Herpes Simplex Virus Infection Research Articles

Breaching the Barrier: Investigating Initial Herpes Simplex Viral Infection and Spread in Human Skin and Mucosa

Herpes simplex virus (HSV) is sexually transmitted via the anogenital mucosa where it initially infects epidermal keratinocytes and mononuclear phagocytes (MNPs). It then spreads to the dorsal root ganglion via sensory nerve endings, to remain latent for life with periodic reactivation. Currently, there is no cure or vaccine. Initial or recurrent HSV infection can produce serious complications and mediate acquisition of HIV. This review outlines the initial events after the HSV infection of human anogenital mucosa to determine the optimal window to target the virus before it becomes latent. After infection, HSV spreads rapidly within the mid-layers of epidermal keratinocytes in the explanted human inner foreskin. Infected cells produce chemokines, which modulate nectin-1 distribution on the surface of adjacent keratinocytes, facilitating viral spread. Epidermal Langerhans cells and dendritic cells become infected with HSV followed by a “viral relay” to dermal MNPs, which then present viral antigen to T cells in the dermis or lymph nodes. These data indicate the need for interruption of spread within 24 h by diffusible vaccine-induced mediators such as antiviral cytokines from resident immune cells or antibodies. Intradermal/mucosal vaccines would need to target the relevant dermal MNPs to induce HSV-specific CD4+ and CD8+ T cells.

Parenteral aciclovir for suspected herpes simplex virus infection in children: 0–18 years

Abstract Background Variations in neonatal aciclovir prescribing for suspected herpes simplex virus (HSV) disease are well-known, but there are limited data describing aciclovir prescribing in older children. Methods Medical records of neonates (≤28 days) and children (29 days to 18 years) prescribed intravenous aciclovir for suspected HSV disease (1 January 2019–12 December 2019) in eight Australian and New Zealand hospitals were reviewed. Prescribing indication, HSV testing, aciclovir prescription details, adverse events and discharge diagnosis were recorded. Results 1426 received empirical aciclovir. For neonates (n = 425), the median duration was 1 day (IQR 1–3), 411/425 underwent HSV investigations and 13/425 had HSV disease (two with disseminated encephalitis, four with encephalitis and seven with skin, eye, mouth disease). Of the 1001 children, 906 were immunocompetent. 136/906 suspected of mucocutaneous disease received aciclovir for a median of 2 days (1–2), 121/136 underwent HSV testing, and 69/136 had proven disease. 770/906 received aciclovir for suspected disseminated disease or encephalitis for a median of 1 day (1–2), 556/770 underwent HSV testing, and 5/770 had disseminated disease or encephalitis. Among 95 immunocompromised children, 53/58 with suspected mucocutaneous disease had HSV testing and this was confirmed in 22. Disseminated disease or encephalitis was suspected in 37/95, HSV testing conducted in 23/37 and detected in one. The median aciclovir duration was 3 (2–7) days for immunocompromised children. Nephrotoxicity occurred in 7/1426 and 24/1426 had an extravasation injury. Conclusion Frequent and often unnecessary intravenous aciclovir prescribing for suspected HSV encephalitis or disseminated disease occurred in children, as evidenced by incomplete HSV investigations and only 5/770 older children having the diagnosis confirmed.

The herpes simplex virus alkaline nuclease is required to maintain replication fork progression.

Herpes simplex virus 1 (HSV-1) is a near-ubiquitous pathogen within the global population, causing a lifelong latent infection with sporadic reactivation throughout the life of the host. Within at-risk and immunocompromised communities, HSV-1 infection can cause serious morbidities including herpes keratitis and encephalitis. With the possibility of herpesviruses to evade established antiviral therapies and there being no approved HSV-1 vaccine, there comes a need to investigate potential targets for intervention against infection and subsequent disease. UL12 is the viral 5'-3' exonuclease, which is required for the production of infectious progeny. In this study, we show that in the absence of UL12, viral replication fork progression is abrogated. These data point to UL12 as an attractive target for intervention, which could lead to better clinical outcomes of HSV-1-associated disease in the future.

