1.30, 95 % CI [1.07,1.59], p = 0.037) signal and those newborns later being diagnosed with ADHD. The risk estimate remained increased when controlling for ADHD polygenic risk score as well as penicillin prescriptions. We saw a dose-response association with the amount of positive anti-microorganism titers increasing the risk of being diagnosed with ADHD later in life (p = 0.01 for the trend), suggesting that the more activated the immune system is prior to or at birth, the higher the risk is for a later diagnosis with ADHD. If the associations are causal, they emphasize the importance of a healthy life style during pregnancy to reduce the risk of infections when pregnant and the associated risks for the child., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Inducing tertiary lymphoid structure (TLS) formation can fuel antitumor immunity. It is necessary to create mouse models containing TLS to explore strategies of TLS formation. Oncolytic herpes simplex virus-1 (oHSV) exhibited intense effects in preclinical and clinical trials. However, the role of oHSV in TLS formation remains to be elucidated. Here, we observed the presence of TLS in 4MOSC1 and MC38 subcutaneous tumour models. Interestingly, oHSV evoked TLS formation, and increased infiltration of B cells and stem-like TCF1 + CD8 + T cells proliferation. Mechanistically, oHSV increased the expression of TLS-related chemokines, along with upregulated CXCL10/CXCR3 to facilitate TLS formation. Notably, CXCL10 and CXCR3 were favourable prognostic factors for cancer patients, and closely related with immune cells infiltration. Inhibiting CXCL10/CXCR3 reduced TCF1 + CD8 + T cells and granzyme B expression, and impaired oHSV-mediated TLS formation. Furthermore, oHSV-mediated TLS formation revealed superior response and survival rate when combined with αPD-1 treatment. Collectively, these findings indicate that oHSV recruits stem-like TCF1 + CD8 + T cells through CXCL10/CXCR3 pathway to propagate TLS formation, and warrants future antitumor immunity development., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The innate immune system relies on a variety of pathogen recognition receptors (PRRs) as the first line of defense against pathogenic invasions. Viruses have evolved multiple strategies to evade the host immune system through coevolution with hosts. The CRISPR-Cas system is an adaptive immune system in bacteria or archaea that defends against viral reinvasion by targeting nucleic acids for cleavage. Based on the characteristics of Cas proteins and their variants, the CRISPR-Cas system has been developed into a versatile gene-editing tool capable of gene knockout or knock-in operations to achieve genetic variations in organisms. It is now widely used in the study of viral immune evasion mechanisms. This chapter will introduce the use of the CRISPR-Cas9 system for editing herpes simplex virus 1 (HSV-1) genes to explore the mechanisms by which HSV-1 evades host innate immunity and the experimental procedures involved., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Herpes simplex virus (HSV) in humans and pseudorabies virus (PRV) in pigs are both alphaherpesviruses. Plasmacytoid dendritic cells (pDCs) make part of the peripheral blood mononuclear cells (PBMCs) and are specialized in producing large amounts of antiviral type I interferon (IFN-I). IFN-I production by PBMCs in response to both HSV-1 and PRV can be virtually exclusively attributed to pDCs. Recently, we discovered that cells infected with gEnull PRV trigger increased production of IFNalpha by porcine PBMCs/pDCs compared with cells infected with wild-type (WT) PRV. This increased IFNalpha response correlates with increased extracellular virus production triggered by gEnull PRV compared with WT PRV. The gE protein and some of its currently described functions are conserved in different alphaherpesviruses, including PRV and HSV-1. In the current study, we report that cells infected with gEnull HSV-1 trigger increased IFNalpha production by human PBMCs and increased extracellular virus production compared with WT HSV-1. Hence, these recently described functions of PRV gE are conserved in HSV-1 gE. Since the increased extracellular virus production and IFNalpha response have also been reported for successful (gEnull) PRV vaccines, the current findings may have important consequences for the rational design of HSV vaccines.

Herpes simplex virus type 1 (HSV-1) is the leading pathogen in the maxillo-facial region, affecting millions of individuals worldwide. Its periodic reactivation aligns with the most common course pattern of periodontal disease. The present study used RNA sequencing to investigate the transcriptomes of human gingival fibroblasts (HGFs) following HSV-1 infection from the early to late stages (12-72 h). At the early stage of infection (12 h post-infection), the most upregulated genes were interferon (IFN) regulatory factor family members, toll-like receptor (TLR) family members, IFN-β1, interleukin (IL)-1, C-C motif ligands, chemokine (C-X-C motif) ligands (CXCLs), and tumor necrosis factor (TNF). The strongest differential expression was observed in TNF, nucleotide-binding oligomerization domain-like receptor (NLR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. At the late stage of infection, the most upregulated genes were CXCLs and ILs. The differentially expressed genes were divided into nine clusters, according to the time series expression trend. Next, the prominent activation of TLRs, retinoic acid-inducible gene I-like receptor signaling, NLRs, and downstream IFNAR-JAK-STAT signaling pathways were observed via a modified HSV-1 infection map. The HSV-1-induced upregulation of inflammatory cytokines in HGFs may drive inflammatory processes in periodontitis. The dynamic variations in mRNAs in HGFs from the early to late stages after HSV-1 infection can provide an analytical framework for determining the host anti-viral defense response to antagonize HSV-1 infection in periodontal tissues., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethical Review Board of the Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, China (Protocol code: SH9H-2019-T76-2, Approval date: 2020/10/08). A written informed consent was obtained from all subjects involved in the study. Consent for publication: Not applicable. Competing interests: The authors declare that they have no conflicts of interest., (© 2024. The Author(s).)

