Combined Effect of Basic Antiherpetic Drugs with a New Inhibitor of the Terminase Complex of Herpes Simplex Virus Type 1 in Vero Cell Cultures.

Abstract-Carriers of herpes simplex virus type 1 (HSV-1) account for more than 90% of the global population. Infection manifests itself in the formation of blisters and ulcers on the face or genitals and can cause blindness, encephalitis, and generalized infection. All first- and second-line modern antiherpetic drugs selectively inhibit viral DNA polymerase. The purine-benzoxazine conjugate LAS-131 ((S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine), which we have described earlier, uses the large subunit of the HSV-1 terminase complex as a biotarget and selectively inhibits HSV-1 reproduction in vitro. Basically new results were for the first time obtained to characterize the combined effect on human herpesvirus infection for LAS-131 used in combination with practically significant antiviral compounds, including the nucleoside analogs acyclovir (ACV), penciclovir (PCV), ganciclovir (GCV), brivudine (BVdU), iododeoxyuridine (IdU), and adenine arabinoside (Ara-A); the nucleoside phosphonate analog cidofovir (CDV); and the pyrophosphate analog foscarnet (FOS). A cytopathic effect (CPE) inhibition assay showed that the drug concentration that inhibited the virus-induced CPE by 50% decreased by a factor of 2 (an additive effect, FOS) or more (a synergistic effect; ACV, PCV, GCV, IdU, BVdU, Ara-A, and CDV) when the drugs were used in combination with LAS-131. Nonpermissive conditions for HSV-1 reproduction were thus created at lower drug concentrations, opening up new real possibilities to control human herpesvirus infection.

Antiviral Effect of Ferula Plants and their Potential for Treatment of COVID-19: A Comprehensive Review.

Viral diseases have always been a threat to mankind throughout history, and many people have lost their lives due to the epidemic of these diseases. In recent years, despite the progress of science, we are still witnessing a pandemic of dangerous diseases such as COVID-19 all over the world, which can be a warning for humanity. Ferula is a genus of flowering plants commonly found in Central Asia, and its species have shown antiviral activity against a variety of viruses, including respiratory syncytial virus, Herpes simplex virus type 1, influenza, human immunodeficiency virus, hepatitis B, and coronaviruses. In this study, we intend to review the antiviral effects of Ferula plants, emphasizing the therapeutic potential of these plants in the treatment of COVID-19. Google, PubMed, Web of Science, and Scopus databases were searched to review the relevant literature on the antiviral effect of Ferula or its isolated compounds. The search was performed using the keywords Ferula, antiviral, Coronaviruses, respiratory syncytial virus, Herpes simplex virus type 1, influenza, human immunodeficiency virus, and hepatitis B. According to the reviewed articles and available scientific evidence, it was determined that the plants of this genus have strong antiviral effects. Also, clinical studies have shown that some species, such as Ferula assa-foetida, can be used effectively in the treatment of COVID-19. Ferula plants have inhibitory effects on various viruses, making them an attractive alternative to conventional antiviral agents. Therefore, these plants are a natural source of valuable compounds that can help us fight infectious diseases.

Herpes Simplex Virus type 1 inhibits autophagy in glial cells but requires ATG5 for the success of viral replication.

Herpes Simplex Virus type 1 (HSV-1) 1 is a neurotropic virus that has been associated with neurodegenerative disorders. The dysregulation of autophagy by HSV-1 has been proposed as a potential cause of neurodegeneration. While studies have extensively tackled the interaction between autophagy and HSV-1 in neurons, research in glial cells is currently limited. Our studies demonstrate that HSV-1 inhibits, but not completely blocks, the formation of autophagosomes in human oligodendroglioma- and astrocytoma- derived cell lines. These findings have been confirmed in murine oligodendrocyte precursor cells (OPCs). Finally, this study investigates the impact of autophagy on HSV-1 infection in glial cells. While the lack of basal autophagy in LC3B knockout glial cells does not have a significant effect on viral infection, cells without the autophagy-related protein ATG5 exhibit reduced viral production. The absence of ATG5 leads to a decrease in the transcription and replication of viral genes, as well as a delay in the initial stages of the formation of HSV-1 replication compartments. These findings indicate that while autophagy may not play a significant role in antiviral defense in glial cells, HSV-1 may be inhibiting autophagy to exploit non-canonical functions of certain components of the autophagic machinery, such as ATG5, to benefit its lifecycle.