Disseminated herpes simplex virus infection in pregnancy

Herpes simplex virus (HSV) types 1 and 2 produce the most common sexually transmitted infection in women, with a higher incidence reported in developing countries. When the first infection occurs during the perinatal period, it can spread, resulting in high morbidity and mortality of the mother and child, in addition to mainly neurological sequelae in the newborn. Despite having reliable laboratory tests, the diagnosis of herpes simplex virus infection in this population is complex since the clinical presentation ranges from asymptomatic or with non-specific symptoms without lesions on the skin or mucous membranes. For this reason, a high clinical suspicion is necessary. Here, we present the case of a mother with disseminated herpes simplex virus type 2 infection with viral hepatitis and fetal death, highlighting the importance of suspecting the diagnosis in febrile women with systemic compromise during the perinatal period, even in the absence of rash.

CRISPR-Cas12a based HSV DNA detection method using quantum dot-labeled immunochromatographic strips

Herpes simplex virus (HSV) infection poses a significant public health challenge, particularly affecting vulnerable populations such as pregnant women, newborns, and immunocompromised individuals. Traditional diagnostic methods for HSV are often time-consuming, requiring specialized expertise and infrastructure, resulting in delays and limitations in resource-limited regions. In this research, we established a novel detection method that integrates CRISPR-Cas12a with Recombinase Assisted Amplification (RAA), enabling the sensitive and specific detection of HSV DNA. Compared to TaqMan PCR, our CRISPR-Cas12a-based lateral flow assay (CRI-LFA) using universal primers demonstrated a sensitivity of 90.38 %, specificity of 98.08 %, positive predictive value (PPV) of 100 %, negative predictive value (NPV) of 91.22 %, kappa value of 0.904, and an area under the receiver operating characteristic curve (AUC) of 0.973. The subsequent typing tests on our platform for HSV-1 and HSV-2 showed a sensitivity of 100 % (95 % CI: 74.12 %–100 %) and 95.83 % (95 % CI: 86.02 %–99.26 %), respectively. Specificity was 97.85 % (95 % CI: 92.49 %–99.62 %) for HSV-1 and 96.64 % (95 % CI: 85.39 %–98.54 %) for HSV-2. The kappa values were 0.906 for HSV-1 and 0.883 for HSV-2, with PPV of 84.6 % and 97.7 %, and NPV of 100 % and 91.7 %, respectively. Our portable paper strip assay provides a convenient and user-friendly testing option suitable for decentralized settings. This approach has the potential to facilitate early detection and enhance public health efforts in controlling HSV transmission.

γδ T17 Cells Regulate the Acute Antiviral Response of NK Cells in HSV-1-Infected Corneas.

To determine whether γδ T cells regulate natural killer (NK) cells in the herpes simplex virus 1 (HSV-1)-infected cornea. CD57Bl/6 (wild-type [WT]), TCRδ-/-, and IFN-γ-/- mice were infected intracorneally with HSV-1. TCR-/- mice were treated with IL-17A at 24 hours post-infection (PI), and the WT mice received treatments of fingolimod (FTY720) and anti-IL-17A. At 48hours PI, corneas were excised, and intracellular staining flow cytometry was performed, as well as multiplex analysis. Additionally, single-cell RNA sequencing (scRNAseq) was done to analyze the transcriptome of NK cells from WT and TCRδ-/- mice. In mice lacking γδ T cells, there were significantly fewer NK cells following ocular HSV-1 infection. This reduction of NK cells corresponded with lower levels of cytokines and chemokines associated with the antiviral response. Furthermore, NK cells from WT mice had enriched IL-17A signaling compared to those from TCRδ-/- mice. The NK cell response was partially rescued in TCRδ-/- mice by administration of IL-17A. Correspondingly, the NK cell response could be blunted in WT mice by administration of anti-IL-17A. Finally, IFN-γ-/- mice had significantly less IL-17A production compared to WT mice. γδ T17 cells promote NK cell accumulation in HSV-1-infected corneas. In turn, NK cells secrete IFN-γ, which negatively regulates further IL-17A production by γδ T cells.

Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy

Globally, nearly half of all pregnancies are unintended, ~1.3 million new human immunodeficiency virus (HIV) infections are reported every year, and more than 500 million people are estimated to have a genital herpes simplex virus (HSV-2) infection. Here we report the first 3D printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for prevention of HIV, HSV-2, and unintended pregnancy. The IVRs were fabricated using state-of-the-art Continuous Liquid Interface Production (CLIP™) 3D printing technology using a biocompatible silicone-urethane based resin. Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue. All three active pharmaceutical ingredients (APIs) were loaded in the IVR using a single-step drug loading process driven by absorption. DPV, PTV, and LNG elicited zero-order release kinetics in vitro in simulated vaginal fluid (SVF) at pH 4 and pH 8 relevant to human and macaque vaginal pH respectively. CLIP 3D printed MPT IVRs remained stable after 6 months of storage at 4 °C with no change in physical, dimensional, or mechanical properties and no change in drug concentration and absence of drug degradation byproducts. The MPT IVRs elicited sustained release of all three APIs in macaques for 28 days with median plasma concentrations of 138 pg/mL (DPV), 18,700 pg/mL (PTV), and 335 pg/mL (LNG). Safety studies demonstrated that the MPT IVRs were safe and well tolerated in the macaques with no observed change or abnormalities in vaginal pH and no significant changes in any of the 22 mucosal cytokines and chemokines tested including pro-inflammatory (IL-1β, IL-6, IL-8, IFN-γ, TNF-α, IL-17, IL-18) and anti-inflammatory (IL-10, IL-12) cytokines while the MPT IVR was in place or after its removal. Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy against two highly prevalent sexually transmitted infections (STIs).

Impact of Tobacco Use on Herpes Simplex Virus Infections: Findings From a National Survey.

Herpes simplex virus (HSV) infections, primarily caused by HSV-1 and HSV-2, are prevalent worldwide and carry significant health implications. The impact of tobacco use on HSV infections, however, remains underexplored. This cross-sectional study utilized the National Health and Nutrition Examination Survey (NHANES) database (2009-2016) to investigate the link between Tobacco use and HSV infections among U.S. adults. Smoking status, volume, and serum cotinine levels were analyzed, alongside demographic and behavioral factors. Propensity score matching (PSM) was employed to adjust for confounders such as sexual behavior. Our study involved 5693 participants to explore the relationship between tobacco use and HSV infection. We found that smokers, particularly current smokers, have a significantly increased risk of both HSV-1 and HSV-2 infections compared to non-smokers. Specifically, the adjusted odds ratio (OR) for HSV-1 in current smokers was 1.36 (95% CI: 1.16-1.59, p < 0.001), and for HSV-2, it was 2.37 (95% CI: 1.88-3, p < 0.001). The risk escalates with the intensity of smoking. Elevated serum cotinine levels correlated with an increased risk of HSV infection (HSV-1:1.13 [95% CI:1.09-1.18, p < 0.001]; HSV-2:1.33 [95% CI:1.25-1.41, p < 0.001]). After PSM for factors such as age, gender, sexual behavior, and condom use, these associations remained significant. Tobacco use is significantly associated with an increased risk of HSV infections, highlighting the importance of reducing tobacco exposure in public health strategies against HSV. Further, longitudinal studies are warranted to establish causality and explore underlying mechanisms.

Association of Herpes simplex infection with significantly increased risk of head and neck cancer: real-world evidence of about 500,000 patients.

The role of viral agents in the development of head and neck cancers has remained controversial. While markers of viral origin have been isolated from oral cancer tissues, a causative relationship has yet to be shown. The aim of this study was to evaluate the relationship between head and neck cancers and Herpes simplex virus, one of the most common viral infections of the oral orifice. Here, we conducted a retrospective analysis of two age- and gender-matched cohorts extracted from the real-world database TriNetX on March 10th, 2023, each consisting of 249,272 patients with and without Herpes simplex infections (ICD-10: B00). The diagnoses C00-C14 were analyzed, and risk analysis and Kaplan-Meier survival statics were computed. The strongest association was found for lip cancer (ICD-10: C00) with a hazard ratio [HR (CI 95% low-high)] of 3.08 (1.77-5.35). A significant association with HR of 1.17 (1.02-1.34) was found for the entire group of head and neck cancers. Confounders like smoking and alcohol dependence were considered using propensity score matching. The surprisingly strong correlation with lip, oral cavity, and pharynx neoplasms sheds new light on supposedly harmless herpes simplex infections, suggesting them as a possible new factor for risk stratification.

Recurrent Bilateral Facial Palsy Associated with Herpes Simplex Virus Infection

Bell's palsy is the most common cause of facial paralysis with a lifetime risk of one in 60 in general population. The exact pathophysiology is unknown, but it is suspected to be associated with viral infections such as herpes simplex virus (HSV). Recurrent facial palsy is a rare condition that can be caused by various factors but the cause remains unknown. We report a case of recurrent facial palsy who had antibodies of Lyme immunoglobulin G (IgG), HSV IgG, and IgM.