Infections with Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV1) and Toxoplasma gondii (TG) have been implicated in severe mental illness. All three pathogens have high seroprevalence in the human population, are neurotropic and establish a persistent infection. We hypothesized that exposed (seropositive) patients with severe mental illness would show higher immunoglobulin G (IgG) concentrations than exposed healthy controls (HC). We included 765 patients with severe mental illness (schizophrenia n = 515, bipolar disorder n = 250) and 541 HC. CMV, HSV1 and TG IgG seropositivity and concentrations were measured with immunoassays (seropositivity: CMV, n = 447 patients vs. 296 HC; HSV1, n = 355 vs. 238; and TG, n = 159 vs. 126). Among seropositive participants, patients had higher HSV1 (p < 0.001) and TG (p = 0.003) IgG concentrations than HC. Stratifying by diagnosis, both schizophrenia (p = 0.001) and bipolar disorder (p = 0.001) had higher HSV1 IgG concentrations, while schizophrenia only had higher TG (p = 0.009) and CMV (p = 0.045) IgG concentrations than HC. In SZ, higher HSV1 IgG concentrations were associated with higher psychotic (p = 0.030) and manic (p = 0.008) symptom scores, but only among CMV- or TG-infected patients which suggests synergistic effects. Among all participants, HSV1 IgG concentrations were inversely associated with interleukin-18 (p < 0.001) and positively associated with high-sensitivity C-reactive protein (p = 0.002) and B cell-activating factor (p = 0.004), possibly indicating T cell exhaustion, enhanced inflammation, and increased B-cell response, respectively. Patients with severe mental illness exhibit a heightened immune system response to HSV1, TG, and CMV infections suggesting immune system dysfunction and/or a more severe infection. For HSV1, higher IgG concentrations were linked to a greater clinical burden., Competing Interests: Competing interests: OAA is a consultant to HealthLytix and received speaker’s honoraria from Lundbeck and Sunovion. IA received speaker’s honoraria from Lundbeck. All other authors reported no potential conflicts of interest., (© 2024. The Author(s).)

Due to the complex pathogenic and immune escape mechanisms of herpes simplex virus type 1 (HSV-1), especially the failure of induced immune responses to block the initial cell-to-cell transmission of the virus from skin cells to neurons, the body struggles to establish effective prevention and control methods, resulting in the failure of currently developed vaccines. Previous studies have highlighted the crucial roles of surface glycoproteins and nucleocapsid proteins in activating the body's immune defense system against HSV-1 infection. In this study, recombinant adenoviruses were used as vectors to generate adenoviruses carrying the nucleocapsid protein genes UL18 and UL25, as well as the surface glycoprotein gene gB. This approach aimed to mimic the protein expression process that occurs following viral infection of the host and to investigate the immune response characteristics induced by UL18, UL25, and gB proteins. The findings revealed that UL18, UL25, and gB proteins could all trigger the expression of genes associated with innate immune responses; however, the specific genes induced varied in type and level. Furthermore, all three proteins were capable of promoting the proliferation of CD8+ T cells in the lymph nodes. Notably, only UL18 and gB could elicit a Th1 cell immune response. Interestingly, among these proteins, only UL18 could also induce a relatively higher IL-4 level, indicating a Th2 cell immune response. In addition to cellular immunity, all three proteins stimulated the production of specific IgG antibodies. Notably, UL18 induced higher and more sustained levels of specific IgG antibodies in mice. By contrast, only glycoprotein gB induced lower levels of neutralizing antibodies in mice. Moreover, when these mice were challenged with HSV-1, the co-immunization with UL18 and gB provided better protection than gB alone. In conclusion, HSV-1 surface glycoproteins and nucleocapsid proteins exhibit differences in their ability to induce innate and adaptive immunity in the body, suggesting potential avenues for vaccine design by leveraging their complementary advantages.

The cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS)-dependent pathway is a key DNA-sensing pathway that recognizes cytosolic DNA and plays a crucial role in initiating innate immune responses against pathogenic microbes and cancer. Various molecules have been identified as regulators of the cGAS-dependent pathway that controls innate immune responses. However, despite the important roles of Stimulator-of-interferon genes (STING) in the cGAS-dependent pathway, the regulation of its activation has not been elucidated. Here, we show that the E3 ubiquitin ligase, RING finger protein 39 (RNF39), interacts with STING in macrophages and HERK293T cells. Moreover, RNF39 accelerates DNA-sensing pathways by promoting lysine (K)63-linked ubiquitination of STING, and then facilitating the formation of STING-TBK1 complex. Concordantly, Rnf39 deficiency inhibits innate immune responses triggered by DNA viral infection and accelerates viral replication. Furthermore, herpes simplex virus-1 (HSV-1) infection induces RNF39 expression in an IFN-I-dependent manner. Thus, we outline a novel mechanism for controlling STING activation and a feedback mechanism for controlling antiviral immune responses. RNF39 could be a priming intervention target for the prevention and treatment of viral diseases, especially DNA viral infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Herpes simplex virus type 1 (HSV-1) is a globally widespread virus that causes and associates with a wide range of diseases, including herpes simplex encephalitis, herpes simplex keratitis, and herpes labialis. The interaction between HSV-1 and the host involves complex immune response mechanisms, including recognition of viral invasion, maintenance of latent infection, and triggering of reactivation. Antiviral therapy is the core treatment for HSV-1 infections. Meanwhile, vaccine development employs different strategies and methods, and several promising vaccine types have emerged, such as live attenuated, protein subunit, and nucleic acid vaccines, offering new possibilities for the prevention of HSV-1 infection. Moreover, HSV-1 can be modified into a therapeutic vector for gene therapy and tumour immunotherapy. This review provides an in-depth summary of HSV-1 infection-associated innate and adaptive immune responses, disease pathogenesis, current therapeutic approaches, recent advances in vaccine development, and vector therapy applications for cancer treatment. Through a systematic review of multiple aspects of HSV-1, this study aims to provide a comprehensive and detailed reference for the public on the prevention, control, and treatment of HSV-1.

Objectives: To investigate the numbers of natural killer (NK) cells, CD56+ T-cells and CD56- T cells, and the levels ofCD16 in healthy individuals seropositive for herpes simplex virus Type 1 (HSV-1). Specifically, it seeks to measure the levels of these cells to learn about the possible immunological significance during HSV-1 seropositive status., Methods: This study employed a cross-sectional research design to examine the levels of CD56+ T-cells and CD16+ among individuals seropositive for herpes simplex virus type 1 (HSV-1) in Taif city. A total of 112 participants were enrolled, with HSV-1 serostatus determined via ELISA, and cellular evaluation conducted using flow cytometry. The study was performed between January 2023 to July 2023., Results: Our study found 36% HSV-1 seropositivity, contrasting with higher rates in Saudi Arabia. No significant age or gender differences were observed. HSV-1 seropositive individuals showed elevated dim CD56 NK cells and CD56+ T-cells, aligning with prior research on lymphocyte infiltration during HSV-1 activation. Further investigation is warranted for CD56- T-cells and bright NK cells., Conclusion: HSV-1 seropositive individuals showed elevated dim CD56 NK cells and CD56+ T-cells, consistent with lymphocyte activities during viral activation. CD16 expression on CD56+ T-cells suggests their involvement in viral defence, emphasizing the need for further investigation into immune responses against HSV-1., (Copyright: © Saudi Medical Journal.)

