Herpes simplex virus type 1 (HSV-1), a neurotropic DNA virus, establishes latency in neural tissues, with reactivation causing severe consequences like encephalitis. Emerging evidence links HSV-1 infection to chronic neuroinflammation and neurodegenerative diseases. Microglia, the central nervous system\'s (CNS) immune sentinels, express diverse receptors, including α7 nicotinic acetylcholine receptors (α7 nAChRs), critical for immune regulation. Recent studies suggest α7 nAChR activation protects against viral infections. Here, we show that α7 nAChR agonists, choline and PNU-282987, significantly inhibit HSV-1 replication in microglial BV2 cells. Notably, this inhibition is independent of the traditional ionotropic nAChR signaling pathway. mRNA profiling revealed that choline stimulates the expression of antiviral factors, IL-1β and Nos2, and down-regulates the apoptosis genes and type A Lamins in BV2 cells. These findings suggest a novel mechanism by which microglial α7 nAChRs restrict viral infections by regulating innate immune responses.

Herpes simplex virus type 1 (HSV-1) has been known as a common viral pathogen that can infect several parts of the body, leading to various clinical manifestations. According to this diverse manifestation, HSV-1 infection in many cell types was demonstrated. Besides the HSV-1 cell tropism, e.g., fibroblast, epithelial, mucosal cells, and neurons, HSV-1 infections can occur in human T lymphocyte cells, especially in activated T cells. In addition, several studies found that actin polymerization and filopodia formation support HSV-1 infection in diverse cell types. Hence, the goal of this review is to explore the mechanism of HSV-1 infection in various types of cells involving filopodia formation and highlight potential future directions for HSV-1 entry-related research. Moreover, this review covers several strategies for possible anti-HSV drugs focused on the entry step, offering insights into potential therapeutic interventions.

Herpes simplex keratitis (HSK) is a common blinding corneal disease caused by herpes simplex virus type 1 (HSV-1) infection. Antiviral drugs and corticosteroids haven\'t shown adequate therapeutic efficacy. During the early stage of HSV-1 infection, macrophages serve as the first line of defense. In particular, CD169+ macrophages play an important role in phagocytosis and antigen presentation. Therefore, we constructed GM-gD-lip, a ganglioside GM1 liposome vaccine encapsulating HSV-1 glycoprotein D and targeting CD169+ macrophages. After subconjunctival injection of the vaccine, we evaluated the survival rate and ocular surface lesions of the HSK mice, as well as the virus levels in the tear fluid, corneas, and trigeminal ganglia. We discovered that GM-gD-lip reduced HSV-1 viral load and alleviated the clinical severity of HSK. The GM-gD-lip also increased the number of corneal infiltrating macrophages, especially CD169+ macrophages, and polarized them toward M1. Furthermore, the number of dendritic cells (DCs) and CD8+ T cells in the ocular draining lymph nodes was significantly increased. These findings demonstrated that GM-gD-lip polarized CD169+ macrophages toward M1 to eliminate the virus while cross-presenting antigens to CD8+ T cells via DCs to activate adaptive immunity, ultimately attenuating the severity of HSK. The use of GM-gD-lip as an immunotherapeutic method for the treatment of HSK has significant implications.

Human herpesviruses are enveloped viruses with double-stranded linear DNA genomes highly prevalent in the human population. These viruses are subdivided into three subfamilies, namely alphaherpesvirinae (herpes simplex virus type 1, HSV-1; herpes simplex virus type 2, HSV-2; and varicella-zoster virus, VZV), betaherpesvirinae (human cytomegalovirus, HCMV; human herpesvirus 6, HHV-6; and human herpesvirus 7, HHV-7) and gammaherpesvirinae (Epstein-Barr virus, EBV; and Kaposi\'s sarcoma-associated herpesvirus, KSHV). Besides encoding numerous molecular determinants to evade the host antiviral responses, these viruses also modulate cellular metabolic processes to promote their replication. Here, we review and discuss existing studies describing an interplay between carbohydrate metabolism and the replication cycle of herpesviruses, altogether highlighting potentially new molecular targets based on these interactions that could be used to block herpesvirus infections.

