Oncolytic herpes simplex virus expressing IL-2 controls glioblastoma growth and improves survival.

BACKGROUND: Glioblastoma (GBM), a highly immunosuppressive and often fatal primary brain tumor, lacks effective treatment options. GBMs contain a subpopulation of GBM stem-like cells (GSCs) that play a central role in tumor initiation, progression, and treatment resistance. Oncolytic viruses, especially oncolytic herpes simplex virus (oHSV), replicate selectively in cancer cells and trigger antitumor immunity-a phenomenon termed the "in situ vaccine" effect. Although talimogene laherparepvec (T-VEC), an oHSV armed with granulocyte macrophage-colony stimulating factor (GM-CSF), is Food and Drug Administration (FDA)-approved for melanoma, its use in patients with GBM has not been reported. Interleukin 2 (IL-2) is another established immunotherapy that stimulates T cell growth and orchestrates antitumor responses. IL-2 is FDA-approved for melanoma and renal cell carcinoma but has not been widely evaluated in GBM, and IL-2 treatment is limited by its short half-life, minimal tumor accumulation, and significant systemic toxicity. We hypothesize that local intratumoral expression of IL-2 by an oHSV would avoid the systemic IL-2-related therapeutic drawbacks while simultaneously producing beneficial antitumor immunity. METHODS: We developed G47Δ-mIL2 (an oHSV expressing IL-2) using the flip-flop HSV BAC system to deliver IL-2 locally within the tumor microenvironment (TME). We then tested its efficacy in orthotopic mouse GBM models (005 GSC, CT-2A, and GL261) and evaluated immune profiles in the treated tumors and spleens by flow cytometry and immunohistochemistry. RESULTS: G47Δ-mIL2 significantly prolonged median survival without any observable systemic IL-2-related toxicity in the 005 and CT-2A models but not in the GL261 model due to the non-permissive nature of GL261 cells to HSV infection. The therapeutic activity of G47Δ-mIL2 in the 005 GBM model was associated with increased intratumoral infiltration of CD8+ T cells, critically dependent on the release of IL-2 within the TME, and CD4+ T cells as their depletion completely abrogated therapeutic efficacy. The use of anti-PD-1 immune checkpoint blockade did not improve the therapeutic outcome of G47Δ-mIL2. CONCLUSIONS: Our findings illustrate that G47Δ-mIL2 is efficacious, stimulates antitumor immunity against orthotopic GBM, and may also target GSC. OHSV expressing IL-2 may represent an agent that merits further exploration in patients with GBM.

Human in vivo evidence of associations between herpes simplex virus and cerebral amyloid-beta load in normal aging.

BACKGROUND: Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aß) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor. METHODS: To shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aß deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers. RESULTS: We showed that increased anti-HSV IgG levels are associated with higher Aß load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aß load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration. CONCLUSIONS: All together, these results suggest that HSV infection is selectively related to cortical Aß deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

Improving polymerase chain reaction diagnostic rates for herpes simplex keratitis: results of a pilot study.

Background: Laboratory confirmation is crucial for diagnosis and management of herpes simplex virus (HSV) keratitis. However, the sensitivity of polymerase chain reaction (PCR) in keratitis is low (25%) compared with that of mucocutaneous disease (75%). We developed an educational intervention aimed at improving the diagnostic yield of PCR. Methods: The medical records of keratitis cases seen at the emergency department of a London tertiary ophthalmic referral hospital over two distinct periods, before and after an educational program on swab technique, were reviewed retrospectively. Results: A total of 252 HSV cases were included. Increases in the laboratory-confirmed diagnosis of HSV-1 were observed, in both first presentations (11.1%-57.7%) and recurrent cases (20%-57.6%). The rate of positive HSV-1 PCR in eyes with an epithelial defect increased from 19% pre-intervention to 62% post intervention. Notably, 3% were positive for varicella zoster virus DNA, and there was a single case of Acanthamoeba keratitis. Conclusion: Our results suggest that, with proper swabbing technique, PCR may be more sensitive than previously reported.