A critical host response against viral infections entails the activation of innate immune signaling that culminates in the production of antiviral proteins. DNA viruses are sensed by the cytosolic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), which initiates a signaling pathway that results in production of proinflammatory cytokines such as Interferon-β (IFN-β) and activation of the antiviral response. Precise regulation of the antiviral innate immune response is required to avoid deleterious effects of its overactivation. We previously reported that the 4EHP/GIGYF2 translational repressor complex reduces the translation of Ifnb1 mRNA, which encodes IFN-β, upon RNA viral infections. Here, we report a distinct regulatory mechanism by which 4EHP controls replication of DNA viruses by translational repression of the Cgas mRNA, which encodes the DNA viral sensor cGAS. We show that 4EHP is required for effective translational repression of Cgas mRNA triggered by miR-23a. Upon infection, 4EHP deficiency bolsters the elicited innate immune response against the diverse DNA viruses Herpes simplex virus 1 (HSV-1) and Vaccinia Virus (VacV) and concomitantly reduces their rate of replication in vitro and in vivo. This study elucidates an intrinsic regulatory mechanism of the host response to DNA viruses which may provide unique opportunities for countering viral infections., Competing Interests: Competing interests statement:The authors declare no competing interest.

Genital herpes simplex virus (HSV) is associated with a reduction in quality of life and adverse outcomes. The aim of this study is to assess the interest and expectations for a therapeutic HSV vaccine among individuals diagnosed with genital herpes in Italy. A retrospective survey was conducted at the Infectious Diseases Unit of the IRCCS San Raffaele Scientific Institute, Milan, Italy. The study collected data on demographics, clinical history and interest in HSV vaccination. The results showed that 87.5% of participants were interested in a therapeutic vaccine, with interest higher among younger people and those with frequent genital herpes recurrences. Participants most expected the vaccine to reduce the pain associated with outbreaks, followed by a reduction in the frequency and duration of recurrences. These findings underscore the strong demand for a therapeutic HSV vaccine, especially among those who experience recurrent outbreaks, and highlight the importance of considering patient expectations when developing preventive and therapeutic strategies for genital herpes.

Herpesviruses are ubiquitous DNA viruses that can establish latency and cause a range of mild to life-threatening diseases in humans. Upon infection, herpesviruses trigger the activation of several host antiviral defense programs that play critical roles in curbing virus replication and dissemination. Recent work from many groups has integrated our understanding of TRIM ( tripartite motif ) proteins, a specific group of E3 ligase enzymes, as pivotal orchestrators of mammalian antiviral immunity. In this review, we summarize recent advances in the modulation of innate immune signaling by TRIM proteins during herpesvirus infection, with a focus on the detection of herpes simplex virus type 1 (HSV-1, a prototype herpesvirus) by cGAS-STING, RIG-I-like receptors, and Toll-like receptors. We also review the latest progress in understanding the intricate relationship between herpesvirus replication and TRIM protein-regulated autophagy and apoptosis. Finally, we discuss the maneuvers used by HSV-1 and other herpesviruses to overcome TRIM protein-mediated virus restriction.

Background: Information related to herpes simplex virus 1 and 2 (HSV-1 and 2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) seroprevalence in France is either lacking, incomplete, or outdated, despite their public health burden., Method: We used routinely collected serological data between 2018 and 2022 to estimate HSV-1, HSV-2, VZV, EBV, and CMV seroprevalence in France. To account for demographic differences between our analytic samples and the French population and get estimates for sparsely sampled districts and age classes, we used a multilevel regression and poststratification approach combined with Bayesian model averaging via stacking weights., Results: The observed seroprevalence (number of positive tests/number of tests) were 64.6% (93,294/144,424), 16.9% (24,316/144,159), 93.0% (141,419/152,084), 83.4% (63,199/75, 781), and 49.0% (23,276/47,525), respectively, for HSV-1, HSV-2, VZV, EBV, and CMV. Between 2018 and 2022, France had a model-based average (equal-tailed interval at 95%) expected seroprevalence equal to 61.1% (60.7,61.5), 14.5% (14.2,14.81), 89.5% (89.3,89.8), 85.6% (85.2,86.0), and 50.5% (49.3,51.7), respectively, for HSV-1, HSV-2, VZV, EBV, and CMV infections. We found an almost certain lower expected seroprevalence in Metropolitan France than in overseas territories for all viruses but VZV, for which it was almost certainly greater. The expected seroprevalences were likely greater among females for all viruses., Limitations: Our results relied on the assumption that individuals were sampled at random conditionally to variables used to build the poststratification table., Implications: The analysis highlights spatial and demographic patterns in seroprevalence that should be considered for designing tailored public health policies.

Influenza virus is a major respiratory viral pathogen responsible for the deaths of hundreds of thousands worldwide each year. Current vaccines provide protection primarily by inducing strain-specific antibody responses with the requirement of a match between vaccine strains and circulating strains. It has been suggested that anti-influenza T-cell responses, in addition to antibody responses may provide the broadest protection against different flu strains. Therefore, to address this urgent need, it is desirable to develop a vaccine candidate with an ability to induce balanced adaptive immunity including cell mediated immune responses. Here, we explored the potential of VC2, a well-characterized Herpes Simplex Virus type 1 vaccine vector, as a live attenuated influenza vaccine candidate. We generated a recombinant VC2 virus expressing the influenza A hemagglutinin protein. We show that this virus is capable of generating potent and specific anti-influenza humoral and cell-mediated immune responses. We further show that a single vaccination with the VC2-derived influenza vaccine protects mice from lethal challenge with influenza virus. Our data support the continued development of VC2-derived influenza vaccines for protection of human populations from both seasonal and pandemic strains of influenza. Finally, our results support the potential of VC2-derived vaccines as a platform for the rapid development of vaccines against emerging and established pathogens, particularly respiratory pathogens., (© 2024 Wiley Periodicals LLC.)