In vitro anti-HSV1 activity of aqueous extract of Areca catechu L.

Background and Objectives: HSV-1 is known as a very contagious virus and the main cause of cold sores or fever blisters. Herein, the aqueous extract of Areca catechu L. was evaluated for its anti-HSV-1 activity, compared to the standard control (acyclovir). Also, the effect of extract on the expression of UL46 and US6 genes that accumulate late in viral infection, was studied. Materials and Methods: The aqueous extract was obtained by the maceration of powdered plant in boiling water. Its antiviral activity was evaluated on Vero cells infected with HSV-1 at different times: 2 h pre-infection, simultaneous infection, and 4 h post-infection, using MTT assay. The effect of extract on the expression of genes was investigated with quantitative real-time PCR. Results: The aqueous extract of A. catechu induced the inhibition of infection with the IC50 value of 110.52 ± 1.36 µg/ml. Also, it reduced the expression of UL46 when it was added 2 h pre-infection at 100 µg/ml. Moreover, reduction of expression of US6 was observed at the same concentration when the extract was used simultaneously with the occurrence of infection and 4 h post-infection. Conclusion: A. catechu can be considered an essential element of natural-based anti-HSV-1 agents.

Integrating pan-genome and reverse vaccinology to design multi-epitope vaccine against Herpes simplex virus type-1.

Herpes simplex virus type-1 (HSV-1), the etiological agent of sporadic encephalitis and recurring oral (sometimes genital) infections in humans, affects millions each year. The evolving viral genome reduces susceptibility to existing antivirals and, thus, necessitates new therapeutic strategies. Immunoinformatics strategies have shown promise in designing novel vaccine candidates in the absence of a clinically licensed vaccine to prevent HSV-1. However, to encourage clinical translation, the HSV-1 pan-genome was integrated with the reverse-vaccinology pipeline for rigorous screening of universal vaccine candidates. Viral targets were screened from 104 available complete genomes. Among 364 proteins, envelope glycoprotein D being an outer membrane protein with a high antigenicity score (> 0.4) and solubility (> 0.6) was selected for epitope screening. A total of 17 T-cell and 4 B-cell epitopes with highly antigenic, immunogenic, non-toxic properties and high global population coverage were identified. Furthermore, 8 vaccine constructs were designed using different combinations of epitopes and suitable linkers. VC-8 was identified as the most potential vaccine candidate regarding chemical and structural stability. Molecular docking revealed high interactive affinity (low binding energy: - 56.25 kcal/mol) of VC-8 with the target elicited by firm intermolecular H-bonds, salt-bridges, and hydrophobic interactions, which was validated with simulations. Compatibility of the vaccine candidate to be expressed in pET-29(a) + plasmid was established by in silico cloning studies. Immune simulations confirmed the potential of VC-8 to trigger robust B-cell, T-cell, cytokine, and antibody-mediated responses, thereby suggesting a promising candidate for the future of HSV-1 prevention. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04022-6.

Development of an HSV-1 production process involving serum-reduced culturing and bead-to-bead transfer.

Herpes simplex virus type 1 (HSV-1) plays an important role in the field of gene therapy and viral vaccines, especially as an oncolytic virus. However, the mass production of HSV-1 viral vectors remains a challenge in the industry. In this study, a microcarrier-mediated serum-reduced medium culture was used to improve the bioprocess of HSV-1 production and increase HSV-1 yields. The composition of the culture media, which included a basal medium, serum concentration, and glutamine additive, was optimized. The process was successfully conducted in a 1 L bioreactor, and virus production was threefold greater than that of conventional processes with a 10% serum medium. The bead-to-bead transfer process was also developed to further increase scalability. In spinner flasks, the detachment rate increased from 49.4 to 80.6% when combined agitation was performed during digestion; the overall recovery proportion increased from 37.9 to 71.1% after the operational steps were optimized. Specifically, microcarrier loss was reduced during aspiration and transfer, and microcarriers and detached cells were separated with filters. Comparable cell growth was achieved with the baseline process using 2D culture as the inoculum by exchanging the subculture medium. To increase virus production after bead-to-bead transfer, critical parameters, including shear stress during digestion, TrypLE and EDTA concentrations in the subculture, and the CCI, were identified from 47 parameters via correlation analysis and principal component analysis. The optimized bead-to-bead transfer process achieved an average of 90.4% overall recovery and comparable virus production compared to that of the baseline process. This study is the first to report the optimization of HSV-1 production in Vero cells cultured on microcarriers in serum-reduced medium after bead-to-bead transfer. KEY POINTS: • An HSV-1 production process was developed that involves culturing in serum-reduced medium, and this process achieved threefold greater virus production than that of traditional processes. • An indirect bead-to-bead transfer process was developed with over 90% recovery yield in bioreactors. • HSV-1 production after bead-to-bead transfer was optimized and was comparable to that achieved with 2D culture as inoculum.

