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BACKGROUND: This study assesses the prevalence of sexually transmitted infections (STIs) in first time visitors to the STIs clinic in Hangzhou, China, considering different genders, ages and symptoms. And also explores howthe COVID-19 pandemic has affected on STIs. METHODS: From 2019 to 2023, 27,283 first time visitors were tested for nine distinct STIs, including Human Papillomavirus (HPV), Human Immunodeficiency Virus (HIV), syphilis, Herpes Simplex Virus type 2 (HSV-2), Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), and vaginal Candida. RESULTS: Symptomatic male and female visitors showed overall STI-positive rates of 39.27% and 59.20%, respectively(p < .001). The top three pathogens in both genders were HPV (47.56% and 56.71%), UU (29.21% and 56.47%), and HSV-2 (22.41% and 52.94%). Among asymptomatic visitors, the total STI-positive rate was 36.63% in males and 52.03% in females. Age-stratified analysis revealed higher STI rates in visitors ≤ 20 or >50 years, regardless of gender and symptoms. During the COVID-19 pandemic, symptomatic visitors showed lower positive rates for HPV, HIV, syphilis, and HSV-2, while Candida, UU, CT, NG, and multiple infections increased. Among asymptomatic visitors, HPV had the lowest positive rate, while NG and multiple infections increased during the pandemic. CONCLUSION: STI prevalence is notably high, particularly in those aged ≤ 20 and >50 years. It emphasizes the need for enhanced health education, condom use, and vaccination. The COVID-19 pandemic impacting STIs through varied factors, such as reduced sexual activity and clinical service interruption.

Asunto(s)

COVID-19 , SARS-CoV-2 , Enfermedades de Transmisión Sexual , Humanos , COVID-19/epidemiología , Femenino , Masculino , China/epidemiología , Adulto , Enfermedades de Transmisión Sexual/epidemiología , Prevalencia , Persona de Mediana Edad , Adulto Joven , Adolescente , Pandemias

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Helicase-primase is an interesting target for small-molecule therapy of herpes simplex virus (HSV) infections. With amenamevir already approved for varicella-zoster virus and herpes simplex in Japan and with pritelivir's granted breakthrough therapy designation for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in helicase-primase inhibitors (HPIs). Here, we analyze the first patent application from Gilead in this field, which pursued a me-too approach combining elements from an old Bayer together with a recent Medshine HPI application (which covers the Phaeno Therapeutics drug candidate HN0037). The asset was contributed to Assembly Biosciences, where it is under development as ABI-1179 at the investigational new drug (IND) enabling stage for high-recurrence genital herpes. A structure proposal for indolinoyl derivative ABI-1179 is presented, showing its potential opportunities and limitations compared to other HPIs.

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Background: The rising prevalence of herpes simplex type 2 (HSV-2) infection poses a growing global public health challenge. A comprehensive understanding of its epidemiology and burden disparities in China is crucial for informing targeted and effective intervention strategies in the future. Methods: We followed Cochrane and PRISMA guidelines for a systematic review and included publications published in Chinese and English bibliographic systems until March 31st, 2024. We synthesized HSV-2 seroprevalence data across different population types. We used random-effects models for meta-analyses and conducted meta-regression to assess the association between population characteristics and seroprevalence. Results: Overall, 23,999 articles were identified, and 402 publications (1,203,362 participants) that reported the overall seroprevalence rates (858 stratified measures) were included. Pooled HSV-2 seroprevalence among the general population (lower risk) was 7.7% (95% CI: 6.8-8.7%). Compared to the general population, there is a higher risk of HSV-2 prevalence among intermediate-risk populations (14.8%, 95% CI: 11.0-19.1%), and key populations (31.7%, 95% CI: 27.4-36.1%). Female sexual workers (FSWs) have the highest HSV-2 risk (ARR:1.69, 95% CI: 1.61-1.78). We found northeastern regions had a higher HSV-2 seroprevalence than other regions (17.0%, 95% CI: 4.3-35.6%, ARR: 1.38, 95% CI: 1.26-1.50, Northern China as the reference group). This highlighted the disparity by population risk levels and regions. We also found lower HSV-2 prevalence estimates in publications in Chinese bibliographic databases than those in English databases among key populations (such as MSM and HIV-discordant populations). Conclusion: There is a gradient increase in HSV-2 prevalence risk stratification. We also identified region, population, and age disparities and heterogeneities by publication language in the HSV-2 burden. This study provides guidance for future HSV-2 prevention to eliminate disparities of HSV-2 infection and reduce overall HSV-2 burden. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=408108, identifier CRD42023408108.