Objective: Biological markers of stress have been associated with HIV progression and pathogenesis but not with HIV incidence. We sought to determine if elevated stress-responsive biomarkers would be associated with incident HIV among adolescent girls and young women (AGYW)., Design: We conducted a case-cohort study within the HIV Prevention Trials Network (HPTN) 068 study among 949 AGYW in South Africa. Cases were AGYW who tested HIV-positive during the eight-year follow-up. Unmatched controls were randomly selected from the HIV-negative population at enrollment., Methods: Dried blood spots from cases and controls were tested from enrollment (2011-2012) for C-reactive protein (CRP), herpes simplex virus type-1 (HSV-1) antibody titers, and cytomegalovirus (CMV) antibody titers. Cox proportional hazards models estimated the association between each biomarker and time to incident HIV., Results: Compared to AGYW with the lowest CRP levels, those with medium and high CRP levels had a higher hazard ratio (HR) of incident HIV [HR: 1.45, 95% confidence interval (CI): 0.95, 2.21; HR: 1.50, 95% CI: 0.98, 2.30, respectively], although not statistically significant. The relative hazard of incident HIV was also higher among AGYW who were CMV seropositive vs. seronegative (low antibodies HR: 2.18, 95% CI: 1.2, 3.87; medium HR: 2.25, 95% CI: 1.28, 3.95; high HR: 1.78, 95% CI: 0.99, 3.21). Those with the highest HSV-1 antibody levels experienced an increased hazard of HIV compared to those who were HSV-1 seronegative (HR: 1.58, 95% CI: 1.03, 2.44)., Conclusions: Biological stress may increase AGYW's susceptibility to HIV acquisition through changes in immune function, viral infection, and increased biological vulnerability to disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Herpesviruses are common co-pathogens in individuals infected with human immunodeficiency virus (HIV). Herpes simplex virus type 1 (HSV1) enhances HIV-1 replication and has evolved mechanisms to evade or disrupt host innate immune responses, including interference with interferon (IFN) signalling pathways., Objectives: The aimed of this work was evaluated whether it HSV1 affects HIV-1 replication through the modulation of the IFN pathway in human macrophages., Methods: Co-infections with HSV1 and HIV-1 were performed in monocyte-derived human macrophages (hMDMs). The production of infectious HIV-1 and HSV-1 was monitored 48 h post-coinfection. Additionally, mRNA and protein expression levels of interferon-stimulated genes (ISGs) were evaluated in both HIV-1-HSV1 coinfections and HSV1 mono-infections., Findings: The HSV1 coinfection increasing the HIV-1 productive replication, following of downregulation of interferon-alpha (IFN-α) and interferon-induced transmembrane protein 3 (IFITM3) expression in hMDMs. Acyclovir treatment, in a dose-dependent manner, mitigated HSV1's ability to decrease IFITM3 levels. Knockdown of HSV1 Us11 and virion host shutoff (VHS) genes reactivated the IFN pathway, evidenced by restored IFITM3 expression and activation of eIF2-α and PKR. This knockdown also returned HIV-1 replication to baseline levels., Main Conclusions: Our data suggested that HSV1 increases HIV-1 replication in human macrophages is associated with the downregulating interferon pathways and ISGs expression.

RNA N 6 -methyladenosine (m 6 A) demethylase AlkB homolog 5 (ALKBH5) plays a crucial role in regulating innate immunity. Lysine acylation, a widespread protein modification, influences protein function, but its impact on ALKBH5 during viral infections has not been well characterized. This study investigates the presence and regulatory mechanisms of a previously unidentified lysine acylation in ALKBH5 and its role in mediating m 6 A modifications to activate antiviral innate immune responses. We demonstrate that ALKBH5 undergoes lactylation, which is essential for an effective innate immune response against DNA herpesviruses, including herpes simplex virus type 1 (HSV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), and mpox virus (MPXV). This lactylation attenuates viral replication. Mechanistically, viral infections enhance ALKBH5 lactylation by increasing its interaction with acetyltransferase ESCO2 and decreasing its interaction with deacetyltransferase SIRT6. Lactylated ALKBH5 binds interferon-beta (IFN-β) messenger RNA (mRNA), leading to demethylation of its m 6 A modifications and promoting IFN-β mRNA biogenesis. Overexpression of ESCO2 or depletion of SIRT6 further enhances ALKBH5 lactylation to strengthen IFN-β mRNA biogenesis. Our results identify a posttranslational modification of ALKBH5 and its role in regulating antiviral innate immune responses through m 6 A modification. The finding provides an understanding of innate immunity and offers a potential therapeutic target for HSV-1, KSHV, and MPXV infections., Competing Interests: Competing interests statement:The authors declare no competing interest.

Knowledge about the underlying causes of the individual occurrence of symptoms during acute COVID-19 disease and during the post-acute sequelae of COVID-19 is limited. In a German COVID-19 follow-up study, we assessed whether elevated antibody responses to herpesviruses were associated with symptom occurrence in acute COVID-19 disease (n = 96 participants) and during 20 months of follow-up (n = 62 participants). Serum samples were analyzed for their antibodies to herpes simplex virus (HSV)-1 and -2, Epstein-Barr virus (EBV), and Cytomegalovirus (CMV) using fluorescent bead-based multiplex serology. The association of herpesvirus antibodies with symptom occurrence (fatigue, fever, dyspnea, decrease in taste, concentration problems) was assessed using multivariate logistic regression models. High EBV antibody levels were significantly associated with a more than fourfold increased odds of experiencing fatigue during acute COVID-19 disease and during follow-up. High CMV antibody levels were significantly associated with a more than threefold increased odds of experiencing concentration problems and a decrease in taste during the follow-up. The HSV-1 and -2 antibody levels were not elevated in the individuals that experienced symptoms. In conclusion, our findings indicate that herpesvirus infections, specifically EBV and CMV infections, might play a role in symptom development during acute and post-acute COVID-19 disease. It remains to be elucidated whether the elevated EBV and CMV antibodies determined in our study are indicators of herpesvirus reactivation.