α7 Nicotinic Receptor Activation Mitigates Herpes Simplex Virus Type 1 Infection in Microglia Cells.

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-1ß 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.

Papulovesicular Riddle in an Atopic Individual.

Atopic dermatitis (AD) characterized by pruritus and eczematous lesions makes individuals susceptible to various viral and bacterial infections. Eczema herpeticum (EH), also known as Kaposi's varicelliform eruption, is a severe herpes simplex virus infection that can be observed in individuals with AD. EH manifests with monomorphic vesicles and "punched-out" erosions accompanied by hemorrhagic crusts, primarily affecting eczematous areas. Misdiagnosis, often as impetigo, can lead to severe complications and even death. Timely diagnosis and treatment with acyclovir are crucial to avert these outcomes. Here we present a case of a 19-year-old male with AD who presented with a monomorphic vesicular rash.

Neuroretinitis With Severe Macular Edema in Dual Infection: Challenges in Management.

Neuroretinitis is a potentially vision-threatening condition distinguished by swelling of the optic disc followed by the emergence of a macular star pattern. The majority of these clinical observations are typically linked to infections caused by bacteria, parasites, or viruses. We report a case of dual infections in neuroretinitis complicated with severe macular edema. A 49-year-old lady presented with sudden onset left eye blurring of vision of one-week duration. Visual acuity was 6/6 in the right eye and 6/60 in the left eye. There was a left positive relative afferent pupillary defect with impaired optic nerve functions. A fundoscopy of the left eye showed optic disc swelling with a macular star. The right optic disc was also swollen. Vasculitis changes were observed in both posterior poles. The ocular coherence tomography of the left eye revealed the existence of macular edema, subretinal fluids, and an epiretinal membrane that extended from the optic disc to the fovea. Serological examinations were positive for toxoplasma and herpes simplex virus type 1. The patient was started on oral azithromycin, oral acyclovir, and oral corticosteroids. Left macular edema persisted despite the treatment. The patient was given a trial of a single injection of intravitreal ranibizumab. A remarkable reduction of subretinal fluids was seen post-intravitreal injection and continuation of medications. Intravitreal ranibizumab has shown significant outcomes in neuroretinitis with severe macula edema.

Docking Proteins Upregulate IL-1ß Expression in Lower Esophageal Sphincter Muscle in Esophageal Achalasia.

Background/Objectives: Esophageal achalasia is an archetypal esophageal motility disorder characterized by abnormal peristalsis of the esophageal body and impaired lower esophageal sphincter (LES) relaxation. Methods: In this study, the mRNA expression of docking proteins 1 and 2 (DOK1 and DOK2, respectively) were analyzed and the mechanisms underlying achalasia onset were investigated. Results:DOK1 and DOK2 mRNA levels significantly increased in the LES of patients with achalasia. Moreover, significant correlations were observed between IL-1ß and DOK1, IL-1ß and DOK2, ATG16L1 and DOK1, and HSV1-miR-H1-3p and DOK2 expression levels. However, a correlation between ATG16L1 and DOK2 or between HSV-miR-H1-3p and DOK1 expression was not observed. In addition, a positive correlation was observed between patient age and DOK1 expression. Microarray analysis revealed a significant decrease in the expression of hsa-miR-377-3p and miR-376a-3p in the LES muscle of patients with achalasia. Conclusions: These miRNAs possessed sequences targeting DOK. The upregulation of DOK1 and DOK2 expression induces IL-1ß expression in the LES of achalasia patients, which may contribute to the development of esophageal motility disorder.

Harmol used for the treatment of herpes simplex virus induced keratitis.