Non-Thermal Plasma Reduces HSV-1 Infection of and Replication in HaCaT Keratinocytes In Vitro.

Herpes simplex virus type 1 (HSV-1) is a lifelong pathogen characterized by asymptomatic latent infection in the trigeminal ganglia (TG), with periodic outbreaks of cold sores caused by virus reactivation in the TG and subsequent replication in the oral mucosa. While antiviral therapies can provide relief from cold sores, they are unable to eliminate HSV-1. We provide experimental results that highlight non-thermal plasma (NTP) as a new alternative therapy for HSV-1 infection that would resolve cold sores faster and reduce the establishment of latent infection in the TG. Additionally, this study is the first to explore the use of NTP as a therapy that can both treat and prevent human viral infections. The antiviral effect of NTP was investigated using an in vitro model of HSV-1 epithelial infection that involved the application of NTP from two separate devices to cell-free HSV-1, HSV-1-infected cells, and uninfected cells. It was found that NTP reduced the infectivity of cell-free HSV-1, reduced viral replication in HSV-1-infected cells, and diminished the susceptibility of uninfected cells to HSV-1 infection. This triad of antiviral mechanisms of action suggests the potential of NTP as a therapeutic agent effective against HSV-1 infection.

Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes.

Herpes simplex virus 1 (HSV-1) latent infection entails repression of viral lytic genes in neurons. By functional screening using luciferase-expressing HSV-1, we identify ten neuron-specific microRNAs potentially repressing HSV-1 neuronal replication. Transfection of miR-9, the most active candidate from the screen, decreases HSV-1 replication and gene expression in Neuro-2a cells. Ectopic expression of miR-9 from lentivirus or recombinant HSV-1 suppresses HSV-1 replication in male primary mouse neurons in culture and mouse trigeminal ganglia in vivo, and reactivation from latency in the primary neurons. Target prediction and validation identify transcription factors Oct-1, a known co-activator of HSV transcription, and all three Onecut family members as miR-9 targets. Knockdown of ONECUT2 decreases HSV-1 yields in Neuro-2a cells. Overexpression of each ONECUT protein increases HSV-1 replication in Neuro-2a cells, human induced pluripotent stem cell-derived neurons, and primary mouse neurons, and accelerates reactivation from latency in the mouse neurons. Mutagenesis, ChIP-seq, RNA-seq, ChIP-qPCR and ATAC-seq results suggest that ONECUT2 can nonspecifically bind to viral genes via its CUT domain, globally stimulate viral gene transcription, reduce viral heterochromatin and enhance the accessibility of viral chromatin. Thus, neuronal miR-9 promotes viral epigenetic silencing and latency by targeting multiple host transcription factors important for lytic gene activation.

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.

The associations of herpes simplex virus and varicella zoster virus infection with dementia: a nationwide retrospective cohort study.

BACKGROUND: In this study, the risk of dementia in patients with a history of herpes simplex virus (HSV) or varicella zoster virus (VZV) infection was evaluated. METHODS: This nationwide cohort study used data from the Korean National Health Insurance Service collected between 2006 and 2017. A total of 752,205 subjects ≥ 45 years of age not diagnosed with dementia until 2006 were included. A multivariate Cox regression model, adjusted for age, sex, and other comorbidities, was used to assess the hazard ratio (HR) for dementia based on VZV or HSV infection. The interaction effects of both viral infections were analysed. Viral infections are classified into four categories: eye, central nervous system (CNS), simple, and complicated. The hazard ratio (HR) of viral infection was analysed based on the type of dementia. RESULTS: In multivariable analysis, both HSV and VZV infection were associated with an increased risk of dementia (HR = 1.38, 95% confidence interval, CI:1.33-1.43) and (HR = 1.41, 95% CI:1.37-1.46), respectively. Patients who experienced both HSV and VZV infections were also at an increased risk of dementia (HR = 1.57, 95% CI:1.50-1.63). The co-infection group showed the shortest time from viral infection to dementia diagnosis (4.09 ± 3.02 years). In the subgroup analysis, all types of HSV and VZV infections were associated with an increased risk of dementia compared to the non-infection group. The eye, CNS, and complicated VZV infections were associated with a significantly higher risk than simple VZV infections. There were no significant differences between the subtypes of HSV infection. Furthermore, HSV, VSV, and co-infection were associated with an increased risk of all dementia types, including Alzheimer's disease (AD) and vascular dementia (VD). CONCLUSIONS: Individual HSV and VZV infections were associated with an increased risk of all types of dementia, including AD and VD. Patients co-infected with HSV and VZV, VZV infection in the eye, CNS, or complicated type were more vulnerable to the development of dementia.