Human immunodeficiency virus (HIV) induced AIDS causes a large number of infections and deaths worldwide every year, still no vaccines are available to prevent infection. Recombinant herpes simplex virus type 1 (HSV-1) vector-based vaccines coding the target proteins of other pathogens have been widely used for disease control. Here, a recombinant virus with HIV-1 gp160 gene integration into the internal reverse (IR) region-deleted HSV-1 vector (HSV-BAC), was obtained by bacterial artificial chromosome (BAC) technology, and its immunogenicity investigated in BALB/c mice. The result showed similar replication ability of the HSV-BAC-based recombinant virus and wild type. Furthermore, humoral and cellular immune response showed superiority of intraperitoneal (IP) administration, compared to intranasally (IN), subcutaneous (SC) and intramuscularly (IM), that evidenced by production of significant antibody and T cell responses. More importantly, in a prime-boost combination study murine model, the recombinant viruses prime followed by HIV-1 VLP boost induced stronger and broader immune responses than single virus or protein vaccination in a similar vaccination regimen. Antibody production was sufficient with huge potential for viral clearance, along with efficient T-cell activation, which were evaluated by the enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FC). Overall, these findings expose the value of combining different vaccine vectors and modalities to improve immunogenicity and breadth against different HIV-1 antigens.

Herpes simplex virus type 1 (HSV-1) causes lifelong infections worldwide, and currently there is no efficient cure or vaccine. HSV-1-derived tools, such as neuronal circuit tracers and oncolytic viruses, have been used extensively; however, further genetic engineering of HSV-1 is hindered by its complex genome structure. In the present study, we designed and constructed a synthetic platform for HSV-1 based on H129-G4. The complete genome was constructed from 10 fragments through 3 rounds of synthesis using transformation-associated recombination (TAR) in yeast, and was named H129-Syn-G2. The H129-Syn-G2 genome contained two copies of the gfp gene and was transfected into cells to rescue the virus. According to growth curve assay and electron microscopy results, the synthetic viruses exhibited more optimized growth properties and similar morphogenesis compared to the parental virus. This synthetic platform will facilitate further manipulation of the HSV-1 genome for the development of neuronal circuit tracers, oncolytic viruses, and vaccines.

Herpes simplex keratitis (HSK) is a severe, infectious corneal disease caused by herpes simplex virus type 1 (HSV-1) infection. The increasing prevalence of acyclovir resistance, the side effects of hormonal drugs, and the ease of recurrence after surgery have made it crucial to develop new methods of treating HSK. HSV-1 evades the host immune response through various mechanisms. Therefore, we explored the role of the immunogenic cell death inducer PKHB1 peptide in HSK. After subconjunctival injection of PKHB1 peptide, we observed the ocular surface lesions and survival of HSK mice and detected the virus levels in tear fluid, corneas, and trigeminal ganglions. We found that PKHB1 peptide reduced HSV-1 levels in the eye and alleviated the severity of HSK. Moreover, it increased the number of corneal infiltrating antigen-presenting cells (APCs), such as macrophages and dendritic cells, and CD8+ T cells in ocular draining lymph nodes. We further observed that PKHB1 peptide promoted the exposure of calreticulin, as well as the release of ATP and high-mobility group box 1 in HSV-1-infected cells in vitro. Our findings suggested that PKHB1 peptide promoted the recruitment and maturation of APCs by inducing the release of large amounts of damage-associated molecular patterns from infected cells. APCs then phagocytized antigenic materials and translocated to the lymph nodes, triggering a cytotoxic T lymphocyte-dependent immune response that ultimately alleviated HSK.