ZC3HAV1 facilitates STING activation and enhances inflammation

Stimulator of interferon genes (STING) is vital in the cytosolic DNA-sensing process and critical for initiating the innate immune response, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases. Zinc finger CCCH-type antiviral protein 1 (ZC3HAV1) specifically binds the CpG dinucleotides in the viral RNAs of multiple viruses and promotes their degradation. ZAPS (ZC3HAV1 short isoform) is a potent stimulator of retinoid acid-inducible gene I (RIG-I) signaling during the antiviral response. However, how ZC3HAV1 controls STING signaling is unclear. Here, we show that ZC3HAV1 specifically potentiates STING activation by associating with STING to promote its oligomerization and translocation from the endoplasmic reticulum (ER) to the Golgi, which facilitates activation of IRF3 and NF-κB pathway. Accordingly, Zc3hav1 deficiency protects mice against herpes simplex virus-1 (HSV-1) infection- or 5,6-dimethylxanthenone-4-acetic acid (DMXAA)-induced inflammation in a STING-dependent manner. These results indicate that ZC3HAV1 is a key regulator of STING signaling, which suggests its possible use as a therapeutic target for STING-dependent inflammation.

HSV-1 Infection Alters MAPT Splicing and Promotes Tau Pathology in Neural Models of Alzheimer's Disease.

Herpes simplex virus 1 (HSV-1) infection alters critical markers of Alzheimer's Disease (AD) in neurons. One key marker of AD is the hyperphosphorylation of Tau, accompanied by altered levels of Tau isoforms. However, an imbalance in these Tau splice variants, specifically resulting from altered 3R to 4R MAPT splicing of exon 10, has yet to be directly associated with HSV-1 infection. To this end, we infected 2D and 3D human neural models with HSV-1 and monitored MAPT splicing and Tau phosphorylation. Further, we transduced SH-SY5Y-neurons with HSV-1 ICP27 which alters RNA splicing to analyze if ICP27 alone is sufficient to induce altered MAPT exon 10 splicing. We show that HSV-1 infection induces altered splicing of MAPT exon 10, increasing 4R-Tau protein levels, Tau hyperphosphorylation, and Tau oligomerization. Our experiments reveal a novel link between HSV-1 infection and the development of cytopathic phenotypes linked with AD progression. HSV-1 infection in forebrain organoids reduces the neurite length of MAP2-positive neurons.HSV-1 infection increases Tau hyperphosphorylation in both two-month-old and four-month-old forebrain organoids. HSV-1 infection increases Exon 10 containing (4R) MAPT mRNA and 4R-Tau protein expression in both forebrain organoids and human SH-SY5Y-neurons. HSV-1 ICP27 is both necessary and sufficient to induce increased 4R MAPT mRNA and 4R-Tau protein expression in SH-SY5Y-neurons. HSV-1 infection increases Tau oligomerization in both forebrain organoids and SH-SY5Y-neurons.

Epidemiology and treatment of herpes simplex virus in the neonatal intensive care unit.

Describe the epidemiology and clinical characteristics of infants in the neonatal intensive care unit (NICU) with acyclovir exposure and herpes simplex virus (HSV) infection. Our primary analysis was to evaluate the prevalence of HSV infection among infants in the NICU who received acyclovir. We compared characteristics of infants with and without HSV and used multivariable regression analyses to assess associations between infection and clinical outcomes. Of 1,057,061 infants, 17,910 (2%) received acyclovir. Of those who received acyclovir, 1090 (5%) had HSV. Infection was associated with lower gestational age and lower birth weight. Multivariable models demonstrated that infected infants had higher mortality, greater postmenstrual age at discharge, and longer length of stay. Infants in the NICU who received acyclovir and have HSV are more likely to be born at lower gestational age, have lower birth weight, and have higher morbidities and mortality.

Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS).