Background: Serodiagnosis of TORCH infections should be performed in pre-pregnancy and reproductive-age women to prevent vertical transmission. Herein, we conducted a 5-year cross-sectional retrospective study in childbearing age women to provide prevalence data. Also, stratifying the cohort into three age groups, we identified those most susceptible to acute TORCH infections., Methods: Between 2019 and 2023, serum samples from 2286 childbearing age women attending the "R. Dulbecco" University Hospital of Catanzaro were collected. Screening for TORCH pathogens, such as: Toxoplasma gondii (TOX), Cytomegalovirus (CMV), Rubella Virus (RUB), Parvovirus B19 (ParvoB19), Herpes Simplex Virus types 1 and 2 (HSV1, HSV2) and Treponema pallidum was carried out using serological tests. Chemiluminescent immunoassay was performed to detect TOX, CMV and ParvoB19 Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies, while Enzyme Linked Fluorescent Assay was performed to detect RUB IgM and IgG antibodies and CMV and TOX IgG Avidity. Enzyme Linked Immunosorbent Assay was performed to detect HSV1 IgG, HSV2 IgG, HSV1/2 IgM, T. pallidum total antibodies and RUB IgG Avidity. Binomial logistic regression models were developed to compare seroprevalence rates among different age groups., Results: The highest immunological protection was observed for RUB infection (87 %), probably associated with vaccination practice, followed by HSV1 and CMV (82 % and 63 %). The 16-25 year age group results as the most susceptible to acute infections as demonstrated by odds of CMV IgM positivity (primary infection) which decreased with age., Conclusions: The TORCH serological screening program should be implemented in women before pregnancy to formulate strategies for serological screening of childbearing age women and guiding clinicians in making decisions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Presentation of metabolites by the major histocompatibility complex class I-related protein 1 (MR1) molecule to mucosal-associated invariant T cells is impaired during herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. This is surprising given these viruses do not directly synthesise MR1 ligands. We have previously identified several HSV proteins responsible for rapidly downregulating the intracellular pool of immature MR1, effectively inhibiting new surface antigen presentation, while preexisting ligand-bound mature MR1 is unexpectedly upregulated by HSV-1. Using flow cytometry, immunoblotting, and high-throughput fluorescence microscopy, we demonstrate that the endocytosis of surface MR1 is impaired during HSV infection and that internalized molecules accumulate in EEA1-labeled early endosomes, avoiding degradation. We establish that the short MR1 cytoplasmic tail is not required for HSV-1-mediated downregulation of immature molecules; however it may play a role in the retention of mature molecules on the surface and in early endosomes. We also determine that the HSV-1 US3 protein, the shorter US3.5 kinase and the full-length HSV-2 homolog, all predominantly target mature surface rather than total MR1 levels. We propose that the downregulation of intracellular and cell surface MR1 molecules by US3 and other HSV proteins is an immune-evasive countermeasure to minimize the effect of impaired MR1 endocytosis, which might otherwise render infected cells susceptible to MR1-mediated killing by mucosal-associated invariant T cells., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published studies have generated compelling results indicating that type I IFN modulates function of HSV-1 latency-associated transcript (LAT). One member of type I IFN is IFNα2A also called Roferon-A). IFNα2A has been used in monotherapy or in combination therapy with other drugs to treat viral infections and different kinds of cancer in humans. The goal of this study was to determine whether the absence of IFNα2A affects primary and latent infections in ocularly infected mice. Therefore, we generated a mouse strain lacking IFNα2A expression (IFNα2A-/-). Ocular HSV-1 replication, IFN and immune cell expressions on days 3 and 5 post infection (PI), as well as eye disease, survival, latency-reactivation, and T cell exhaustion were evaluated in ocularly infected IFNα2A-/- and wild type (WT) control mice. Absence of IFNα2A did not affect other members of the IFNα family but it affected IFNβ and IFNγ expressions as well as some immune cells on day 5 PI compared to WT mice. Viral replication in the eye, eye disease, and survival amongst ocularly infected IFNα2A-/- mice were similar to that of WT infected mice. The absence of IFNα2A significantly reduced the levels of latency and T cell exhaustion but not time of reactivation compared with control mice. Our results suggest that blocking IFNα2A expression may be a useful tool in reducing latency and the subsequent side effects associated with higher levels of latency., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The expanding number of rare immunodeficiency syndromes offers an opportunity to understand key genes that support immune defense against infectious diseases. However, analysis of these in patients is complicated by their treatments and comorbid infections, requiring the use of mouse models for detailed investigations. We developed a mouse model of DOCK2 immunodeficiency and herein demonstrate that these mice have delayed clearance of herpes simplex virus type 1 (HSV-1) infections. We also uncovered a critical, cell-intrinsic role of DOCK2 in the priming of antiviral CD8+ T cells and in particular their initial expansion, despite apparently normal early activation of these cells. When this defect was overcome by priming in vitro, DOCK2-deficient CD8+ T cells were surprisingly protective against HSV-1 disease, albeit not as effectively as wild-type cells. These results shed light on a cellular deficiency that is likely to impact antiviral immunity in DOCK2-deficient patients., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: To investigate the mechanism of Golgi matrix protein 130(GM130) regulating the antiviral immune response of TLR3 after herpes simplex virus type 1(HSV-1) infection of microglia cells. We explored the regulatory effects of berberine on the immune response mediated by GM130 and TLR3., Methods: An in vitro model of HSV-1 infection was established by infecting BV2 cells with HSV-1., Results: Compared to the uninfected group, the Golgi apparatus (GA) fragmentation and GM130 decreased after HSV-1 infection; TLR3 increased at 6 h and began to decrease at 12 h after HSV-1 infection; the secretion of interferon-beta(IFN-β), tumour necrosis factor alpha(TNF-α), and interleukin-6(IL-6) increased after infection. Knockdown of GM130 aggravated fragmentation of the GA and caused TLR3 to further decrease, and the virus titer also increased significantly. GM130 knockdown inhibits the increase in TLR3 and inflammatory factors induced by TLR3 agonists and increases the viral titer. Overexpression of GM130 alleviated fragmentation of the GA induced by HSV-1, partially restored the levels of TLR3, and reduced viral titers. GM130 overexpression reversed the reduction in TLR3 and inflammatory cytokine levels induced by TLR3 inhibitors. Therefore, the decrease in GM130 levels caused by HSV-1 infection leads to increased viral replication by inhibiting TLR3-mediated innate immunity. Berberine can protect the GA and reverse the downregulation of GM130, as well as the downregulation of TLR3 and its downstream factors after HSV-1 infection, reducing the virus titer., Conclusions: In microglia, one mechanism of HSV-1 immune escape is disruption of the GM130/TLR3 pathway. Berberine protects the GA and enhances TLR3-mediated antiviral immune responses., (© 2024. The Author(s).)