Herpes simplex virus type 1 (HSV-1) is the only FDA- and EMA- approved oncolytic virus, and accordingly, many potential oncolytic HSVs (oHSV) are in clinical development. The utilized oHSV parental strains are, however, mostly based on laboratory reference strains, which may possess a compromised cytolytic capacity in contrast to circulating strains of HSV-1. Here, we assess the phenotype of thirty-six circulating HSV-1 strains from Finland to uncover their potential as oHSV backbones. First, we determined their capacity for cell-to-cell versus extracellular spread, to find strains with replication profiles favorable for each application. Second, to unfold the differences, we studied the genetic diversity of two relevant viral glycoproteins (gB/UL27, gI/US7). Third, we examined the oncolytic potential of the strains in cells representing glioma, lymphoma, and colorectal adenocarcinoma. Our results suggest that the phenotype of a circulating isolate, including the oncolytic potential, is highly related to the host cell type. Nevertheless, we identified isolates with increased oncolytic potential in comparison with the reference viruses across many or all of the studied cancer cell types. Our research emphasizes the need for careful selection of the backbone virus in early vector design, and it highlights the potential of clinical isolates as backbones in oHSV development.

A corticosteroid antagonist impairs Herpes Simplex Virus 1 (HSV-1) productive infection and explant-induced reactivation from latency, suggesting corticosteroids and the glucocorticoid receptor (GR) mediate certain aspects of these complex virus-host interactions. GR-hormone complexes regulate transcription positively and negatively, in part, by binding GR response elements (GREs). Recent studies revealed infected cell protein 0 (ICP0), ICP4, and ICP27 promoter/cis-regulatory modules (CRMs) are cooperatively transactivated by GR and Krüppel-like factor 15 (KLF15), which forms a feed-forward transcription loop. We hypothesized the ICP0 promoter contains independent CRMs that are transactivated by GR, KLF15, and the synthetic corticosteroid dexamethasone (DEX). This hypothesis is based on the finding that the ICP0 promoter contains multiple transcription factor binding sites, and GR and KLF15 cooperatively transactivate the full-length ICP0 promoter. ICP0 promoter sequences spanning -800 to -635 (fragment A) were efficiently transactivated by GR, KLF15, and DEX in monkey kidney cells (Vero), whereas GR and DEX significantly enhanced promoter activity in mouse neuroblastoma cells (Neuro-2A). Furthermore, ICP0 fragment B (-458 to -635) was efficiently transactivated by GR, KLF15, and DEX in Vero cells, but not Neuro-2A cells. Finally, fragment D (-232 to -24) was transactivated significantly in Vero cells by GR, KLF15, and DEX, whereas KLF15 and DEX were sufficient for transactivation in Neuro-2A cells. Collectively, these studies revealed efficient transactivation of three independent CRMs within the ICP0 promoter by GR, KLF15, and/or DEX. Finally, GC-rich sequences containing specificity protein 1 (Sp1) binding sites were essential for transactivation.

Herpes simplex virus type-1 (HSV-1) is a human virus that causes lifelong infections in a large population worldwide. Recurrence of HSV-1 from latency in trigeminal ganglion (TG) is the trigger of the morbidities seen with this virus. In addition to causing fever blisters and cold sores, occasionally the virus can also cause corneal lesions resulting in blindness in untreated individuals. Several host cell proteins play important roles in HSV-1 infection of the eye. HSV-1 enters into the corneal epithelial cells via its interactions with cell surface receptors. In parallel, the Toll-like receptors sense viral invasion and activate defense mechanisms to fight the infection. New data shows that Optineurin, a host autophagy receptor is also activated to degrade viral particles. In contrast, activation of heparanase, a host enzyme, induces an immune-inflammatory response, which triggers pro-inflammatory and pro-angiogenic environment and ultimately results in many of the clinical features seen with HSV-1 infection of the cornea. Rarely, HSV-1 can also spread to the central nervous system causing serious diseases. In this review, we summarize the latest knowledge on host molecules that promote pathophysiological aspects of ocular herpes.