FAS gene defects lead to autoimmune lymphoproliferative syndrome (ALPS), which is often inherited in an autosomal dominant and rarely in an autosomal recessive manner. We report a case of a newborn girl with novel compound heterozygous variants in FAS and reveal the underlying mechanism. Whole-exome sequencing (WES) was used to identify pathogenic variants. Multiparametric flow cytometry analysis, phosflow analysis, and FAS-induced apoptosis assays were used to explore the effects of the variants on FAS expression, apoptosis, and immunophenotype. The HEK293T cells were used to assess the impact of the variants on protein expression and FAS-induced apoptosis. The patient was born with hepatosplenomegaly, anemia, and thrombocytopenia. She also experienced COVID-19, rotavirus infection, herpes simplex virus infection, and severe pneumonia. The proportion of double-negative T cells (DNTs) was significantly elevated. Novel FAS compound heterozygous variants c.310T > A (p.C104S) and c.702_704del (p.T235del) were identified. The apoptotic ability of T cells was defective, and FAS expression on the surface of T cells was deficient. The T235del variant decreased FAS expression, and the C104S protein remained in the endoplasmic reticulum (ER) and could not translocate to the cell surface. Both mutations resulted in loss-of-function in terms of FAS-induced apoptosis in HEK293T cells. The DNTs were mainly terminally differentiated T (TEMRA) and CD45RA+HLA-DR+, with high expression of CD85j, PD-1, and CD57. The percentage of Th1, Tfh, and autoreactive B cells were significantly increased in the patient. The abnormal immunophenotyping was partially attenuated by sirolimus treatment. We identified two variants that significantly affect FAS expression or localization, leading to early disease onset of in the fetus. Abnormalities in the mTOR pathway are associated with a favorable response to sirolimus.

Association between human herpes simplex virus and severe headache or migraine among aged 20-49 years: a cross-sectional study.

Previous studies have shown that human herpes simplex virus (HSV) infection may be associated with the onset of headache or migraine. We aimed to investigate the association between HSV infection and severe headache or migraine. The cross-sectional data on 5,730 participants aged 20-49 years were obtained from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). We used weighted logistic regression analysis to assess the association between HSV infection (HSV-1 gG-1 and HSV-2 gG-2) and severe headache or migraine, and performed subgroup analyses. Our study found that women, higher education, higher body mass index, better family conditions, smoking and alcohol consumption were all associated with severe headaches or migraines. After adjusting for confounding factors such as sex, age, race, and education, HSV-2 (+) was still significantly associated with severe headache or migraine (OR = 1.22, 95%CI:1.03-1.46, p = 0.0443). In subgroup analyses, we found that participants with HSV-1 (-) and HSV-2 (+) were also significantly associated with severe headache or migraine (OR = 1.41, 95%CI:1.04-1.91, p = 0.0281). HSV-2 gG-2(+) was significantly associated with severe headache or migraine.

Chimeric antigen receptor-T-cell therapies going viral: latent and incidental viral infections.

Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting. Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation. A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.

Sulfated xylogalactofucans from Spatoglossum asperum: Production, structural features and antiviral activity

In cultured cells, herpes simplex virus (HSV) infectivity is successfully inhibited by sulfated polysaccharides. Herein, we utilized an amalgamated extraction-sulfation procedure to produce two xylogalactofucan sulfates (S203 and S204) from Spatoglossum asperum using ClSO3H.Pyr/DMF and SO3.Pyr/DMF reagents, respectively. Among these xylogalactofucans, the 17 ± 12 kDa polymer (S203) with 14 % sulfate exhibited activity on several HSV variants, including an acyclovir-resistant HSV-1 strain. This is the first report of the anti-HSV activity of a sulfated xylogalactofucan of S. asperum. The effective concentration 50 % (EC50) value of S203 against HSV-1 strain F was 0.6 μg/mL with a selectivity index of 833. The backbone of this polymer (S203) is made up mostly of (1 → 4)-linked-α-l-Fucp units having sulfate groups typically at O–3 and sometimes at O–2 positions. Oligosaccharides containing Xyl, Gal and Fuc units confirms that they are an integral part of a single polymer, another novelty of this study.The EC50 values of the native xylogalactofucan (S202) and the SO3.Pyr/DMF modified polymer (S204), containing 2 % and 6 % sulfates, were >100 and 3.3 μg/mL, respectively. Introduction of sulfate groups enhanced their capability to inhibit the infection of cells by HSV-1. These findings suggest feasibility of inhibiting HSV attachment to cells by blocking viral entry with polysaccharide having specific structure.

Infection risk with JAK inhibitors in dermatoses: a meta-analysis.