Neonatal herpes simplex virus encephalitis with intracranial bleeding in a newborn baby with concurrent rhesus incompatibility.

We report a baby with neonatal herpes simplex virus (HSV) encephalitis concurrent with Rrhesus (Rh) incompatibility. He was delivered by a Ggravida 2 mother with a history of miscarriage in her previous pregnancy at a gestation age of 4 months. She had Bblood group 0 and Rrhesus negative. The baby was noticed to have jaundice on day one1 of life accompanied by generalised petechiae on the face and upper chest. A full blood picture revealed severe anaemia and severe thrombocytopaenia and HSV 1/2 IgM was positive. MRI of the brain showed multiple extensive haemorrhagic lesions on the frontal-temporal regions.

Exploring Heparanase Levels in Tears: Insights From Herpes Simplex Virus-1 Keratitis Patients and Animal Studies.

Purpose: Heparanase (HPSE) cleaves heparan sulfate proteoglycans during herpes simplex virus-1 (HSV-1) infection, aiding in viral egress and disease progression. Its action has been well established in in vitro and in vivo models, but its relevance in human patients remains unclear. This study aimed to specifically evaluate tear HPSE levels of patients with herpes simplex keratitis (HSK) and to correlate these findings with a commonly used murine model. Methods: Tear samples from patient and mice samples were collected at LV Prasad Eye Institute, Hyderabad, India, and at the University of Illinois, Chicago, IL, respectively. Tears were collected from HSV-1 patients, bacterial/fungal keratitis cases, and healthy individuals. For in vivo study, C57BL/6 mice were infected with HSV-1 (McKrae strain) followed by tear fluid collection at various time points (0-10 days). Results: The HSV-1, bacterial keratitis, fungal keratitis, and healthy control groups each had 30 patients. There was a significant difference in HPSE expression in the HSV-1 infected eyes (1.55 ± 0.19 units/mL) compared to HSV-1 contralateral eyes (1.23 ± 0.13 units/mL; P = 0.82), bacterial keratitis eyes (0.87 ± 0.15 units/mL; P = 0.0078), fungal keratitis eyes (0.64 ± 0.09 units/mL; P < 0.00001), and normal controls (0.53 ± 0.06 units/mL; P < 0.00001). C57BL/6 mice tear HPSE expression in infected eyes was 0.66 to 5.57 ng heparan sulfate (HS) removed per minute when compared to non-infected eye (range, 0.70-3.67 ng HS removed per minute). Conclusions: To the best of our knowledge, this study is the first to report elevated HPSE levels in the tears of patients with different forms of HSV-1 keratitis, and it confirms similar findings in a murine model, providing a valuable basis for future in vivo and clinical research on HSV-1 ocular infection.

Time trends in herpesvirus seroepidemiology among Swedish adults.