SUMMARYHuman alphaherpesvirus 1 (HSV-1) is a highly successful neurotropic pathogen that primarily infects the epithelial cells lining the orofacial mucosa. After primary lytic replication in the oral, ocular, and nasal mucosal epithelial cells, HSV-1 establishes life-long latency in neurons within the trigeminal ganglion. Patients with compromised immune systems experience frequent reactivation of HSV-1 from latency, leading to virus entry in the sensory neurons, followed by anterograde transport and lytic replication at the innervated mucosal epithelial surface. Although recurrent infection of the corneal mucosal surface is rare, it can result in a chronic immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK leads to gradual vision loss and can cause permanent blindness in severe untreated cases. Currently, there is no cure or successful vaccine to prevent latent or recurrent HSV-1 infections, posing a significant clinical challenge to managing HSK and preventing vision loss. The conventional clinical management of HSK primarily relies on anti-virals to suppress HSV-1 replication, anti-inflammatory drugs (such as corticosteroids) to provide symptomatic relief from pain and inflammation, and surgical interventions in more severe cases to replace damaged cornea. However, each clinical treatment strategy has limitations, such as local and systemic drug toxicities and the emergence of anti-viral-resistant HSV-1 strains. In this review, we summarize the factors and immune cells involved in HSK pathogenesis and highlight alternate therapeutic strategies for successful clinical management of HSK. We also discuss the therapeutic potential of immunoregulatory cytokines and immunometabolism modulators as promising HSK therapies against emerging anti-viral-resistant HSV-1 strains., Competing Interests: The authors declare no conflict of interest.

Background: Herpes simplex virus type 1 (HSV-1) is a major cause of viral encephalitis, genital mucosal infections, and neonatal infections. Lactococcus lactis (L. lactis) has been proven to be an effective vehicle for delivering protein antigens and stimulating both mucosal and systemic immune responses. In this study, we constructed a recombinant L. lactis system expressing the protective antigen glycoprotein D (gD) of HSV-1., Results: To improve the stability and persistence of antigen stimulation of the local mucosa, we inserted the immunologic adjuvant interleukin (IL)-2 and the Fc fragment of IgG into the expression system, and a recombinant L. lactis named NZ3900-gD-IL-2-Fc was constructed. By utilizing this recombinant L. lactis strain to elicit an immune response and evaluate the protective effect in mice, the recombinant L. lactis vaccine induced a significant increase in specific neutralizing antibodies, IgG, IgA, interferon-γ, and IL-4 levels in the serum of mice. Furthermore, in comparison to the mice in the control group, the vaccine also enhanced the proliferation levels of lymphocytes in response to gD. Moreover, recombinant L. lactis expressing gD significantly boosted nonspecific immune reactions in mice through the activation of immune-related genes. Furthermore, following the HSV-1 challenge of the murine lung mucosa, mice inoculated with the experimental vaccine exhibited less lung damage than control mice., Conclusion: Our study presents a novel method for constructing a recombinant vaccine using the food-grade, non-pathogenic, and non-commercial bacterium L. lactis. The findings indicate that this recombinant vaccine shows promise in preventing HSV-1 infection in mice., (© 2024. The Author(s).)

Serological screening for TORCH(Toxoplasma gondii [TOX], Rubella virus [RV], Cytomegalovirus [CMV], and Herpes simplex virus [HSV]) infections is an effective method for preventing congenital infections caused by TORCH pathogens.In this study, we retrospectively analyzed the characteristics of TORCH infections in 17,807 infertile women of childbearing age in northwest China.We conducted serological detection of TORCH-pathogen-specific IgM and IgG antibodies. The seroprevalence of TORCH infections was statistically analyzed by applying χ2 and Fisher exact-probability tests to evaluate the differences among ages and across quarters of the year. The overall IgM/IgG seroprevalences of TOX, RV, CMV, HSV-1, and HSV-2 were 0.46/3.4%, 0.77/84.93%, 0.68/97.54%, 1.2/82.83%, and 0.62/10.04%, respectively. The positive rates for RV-IgM in women ≥ 40 years old were significantly higher than those for women 25-39 (P < 0.05) years of age. The seroprevalence of HSV1-IgM was higher in the third and fourth quarters of the year (seasons) (P < 0.001), and the seroprevalence of CMV-IgG was statistically significant between differences quarters (P = 0.017), and the seroprevalence of CMV-IgG in the first quarter was lower than that in the third and fourth quarters (Bonferroni correction, P = 0.009 > 0.0083), suggesting no statistically significant difference between the latter two groups. This study showed that in northwestern China the risk of acquiring primary infection by a TORCH pathogen among infertile women of childbearing age were still high, especially Toxoplasma gondii and Herpesvirus type 2 infection. Therefore, effective prevention strategies that include serological screening for TORCH should be implemented., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Our study aims to investigate the dynamics of conventional memory T cells (Tconv) and regulatory memory T cells (Treg) following activation, and to explore potential differences between these two cell types. To achieve this, we developed advanced statistical mixed models based on mathematical models of ordinary differential equations (ODE), which allowed us to transform post-vaccination immunological processes into mathematical formulas. These models were applied to in-house data from a de novo Hepatitis B vaccination trial. By accounting for inter- and intra-individual variability, our models provided good fits for both antigen-specific Tconv and Treg cells, overcoming the challenge of studying these complex processes. Our modeling approach provided a deeper understanding of the immunological processes underlying T cell development after vaccination. Specifically, our analysis revealed several important findings regarding the dynamics of Tconv and Treg cells, as well as their relationship to seropositivity for Herpes Simplex Virus Type 1 (HSV-1) and Epstein-Barr Virus (EBV), and the dynamics of antibody response to vaccination. Firstly, our modeling indicated that Tconv dynamics suggest the existence of two T cell types, in contrast to Treg dynamics where only one T cell type is predicted. Secondly, we found that individuals who converted to a positive antibody response to the vaccine earlier had lower decay rates for both Tregs and Tconv cells, which may have important implications for the development of more effective vaccination strategies. Additionally, our modeling showed that HSV-1 seropositivity negatively influenced Tconv cell expansion after the second vaccination, while EBV seropositivity was associated with higher Treg expansion rates after vaccination. Overall, this study provides a critical foundation for understanding the dynamic processes underlying T cell development after vaccination., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Benson Ogunjimi reports financial support was provided by European Research Council. Benson Ogunjimi reports financial support was provided by Research Foundation Flanders. Philippe Beutels reports financial support was provided by University of Antwerp. Pierre Van Damme reports financial support was provided by University of Antwerp. CONFLICT OF INTEREST STATEMENT: BO declares that the University Hospital Antwerpen and the University of Antwerp have received investigator-initiated grants from Abbvie, Pfizer and Roche. BO is a shareholder and member of the board of ImmuneWatch BV. NH declares that the Universities of Antwerp and Hasselt have received funding for advisory boards and research projects of MSD, GSK, JnJ, Pfizer and the European Commission’s IMI programme outside the proposed work. NH has not received any personal remuneration. PB declares the University of Antwerp received compensation for unrelated consultancy for Pfizer in 2019, research grants from MSD and Pfizer, and the European Commission’s IMI programme. PB has not received any personal remuneration. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. KL is a shareholder and member of the board of ImmuneWatch BV. PM is a shareholder, employee and member of the board of ImmuneWatch BV. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