Evolving evidence suggests that Janus Kinase Inhibitors (JAKi) may predispose to certain infections, including tuberculosis and human herpes viruses. This review aimed to compare the infection risk in patients on a systemic JAKi for a dermatologic indication to a placebo. A systematic review was carried out from inception to June 2023, using the EMBASE, Medline, SCOPUS, and Cochrane Library of Registered Trials databases. Eligible studies included placebo-controlled randomized trials that investigated the incidence of infection in patients with a dermatologic indication. Primary outcomes included the most commonly reported infections pertaining to serious and opportunistic infections, upper respiratory tract infections, nasopharyngitis, herpes simplex, varicella zoster, tuberculosis, neutropenia, and lymphopenia. A meta-analysis of incidence ratios was conducted to determine odds ratios (OR), with a 95% confidence interval (CI) analysis. The meta-analysis found no increased risk of serious (OR: 0.92, 95% CI: 0.61-1.43, P = 0.74) or opportunistic infections (OR: 0.65, 95% CI: 0.32-1.31, P = 0.23). The incidence of varicella-zoster infections was significantly higher in the JAKi cohort (OR: 1.72, 95% CI: 1.08-2.72, P = 0.022). From 25 studies, there was no overall increased risk of herpes simplex infections (OR: 1.43, 95% CI: 0.93-2.23, P = 0.102) to placebo; however, a significantly higher risk in those with atopic dermatitis to alopecia areata was demonstrated (OR: 1.73, 95% CI: 1.13-2.69, P = 0.013). The results of this analysis do not suggest an increased risk of serious and opportunistic infections in those on JAKi compared to placebo. However, they support an increased risk of varicella-zoster infections and a higher risk of herpes simplex infections in those with atopic dermatitis to alopecia areata. The results of this report support these agents' short-term safety but signal that vigilance should be practiced in patients at risk for serious or recurrent herpes virus infections.

Novel Mouse Model of Recurrent Sublethal Herpes Simplex Virus Infection Recapitulates Human Antibody Responses to Primary and Chronic Infection.

Background: Herpes simplex virus (HSV) vaccine development has been impeded by the absence of predictive preclinical models and defined correlates of immune protection. Prior candidates elicited neutralizing responses greater than natural infection but no antibody-dependent cellular cytotoxicity (ADCC) and failed to protect in clinical trials. Primary HSV infection also elicits only neutralizing responses, but ADCC and an expanded antigenic repertoire emerge over time. This evolution may contribute to the decreased frequency and severity of recurrences. To test this notion, we developed a recurrent HSV infection mouse model and evaluated changes in humoral immunity with repeated challenges. Methods: Mice were repeatedly infected intranasally with clinical isolates of HSV-1 or HSV-2 for four months. HSV binding IgG, neutralizing (with or without complement) and ADCC-mediating antibodies were quantified prior to each round of infection. Viral targets were assessed by western blotting. Pooled immune serum (750 μg IgG per mouse) was passively transferred into naïve wild-type or Hvem knockout mice 24 h prior to lethal skin challenge. Results: Repeated exposure to HSV-1 or HSV-2 induced an increase in total HSV-binding IgG but did not boost neutralizing titers. In contrast, ADCC-mediating responses increased significantly from the first to the fourth viral exposure (p < 0.01). The increase was associated with an expanded antigenic repertoire. Passive transfer of fourth round immune serum provided significant protection whereas first round serum failed to protect (p < 0.01). However, protection was lost when serum was transferred into Hvem knockout mice, which are impaired in mediating ADCC killing. Conclusion: This novel model recapitulates clinical responses, highlights the importance of ADCC in protecting against recurrent infection, and provides a strategy for evaluating therapeutic vaccines.

Seroprevalence of Neonatal Herpes Simplex Virus Infection at A Tertiary Teaching Hospital in Malaysia

INTRODUCTION: Neonatal herpes simplex virus (HSV) infection is generally infrequent, despite being a life-threatening illness. Knowledge of its prevalence is limited in Malaysia since most cases are asymptomatic infections and only limited routine neonatal HSV screening is conducted. This study therefore provides a comprehensive investigation of the seroprevalence of HSV-1 and HSV-2 in neonates. MATERIALS AND METHODS: Serological screening for HSV-1 IgG and HSV-2 IgG antibody tests using the Electrochemiluminescence assay was performed on serum samples of 215 neonates delivered from January until December 2022 at Hospital Universiti Sains Malaysia. RESULTS: Of the neonates, 54.4% were found to be HSV-1 positive, while 4.2% were HSV-2 positive. All the HSV-2 neonates were co-infected with HSV-1. Newborns aged 0–10 days were the most infected group by HSV-1 (92.3%) and HSV-2 (55.6%). The most reported clinical presentation was small gestational age (SGA) (60%). Microcephaly and macrocephaly were observed in one neonate each. The clinical presentations of reactive HSV-1 and HSV-2 cases revealed the presence of fever with rash in both cases. CONCLUSION: The high seroprevalence of HSV-1 is alarming. It is hoped that these data will support the advocacy of screening women for HSV before or during pregnancy as a precautionary approach to reducing the risk of vertical transmission.