BACKGROUND: Human herpesviruses are widespread among the human population. The infections often occur unnoticed, but severe disease as well as long-term sequelae are part of the symptom spectrum. The prevalence varies among subpopulations and with time. The aim of this study was to describe the seroprevalence of Immunoglobulin G against Herpes simplex 1, Herpes simplex 2, Epstein-Barr virus and Cytomegalovirus in the adult Swedish population over a time period of several decades. METHODS: Serum samples (n = 892) from biobanks, originating from 30-year-old women, 50-year-old men and 50-year-old women sampled between 1975 and 2018, were analyzed for presence of anti-herpesvirus antibodies. Linear regression analysis was used to test for a correlation between birth year and seroprevalence. Multiple linear regression analysis was used to differentiate between other factors such as age and gender. RESULTS: Birth year correlated negatively with the prevalence of immunoglobulin G against Herpes simplex 1 and Epstein-Barr virus (p = 0.004 and 0.033), and positively with Immunoglobulin G against Cytomegalovirus (p = 0.039). When participant categories were analyzed separately, birth year correlated negatively with the prevalence of Immunoglobulin G against Herpes simplex 1 and Herpes simplex 2 (p = 0.032 and 0.028) in 30-year-old women, and with the prevalence of Immunoglobulin G against Cytomegalovirus in 50-year-old men (p = 0.011). CONCLUSIONS: The prevalence of Immunoglobulin G against Herpes simplex 1, Herpes simplex 2 and Epstein-Barr virus decreases in later birth cohorts. This indicates a trend of declining risk of getting infected with these viruses as a child and adolescent.

Characteristics of reproductive tract infections caused by common pathogens among the outpatients of reproductive medicine center in Putian: retrospective study.

BACKGROUND: This study aims to explore the infection and age distribution of Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Herpes simplex virus type II (HSV II) among the outpatients of Reproductive Medicine Center in Putian, Fujian Province to provide a clinical basis for the early diagnosis and treatment of various reproductive tract diseases and infertility in this region. METHODS: A total of 1736 samples of secretions and exfoliated cervical cells were collected from the outpatients of the Reproductive Medicine Center of the Affiliated Hospital of Putian University from December 2021 to April 2023. The infections of UU, CT, NG and HSVII were detected by real-time fluorescence polymerase chain reaction (PCR), and the infection statuses of the patients with different genders, ages and diagnoses were analysed. RESULTS: Among the 1736 patients, 611 were male and 1125 were female. The male patients had higher UU infection rate but lower HSV II infection rate than the female patients. No significant difference in CT and NG infection rates was observed between the genders. The CT infection rate gradually decreased with the increase in the age. The difference in UU, NG and HSV II infection rates among the different age groups was not statistically significant. For UU infection, the male infertile patients had the highest rate of 37.72% (172/456). Meanwhile, the differences in CT, NG and HSV II infection rates among the different diagnosis groups were not statistically significant. Among the male and female infertile patients, the CT infection rate was the highest in the 21-25 years of age group at 11.11% (2/18) and 9.47% (9/95), respectively. No statistically significant difference in UU, CT, NG and HSV II infection rates was observed among the different age groups of patients diagnosed in relation to the family planning guidance and between the male and female patients with other diagnoses results. CONCLUSIONS: This study showed that UU was the most frequently identified pathogen in infertile men in Putian, Fujian Province. The CT infection rate was the highest in people under 20 years old, and the infection showed a tendency toward young individuals. Therefore, the publicity of sexual health knowledge must be strengthened, and the prevention and treatment of venereal diseases among young and middle-aged people must be improved. Moreover, the pathogen infection is related to infertility to a certain extent, which is conducive to clinical diagnosis and treatment.

PCR testing for herpesviruses in aqueous humor samples from patients with and without clinical corneal endothelial graft rejection.