CD80 is the best-known costimulatory molecule for effective T cell functions. Many different reports have summarized the role of CD80 in HSV-1 and its functions in maintaining adaptive immunity, which is the main player in causing herpes stromal keratitis (HSK). To determine the effects of absence or overexpression of CD80 in HSV-1 infection, we infected CD80 -/- and WT mice with a recombinant HSV-1 expressing murine CD80 (HSV-CD80) in place of the latency associated transcript (LAT). Parental dLAT2903 virus lacking LAT was used as a control. After infection, critical components of infection like virus replication, eye disease, early cellular infiltrates into the corneas and trigeminal ganglia (TG), latency-reactivation in the infected mice were determined. Our findings reveal that the absence of CD80 in the CD80 -/- mice infected with both viruses did not affect the viral titers in the mice eyes or eye disease, but it played a significant role in critical components of HSV-induced immunopathology. The WT mice infected with dLAT2903 virus had significantly higher levels of latency compared with the CD80 -/- mice infected with dLAT2903 virus, while levels of latency as determined by gB DNA expression were similar between the WT and CD80 -/- mice infected with HSV-CD80 virus. In contrast to the differences in the levels of latency between the infected groups, the absence of CD80 expression in the CD80 -/- mice or its overexpression by HSV-CD80 virus did not have any effect on the time of reactivation. Furthermore, the absence of CD80 expression contributed to more inflammation in the CD80 -/- -infected mice. Overall, this study suggests that in the absence of CD80, inflammation increases, latency is reduced, but reactivation is not affected. Altogether, our study suggests that reduced latency correlated with reduced levels of inflammatory molecules and blocking or reducing expression of CD80 could be used to mitigate the immune responses, therefore controlling HSV-induced infection.

Herpes simplex keratitis (HSK) is a blinding disease caused by herpes simplex virus type 1 (HSV-1) infection, and rapid eradication of the virus from the affected cornea is imperative. Nod-like receptors (NLRs) are intracellular innate immune sensors closely associated with cell death, inflammation and immune responses. In this study, we investigated the role of NLRP12 in the antiviral immunology in HSK and the underlying mechanisms. We found that NLRP12 expression was significantly decreased in HSV-1-infected human corneal epithelial cells (HCE-Ts) and HSK mouse corneas. Overexpression of NLRP12 significantly reduced viral replication in infected HCE-Ts and functioned through inflammasome-mediated pyroptosis and downstream IL-18-IFN-γ axis. In HSK mouse models, overexpression of NLRP12 reduced viral replication in the cornea and alleviated HSK symptoms. This resulted from enhanced antiviral immune responses including the activation of specific immune cells in both the cornea and the draining lymph nodes. Specifically, the NLRP12-IL-18-IFN-γ axis regulated the interaction between infected corneal epithelial cells and macrophages. In conclusion, our study identified a role of NLRP12 in mediating pyroptosis and regulating antiviral immune responses. This novel finding opens the possibilities of NLRP12 as a viable target in the therapeutic strategies for HSV-1 infection., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Stimulator of IFN genes (STING) is a critical component of the innate immune system, playing an essential role in defending against DNA virus infections. However, the mechanisms governing basal STING regulation remain poorly understood. In this study, we demonstrate that the basal level of STING is critically maintained by hypoxia-inducible factor 1 (HIF-1)α through transcription. Under normal conditions, HIF-1α binds constitutively to the promoter region of STING, actively promoting its transcription. Knocking down HIF-1α results in a decrease in STING expression in multiple cell lines and zebrafish, which in turn reduces cellular responses to synthetic dsDNAs, including cell signaling and IFN production. Moreover, this decrease in STING levels leads to an increase in cellular susceptibility to DNA viruses HSV-1 and pseudorabies virus. These findings unveil a (to our knowledge) novel role of HIF-1α in maintaining basal STING levels and provide valuable insights into STING-mediated antiviral activities and associated diseases., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Fundamental to mammalian intrinsic and innate immune defenses against pathogens is the production of Type I and Type II interferons, such as IFN-β and IFN-γ, respectively. The comparative effects of IFN classes on the cellular proteome, protein interactions, and virus restriction within cell types that differentially contribute to immune defenses are needed for understanding immune signaling. Here, a multilayered proteomic analysis, paired with biochemical and molecular virology assays, allows distinguishing host responses to IFN-β and IFN-γ and associated antiviral impacts during infection with several ubiquitous human viruses. In differentiated macrophage-like monocytic cells, we classified proteins upregulated by IFN-β, IFN-γ, or pro-inflammatory LPS. Using parallel reaction monitoring, we developed a proteotypic peptide library for shared and unique ISG signatures of each IFN class, enabling orthogonal confirmation of protein alterations. Thermal proximity coaggregation analysis identified the assembly and maintenance of IFN-induced protein interactions. Comparative proteomics and cytokine responses in macrophage-like monocytic cells and primary keratinocytes provided contextualization of their relative capacities to restrict virus production during infection with herpes simplex virus type-1, adenovirus, and human cytomegalovirus. Our findings demonstrate how IFN classes induce distinct ISG abundance and interaction profiles that drive antiviral defenses within cell types that differentially coordinate mammalian immune responses.