Herpes simplex virus type 1 (HSV-1) infection of the eyes results in herpes simplex keratitis (HSK), which has led to vision loss and even blindness in patients. However, the rate of drug resistance in HSV is on the rise; therefore, new antiviral agents with sufficient safety profiles must be developed. At present, we assessed the anti-HSV-1 activity of 502 natural compounds and their ability to reduce the HSV-1-induced cytopathic effect. We chose harmol for further studies because it exhibited the highest antiviral activity. We found that harmol inhibited both HSV-1 F and HSV-1/153 (a clinical drug-resistant strain) replication, with an EC50 of 9.34 µM and 5.84 µM, respectively. Moreover, harmol reduced HSV-1 replication in corneal tissues and viral progeny production in tears, and also alleviated early corneal surface lesions related to HSK. For example, harmol treatment preserved corneal thickness and nerve density in HSK mice. Interestingly, harmol also showed a promising antiviral effect on HSV-1/153 induced HSK in mouse model. Furthermore, harmol combined with acyclovir (ACV) treatment showed a greater antiviral effect than either one alone in vitro. Therefore, harmol may be a promising therapeutic agent for managing HSK.

Enhancement of HSV-1 cell-free virion release by the envelope protein gC.

Glycoprotein C (gC), one of ∼12 HSV-1 envelope glycoproteins, carries out several important functions during infection, including the enhancement of virion attachment by binding to host cell heparan sulfate proteoglycans (HSPG). Here we report that gC can also enhance the release of cell-free progeny virions at the end of the infectious cycle. This activity was observed in multiple cellular contexts including Vero cells and immortalized human keratinocytes. In the absence of gC, progeny virions bound more tightly to infected cells, suggesting that gC promotes the detachment of virions from the infected cell surface. Given this finding, we analyzed the biochemical interactions that tether progeny virions to cells and report evidence for two distinct modes of binding. One is consistent with a direct interaction between gC and HSPG, whereas the other is gC-independent and likely does not involve HSPG. Together, our results i) identify a novel function for a long-studied HSV-1 glycoprotein, and ii) demonstrate that the extracellular release of HSV-1 virions is a dynamic process involving multiple viral and host components.

Development of a novel, high-efficacy oncolytic herpes simplex virus type 1 platform equipped with two distinct retargeting modalities.

To retarget oncolytic herpes simplex virus (oHSV) to cancer-specific antigens, we designed a novel, double-retargeted oHSV platform that uses single-chain antibodies (scFvs) incorporated into both glycoprotein H and a bispecific adapter expressed from the viral genome to mediate infection predominantly via tumor-associated antigens. Successful retargeting was achieved using a nectin-1-detargeted HSV that remains capable of interacting with herpesvirus entry mediator (HVEM), the second canonical HSV entry receptor, and is, therefore, recognized by the adapter consisting of the virus-binding N-terminal 82 residues of HVEM fused to the target-specific scFv. We tested both an epithelial cell adhesion molecule (EpCAM)- and a human epidermal growth factor receptor 2-specific scFv separately and together to target cells expressing one, the other, or both receptors. Our results show not only dose-dependent, target receptor-specific infection in vitro, but also enhanced virus spread compared with single-retargeted virus. In addition, we observed effective infection and spreading of the EpCAM double-retargeted virus in vivo. Remarkably, a single intravenous dose of the EpCAM-specific virus eliminated all detectable tumors in a subcutaneous xenograft model, and the same intravenous dose seemed to be harmless in immunocompetent FVB/N mice. Our findings suggest that our double-retargeted oHSV platform can provide a potent, versatile, and systemically deliverable class of anti-cancer therapeutics that specifically target cancer cells while ensuring safety.

Evaluation of Oral Health-Related Quality of Life in Patient with Herpes-Associated Erythema Multiforme: A Unique Case Report.

Introduction: Erythema multiforme (EM) is an acute mucocutaneous hypersensitivity reaction with various etiological factors, including herpes simplex virus type 1 (HSV-1) infection, known as herpes-associated erythema multiforme (HAEM). Oral health-related quality of life (OHRQoL) is a multidimensional concept of biopsychosocial aspects related to oral health. OHRQol contains information for patient-centered treatment plan development. The OHRQoL measurement instrument widely used by clinicians is the oral health impact profile-14 (OHIP-14). This case report aimed to evaluate OHRQoL in HAEM patient, which only manifests on the lips and oral cavity. Case: A 25-year-old male patient came to the Department of Oral Medicine with the chief complaint of painful canker sores on the lips. Extra-oral examination revealed serosanguineous crusts on the lips that were painful and easily bleed. Intra-oral examination showed diffused and painful irregular erythematous lesions on the upper and lower labial mucosa. The anti-HSV1 IgG test was positive. The patient was diagnosed with HAEM. Case Management: Pharmacological therapy included triamcinolone acetonide 0.1% in orabase, acyclovir tablets, multivitamins, and 0.9% NaCl. Non-pharmacological therapy included advice on maintaining good oral hygiene, avoiding spicy and sour foods, and breaking the bad habit of licking the lips. Conclusion: The patient's physical, psychological, and social conditions showed improvement and returned to normal after 7 days of treatment. In conclusion, oral health is an important factor that can improve the quality of life of HAEM patient.