To compare prevalence of positive PCR tests for herpesviruses between patients with and without a history of clinical corneal endothelial allograft rejection (AGR). Retrospective cross-sectional study with two-group comparison. A total of 307 aqueous humor (AH) samples from 235 Patients and 244 eyes who underwent penetrating keratoplasty or Descemet membrane endothelial keratoplasty or had a diagnostic AH aspiration due to clinical AGR between 2019 and 2023 were tested for DNA of herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). PCR test results were compared between the two groups (with/without AGR). Another sub-analysis examined the results of patients without a history of herpetic keratitis. A total of 8% of eyes with clinical AGR (9/108) had a positive PCR result for one of the herpesviruses (HSV:3, CMV:3, EBV:2, VZV:1). All patients in the group without AGR had negative PCR results for all previous viruses (0/136). The difference was statistically significant (p < 0.001). The sub-analysis of eyes without a history of herpetic keratitis also revealed significantly more positive herpes PCR results (7/87) in eyes with AGR than in eyes without AGR (0/42, p = 0.005). Clinical AGR after keratoplasty shows a significant correlation to viral replication. Herpetic infection and AGR could occur simultaneously and act synergistically. Timely differentiation between active herpetic infection and/or AGR is pivotal for proper treatment and graft preservation.

Herpes Simplex Virus Bronchopneumonitis in Critically Ill Patients with Acute on Chronic Liver Failure: A Retrospective Analysis.

(1) Background: Critically ill patients are frequently diagnosed with pulmonary Herpes simplex virus-1 (HSV) reactivation, which then can lead to HSV bronchopneumonitis and is associated with higher mortality and longer mechanical ventilation. For the particular subgroup of critically ill patients with acute on chronic liver failure (ACLF), however, the impact of HSV reactivation is unknown. We investigated the impact of HSV reactivation in these patients. (2) Methods: We conducted a retrospective analysis, evaluating data from 136 mechanically ventilated patients with ACLF between January 2016 and August 2023. Clinical parameters were compared between patients with and without HSV bronchopneumonitis. (3) Results: 10.3% were diagnosed with HSV bronchopneumonitis (HSV group). Mortality did not differ between the HSV and non-HSV group (85.7% vs. 75.4%, p = 0.52). However, the clinical course in the HSV group was more complicated as patients required significantly longer mechanical ventilation (14 vs. 21 days, p = 0.04). Furthermore, fungal superinfections were significantly more frequent in the HSV group (28.6% vs. 6.6%, p = 0.006). (4) Conclusions: Mortality of critically ill patients with ACLF with HSV bronchopneumonitis was not increased in spite of the cirrhosis-associated immune dysfunction. Their clinical course, however, was more complicated with significantly longer mechanical ventilation.

UVB induced reactivation leads to HSV1 in the corneas of virtually all latently infected mice and requires STING to develop corneal disease.

Reactivation of latent herpes simplex type 1 results in virus returning to the cornea leading to recurrent herpetic stromal keratitis (rHSK). We compare two competing models to reactivate viruses from latency, UV-B irradiation and cyclophosphamide (CP). Results revealed that while both result in corneal recrudescence, only UV-B irradiation results in rHSK. To better understand the dynamics of reactivation, we analyzed corneas for both the presence of infectious viruses and the dynamics of exposure to multiple reactivations using UV-B. We noted that multiple reactivations result in progressively worse corneal disease. We also noted that expression of IFNα and STING, surragate markers for the presence of virus, are induced by the presence of reactivated virus. Studies to determine the importance of STING to the development of HSK revealed that in the absence of STING, mice do not develop significant HSK and the magnitude of the infiltrate of CD45+ cells in these corneas is significantly reduced. The resulting paucity of CD45+CD11b+GR-1+F4/80-neutrophils, and to a lesser extent CD45+CD11b+GR-1-F4/80+ macrophages in B6-STING KO mice following reactivation is likely the underlying cause for lack of rHSK as has been noted by ourselves and others. These results underscore the critical importance of STING's role in developing rHSK.

Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. PURPOSE: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. METHODS: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90ß) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. RESULTS: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90ß, thus disrupting the HSP90ß-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. CONCLUSION: Resveratrol acted as a non-classical HSP90ß inhibitor, binding to the STING-HSP90ß interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90ß and resveratrol-mediated inhibition of HSP90ß as a potential antiviral approach.