Background: Sexually transmitted infections (STIs) may cause substantial individual suffering and a large economic burden for society. This study examined the seroprevalence of Chlamydia trachomatis , Mycoplasma genitalium , herpes simplex virus (HSV) types 1 and 2, and several human papillomaviruses (HPV) in the Swedish population over time., Methods: The study population consisted of 30-year-old women attending maternity care, and 50 year-old men and women attending health check-ups, from 1975 to 2018. Antibody status was determined by multiplex serology and quantified using median reporter fluorescence intensity (MFI)., Results: A total of 891 samples were analysed (519 from 30-year-old women, 186 from 50 year-old women and 186 from 50 year-old men). Of these, 41.5% showed seropositivity for Chlamydia trachomatis , 16.7% for Mycoplasma genitalium , 70.5% for HSV-1, 14.9% for HSV-2, 13.2% for high-risk HPV, and 8.3% for low-risk HPV. Seropositivity for Mycoplasma genitalium , HSV-1 and especially Chlamydia trachomatis decreased over time., Conclusions: There was a decrease over time in Chlamydia trachomatis seroprevalence, probably due to contact tracing, testing and early treatment; this might also have affected Mycoplasma genitalium seroprevalence. Despite the reduction, seroprevalences are still high, so continued and new efforts to reduce STI incidence are essential., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

The brain is highly sensitive to damage caused by infection and inflammation 1,2 . Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis 3 . It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively 4-6 . Notably, Tmeff1 -/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are chronic, highly prevalent viral infections that cause significant morbidity around the world. HSV-2 is sexually transmitted and is the leading cause of genital ulcer disease (GUD). It also increases the risk of HIV acquisition, fueling the HIV epidemic. HSV-1 is typically acquired in childhood through nonsexual contact and contributes to oral and ocular disease, but it can also be sexually transmitted to cause GUD. Both HSV-1 and HSV-2 cause neonatal herpes and neurologic disease. Given the ubiquitous nature of HSV-1 and HSV-2 infections and the limited existing prevention and control measures, vaccination would be the most efficient strategy to reduce the global burden of morbidity related to HSV infection. Vaccine strategies include prophylactic vaccination, which would prevent infection among susceptible persons and would likely be given to adolescents, and therapeutic vaccinations, which would be given to people with symptomatic genital HSV-2 infection. This document discusses the vaccine value profile of both types of vaccines. This 'Vaccine Value Profile' (VVP) for HSV is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by subject matter experts from academia, non-profit organizations, government agencies and multi-lateral organizations. All contributors have extensive expertise on various elements of the HSV VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christine Johnston reports a relationship with GSK that includes: consulting or advisory and research funding. Christine Johnston reports a relationship with Assembly Biosciences Inc that includes: consulting or advisory. Christine Johnston reports a relationship with Gilead Sciences Inc that includes: funding grants. Christine Johnston reports a relationship with Moderna that includes: research funding. Katharine Looker reports a relationship with GSK that includes: funding grants. SS, LG, MCB, NC, CD, SDM, SL, CM, MBM, FN, SG report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Zhang, Liu, Yang, Yang, Liu and Hu.)

Background: The indigenous population located in the central region of Brazil, is the second largest in terms of population size in the country. The Indigenous Reserve of Dourados has risk factors that increase the vulnerability of the indigenous population to infectious diseases, especially Human alphaherpesvirus (HSV-1), a neglected disease with high prevalence in priority populations in developing countries. The virus can also cause many more severe diseases, including widespread neonatal infections, herpetic keratitis, and herpes encephalitis, which can be fatal if left untreated. We estimated the prevalence of anti-HSV-1 antibodies and correlated it with the demographic and behavioral characteristics of the Indigenous population of the Jaguapirú and Bororó villages (Dourados, Mato Grosso do Sul (MS), Brazil)., Methods: Our approach was cross-sectional. From March 2017 to November 2018. Using anti-HSV-1 (Gg1) IgM and anti-HSV-1 (gG1) IgG Euroimmun and the detection and quantification of HSV-1 viral load in plasma samples, through real-time PCR. The maps were constructed using QGIS and the statistical analyses using R Studio software., Results: A total of 1138 individuals (> 18 years old) were enrolled. The prevalence of anti-HSV-1 IgM and IgG were 20% and 97.5%, respectively. The prevalence of anti-HSV-1 antibodies for IgG was higher in both sexes. Anti-HSV-1 IgM antibodies were present in 17.1%, 21.2%, 12.5%, and 22% of the participants with urinary problems, genital wounds, genital warts, and urethral discharge, respectively. Real-time PCR was used for confirmatory testing; HSV-1 DNA was detected in 25.6% (54/211) of anti-HSV1 IgM-positive samples. Viral loads ranged from 5.99E + 02 to 3.36E + 13., Conclusions: The seroprevalence of HSV-1 IgM and detection of HSV-1 DNA in the Indigenous population confirmed high silent prevalence. Furthermore, the seroprevalence of HSV-1 in the Indigenous population was higher than that reported in the general adult Brazilian population. Various socioeconomic factors, drug use, and health and sexual behaviors could contribute to the facilitation of HSV-1 transmission in the Indigenous population. Our results may help develop culturally appropriate intervention programs that eliminate health access barriers and improve the implementation of public health policies aimed at promoting information regarding the prevention, treatment, and control of HSV-1 infection in Brazilian Indigenous populations., (© 2024. The Author(s).)