In vitro evaluation of inhibitory effect of Lactobacillus reuteri supernatant on the replication of herpes simplex virus type 1 and expression of UL54, UL52 and UL27 genes.

Background and Objectives: Human herpes virus type 1 (HSV-1) is a neurotropic pathogen that is infected more than 70% of the world population. The increasing of viral resistance to antiviral drugs and the emergence of side effects has motivated researchers to study the use of probiotics as new antiviral agents. The aim of the present study was to study for the first time the potential antiviral activity of Lactobacillus reuteri (L. reuteri) supernatant against HSV-1. Materials and Methods: After measuring the cytotoxicity of L. reuteri supernatant by MTT assay, 1:16 dilution of it was added to HeLa cells before and after HSV-1 infection, after 1.5 hours incubation with HSV-1, and simultaneously with HSV-1 infection. After 48 hours of incubation at 37°C, the viral titer and expression levels of UL54, UL52 and UL27 genes were measured by tissue culture infectious dose 50 (TCID50 ) and Real-Time PCR methods, respectively. Results: HSV-1 titer in the treatment conditions before infection, incubation with HSV-1, simultaneously with infection and after infection was reduced by 0.42, 3.42, 1.83, and 0.83 log 10 TCID50/ml, respectively. When the bacterial supernatant was first incubated with the virus and then added to the cell, or when it was added simultaneously with the virus, the expression of the UL27, UL52, and UL54 genes decreased significantly (p<0.05). When the bacterial supernatant is added to the cell before or after virus infection, the expression of UL52 and UL54 genes does not change significantly (P>0.05). Conclusion: The study findings indicated that the supernatant of L. reuteri has a potent anti-HSV-1 effect especially if it is incubated with the virus before inoculation into the cell. Its possible antiviral mechanism is to inhibit the virus by binding to it or changing the surface structure of the virus. Metabolites of L. reuteri can be considered as a novel inhibitor of HSV-1 infection.

Vaginal Lactobacilli Supernatants Protect from Herpes Simplex Virus Type 1 Infection in Cell Culture Models.

A healthy vaginal microbiota hosts Lactobacillus as the most predominant genus. Lactobacilli play a role in human health through the production of diverse antimicrobial substances that can act against human pathogens or modulate the immune system. Previous reports highlighted the ability of vaginal lactobacilli to counteract viruses causing STIs, e.g., HIV-1 and HSV-2. In this report, we analyze the activity of supernatants of vaginal lactobacilli against HSV-1 infection, which is becoming increasingly relevant as a STI. We show that the supernatants of two vaginal Lactobacillus species (i.e., L. crispatus and L. gasseri) were active at neutralizing HSV-1 infection in two different cell lines of human and simian origin. Specifically, we demonstrate that L. crispatus strains are the most effective in antiviral activity, as evidenced by the comparison with a vaginal pathogen taken as reference. The effect was specific and not attributable to the generic toxicity of the supernatants to the cells. Our results pave the way for the development of probiotics to limit the impact of HSV-1 infection on women's health.

Trigeminal Neuralgia Secondary to Herpes Simplex Virus Type 1 Infection Treated With Oral Acyclovir.

Trigeminal neuralgia (TN) is characterized by episodic electric, shock-like facial pain. Though often idiopathic, herpes simplex virus type 1 (HSV-1) reactivation can rarely cause symptomatic TN. We report the case of a 30-year-old woman who developed oral HSV-1 lesions followed by right-sided TN pain. MRI of the brain did not reveal neurovascular compression. TN pain completely resolved with oral acyclovir treatment alone, without anticonvulsants. This highlights the importance of considering atypical etiologies such as HSV-1 reactivation in TN evaluation. Early antiviral therapy may treat underlying inflammation and provide sustained symptom relief in HSV-associated TN.

Molecular Dissection of Herpes Simplex Virus Type 1 to Elucidate Molecular Mechanisms Behind Latency and Comparison of Its Codon Usage Patterns with Genes Modulated During Alzheimer's Disease as a Part of Host-Pathogen Interaction.