Impact of Toll-Like Receptors (TLRs) and TLR Signaling Proteins in Trigeminal Ganglia Impairing Herpes Simplex Virus 1 (HSV-1) Progression to Encephalitis: Insights from Mouse Models.

Herpes simplex virus 1 (HSV-1) or simplexvirus humanalpha 1 is a neurotropic virus that is responsible for orofacial infections in humans. More than 70% of the world's population may have seropositivity for HSV-1, and this virus is a leading cause of sporadic lethal encephalitis in humans. The role of toll-like receptors (TLRs) in defending against HSV-1 infection has been explored, including the consequences of lacking these receptors or other proteins in the TLR pathway. Cell and mouse models have been used to study the importance of these receptors in combating HSV-1, how they relate to the innate immune response, and how they participate in the orchestration of the adaptive immune response. Myeloid differentiation factor 88 (MyD88) is a protein involved in the downstream activation of TLRs and plays a crucial role in this signaling. Mice with functional MyD88 or TLR2 and TLR9 can survive HSV-1 infection. However, they can develop encephalitis and face a 100% mortality rate in a dose-dependent manner when MyD88 or TLR2 plus TLR9 proteins are non-functional. In TLR2/9 knockout mice, an increase in chemokines and decreases in nitric oxide (NO), interferon (IFN) gamma, and interleukin 1 (IL-1) levels in the trigeminal ganglia (TG) have been correlated with mortality.

Downregulation of endogenous nectin1 in human keratinocytes by herpes simplex virus 1 glycoprotein D excludes superinfection but does not affect NK cell function.

Many viruses downregulate their cognate receptors, facilitating virus replication and pathogenesis via processes that are not yet fully understood. In the case of herpes simplex virus 1 (HSV1), the receptor binding protein glycoprotein D (gD) has been implicated in downregulation of its receptor nectin1, but current understanding of the process is limited. Some studies suggest that gD on the incoming virion is sufficient to achieve nectin1 downregulation, but the virus-encoded E3 ubiquitin ligase ICP0 has also been implicated. Here we have used the physiologically relevant nTERT human keratinocyte cell type - which we have previously shown to express readily detectable levels of endogenous nectin1 - to conduct a detailed investigation of nectin1 expression during HSV1 infection. In these cells, nectin1, but not nectin2 or the transferrin receptor, disappeared from the cell surface in a process that required virus protein synthesis rather than incoming virus, but did not involve virus-induced host shutoff. Furthermore, gD was not only required but was sufficient for nectin1 depletion, indicating that no other virus proteins are essential. NK cells were shown to be activated in the presence of keratinocytes, a process that was greatly inhibited in cells infected with wild-type virus. However, degranulation of NK cells was also inhibited in ΔgD-infected cells, indicating that blocking of NK cell activation was independent of gD downregulation of nectin1. By contrast, a superinfection time-course revealed that the ability of HSV1 infection to block subsequent infection of a GFP-expressing HSV1 was dependent on gD and occurred in line with the timing of nectin1 downregulation. Thus, the role of gD-dependent nectin1 impairment during HSV infection is important for virus infection, but not immune evasion, which is achieved by other mechanisms.

THE COMBINATION OF ORAL VALACYCLOVIR WITH TOPICAL CLOBETASOL THERAPY WAS THE MOST EFFECTIVE IN REDUCING THE TIME TO HEAL FROM HERPES LABIALIS.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Koe KH, Veettil SK, Maharajan MK, Syeed MS, Nair AB, Gopinath D. comparative efficacy of antiviral agents for prevention and management of herpes labialis: A systematic review and network meta-analysis. J Evid Based Dent Pract. 2023 Mar; 23(1):101778. doi: 10.1016/j.jebdp.2022.101778. Epub 2022 Sep 14. PMID: 36914303. SOURCE OF FUNDING: None. TYPE OF STUDY/DESIGN: Systematic review with meta-analysis.