BACKGROUND: Herpes simplex virus type 1 (HSV-1) is associated with Alzheimer's disease, which goes into a cycle of latency and reactivation. The present study was envisaged to understand the reasons for latency and specific molecular patterns present in the HSV-1. OBJECTIVE: The objective is the molecular dissection of Herpes simplex virus type 1 to elucidate molecular mechanisms behind latency and compare its codon usage patterns with genes modulated during Alzheimer's disease as a part of host-pathogen interaction. METHODS: In the present study, we tried to investigate the potential reasons for the latency of HSV-1 virus bioinformatically by determining the CpG patterns. Also, we investigated the codon usage pattern, the presence of rare codons, codon context, and protein properties. RESULTS: The top 222 codon pairs graded based on their frequency in the HSV-1 genome revealed that with only one exception (CUG-UUU), all other codon pairs have codons ending with G/C. Considering it an extension of host-pathogen interaction, we compared HSV-1 codon usage with that of codon usage of genes modulated during Alzheimer's disease, and we found that CGT and TTT are only two codons that exhibited similar codon usage patterns and other codons showed statistically highly significant different codon preferences. Dinucleotide CpG tends to mutate to TpG, suggesting the presence of mutational forces and the imperative role of CpG methylation in HSV-1 latency. CONCLUSIONS: Upon comparison of codon usage between HSV-1 and Alzheimer's disease genes, no similarities in codon usage were found as a part of host-pathogen interaction. CpG methylation plays an imperative role in latency HSV-1.

Hemophagocytic lymphohistiocytosis caused by herpes simplex virus type 1 in a young adult: a case report with literature review.

Hemophagocytic lymphohistiocytosis is a severe hyperinflammatory syndrome that can be potentially life-threatening without appropriate treatment. Although viral infection is the most common trigger of hemophagocytic lymphohistiocytosis, cases of herpes simplex virus type 1-induced hemophagocytic lymphohistiocytosis are rare in adults. This study aims to provide a comprehensive overview of the clinical characteristics and treatment outcomes associated with HSV-1-induced HLH. We herein report an adult case of hemophagocytic lymphohistiocytosis caused by herpes simplex virus type 1, diagnosed on the basis of peripheral blood metagenomic next-generation sequencing results. The patient exhibited a favorable response to treatment, involving dexamethasone, intravenous immunoglobulin, and acyclovir. Notably, etoposide administration was deemed unnecessary, and there has been no recurrence of the disease within the year following treatment. Early and sensitive recognition, rapid and precise diagnosis, and timely and appropriate treatment facilitated the successful treatment of this case.

Complement Suppresses the Initial Type 1 Interferon Response to Ocular Herpes Simplex Virus Type 1 Infection in Mice.

The complement system (CS) contributes to the initial containment of viral and bacterial pathogens and clearance of dying cells in circulation. We previously reported mice deficient in complement component 3 (C3KO mice) were more sensitive than wild-type (WT) mice to ocular HSV-1 infection, as measured by a reduction in cumulative survival and elevated viral titers in the nervous system but not the cornea between days three and seven post infection (pi). The present study was undertaken to determine if complement deficiency impacted virus replication and associated changes in inflammation at earlier time points in the cornea. C3KO mice were found to possess significantly (p < 0.05) less infectious virus in the cornea at 24 h pi that corresponded with a decrease in HSV-1 lytic gene expression at 12 and 24 h pi compared to WT animals. Flow cytometry acquisition found no differences in the myeloid cell populations residing in the cornea including total macrophage and neutrophil populations at 24 h pi with minimal infiltrating cell populations detected at the 12 h pi time point. Analysis of cytokine and chemokine content in the cornea measured at 12 and 24 h pi revealed that only CCL3 (MIP-1α) was found to be different between WT and C3KO mice with >2-fold increased levels (p < 0.05, ANOVA and Tukey's post hoc t-test) in the cornea of WT mice at 12 h pi. C3KO mouse resistance to HSV-1 infection at the early time points correlated with a significant increase in type I interferon (IFN) gene expression including IFN-α1 and IFN-ß and downstream effector genes including tetherin and RNase L (p < 0.05, Mann-Whitney rank order test). These results suggest early activation of the CS interferes with the induction of the type I IFN response and leads to a transient increase in virus replication following corneal HSV-1 infection.