Asunto(s)

Herpes Genital , Herpesvirus Humano 2 , Humanos , Herpesvirus Humano 2/inmunología , China/epidemiología , Herpes Genital/epidemiología , Estudios Seroepidemiológicos , Prevalencia , Femenino , Masculino , Factores de Riesgo

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Objective: To assess the accuracy of HSV1and HSV2 antibody testing in identifying genital herpes infection. Methods: A cohort of 299 patients previously diagnosed with recurrent genital herpes, confirmed via PCR, were tested using ELISA for HSV1 and HSV2 IgM and IgG antibodies. The study compared the accuracy of HSV1 and HSV2 antibody tests in diagnosing genital herpes. Results: Among 299 patients, 14 tested positives for HSV1 DNA. Of these, 9 had HSV1 IgG antibodies, but none had HSV2 IgG antibody. Among 278 patients with HSV2 DNA, 149 had HSV1 IgG, 9 had HSV2 IgG, and 97 had both. Seven patients had both HSV1 and HSV2 DNA; 3 had HSV1 IgG, 1 had HSV2 IgG, and 3 had both. The accuracy of HSV1 IgG for HSV1 infection was 64.2%, and for HSV1 and HSV2 co-infection, 85.7%. The accuracy of HSV2 IgG for HSV2 infection was 38.1%, and for HSV1 and HSV2 co-infection, 57.1%. The combined antibody positivity accuracy was 34.9%. Conclusion: Genital herpes is primarily caused by HSV2 (92.98%). A smaller percentage is HSV1 (4.67%) or co-infection (2.34%). Despite relatively low diagnostic accuracy (34.9-85.7%) for antibody detection, combined antibody testing is necessary. Herpes DNA testing is recommended for accurate diagnosis. Absence of antibodies does not rule out genital herpes and clinical assessment is essential.

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Coridothymus capitatus is a perennial herb with aromatic leaves and flowers, distinct from Thymus vulgaris in its chemical composition, resulting in a unique Thymus Essential Oil (TEO). A main component of TEO, carvacrol, is known for its antimicrobial and insecticidal activity. Carvacrol has potent antibacterial, antioxidant, anti-inflammatory, and antifungal properties, generating interest in traditional medicine. However, studies on its antiviral activity are limited. Given the rise in viral infections and limitations of synthetic antiviral drugs, natural antiviral agents are promising due to their efficacy, lower resistance development, and reduced side effects. This study assessed the antiviral efficacy of TEO compared to that of pure carvacrol. We tested various viruses, revealing significant inhibitory effects of TEO on the replication of only Simplexvirus humanalpha1 (HSV-1) and Simplexvirus humanalpha2 (HSV-2), with specific interference during the early stages of the viral replication cycle after the adsorption period. TEO exhibited inhibitory effects at doses below the cytotoxic threshold, with IC50 values of 47 µg/mL for HSV-1 and 40 µg/mL for HSV-2. Maximum virus inhibition was achieved when TEO was added within 90 min post-infection, indicating interference with early viral replication steps. These findings highlight the potential of TEO as a natural antiviral agent and suggest further research into its mechanisms and clinical applications.

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Protein expression is regulated through multiple mechanisms, including post-translational modifications (PTMs), which can alter protein structure, stability, localization, and function. Among these, citrullination stands out due to its ability to convert arginine residues into citrulline, altering protein charge and mass. This modification is catalyzed by calcium-dependent protein arginine deiminases (PADs), enzymes implicated in various inflammatory diseases. We have recently shown that human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) exploit these enzymes to enhance their replication capabilities. Although the role of PADs in HCMV and HSV-1 infections is well documented, their involvement in HSV-2 infection has not yet been thoroughly investigated. Here, we demonstrate that HSV-2 manipulates the overall protein citrullination profile by activating three PAD isoforms: PAD2, PAD3, and PAD4. However, as previously observed during HSV-1 infection, PAD3 is the most significantly upregulated isoform, both at the mRNA and protein levels. Consistently, we demonstrate that inhibiting PAD3, either through the specific inhibitor CAY10727 or via CRISPR/Cas9-mediated gene silencing, markedly reduces HSV-2 replication and viral protein expression. Lastly, we show that CAY10727 displays an IC50 value of 0.3 µM, which is extremely close to what was previously observed for HSV-1. Overall, our findings highlight the crucial role of PAD3 in the life cycle of HSV-2 and suggest that the targeted inhibition of PAD3 may represent a promising approach for treating HSV-2 infections, especially in cases resistant to existing antiviral therapies.

Asunto(s)

Herpesvirus Humano 2 , Arginina Deiminasa Proteína-Tipo 3 , Humanos , Herpesvirus Humano 2/fisiología , Herpesvirus Humano 2/genética , Arginina Deiminasa Proteína-Tipo 3/metabolismo , Citrulinación , Herpes Simple/virología , Herpes Simple/metabolismo , Replicación Viral/efectos de los fármacos , Animales , Herpes Genital/metabolismo , Herpes Genital/virología , Herpes Genital/tratamiento farmacológico , Arginina Deiminasa Proteína-Tipo 2/metabolismo , Antivirales/farmacología

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From established latency, human herpes virus type 2 (HSV-2) frequently reactivates into the genital tract, resulting in symptomatic ulcers or subclinical shedding. Tissue-resident memory (TRM) CD8+ T cells that accumulate and persist in the genital skin at the local site of recrudescence are the "first responders" to viral reactivation, performing immunosurveillance and containment and aborting the ability of the virus to induce clinical lesions. This review describes the unique spatiotemporal characteristics, transcriptional signatures, and noncatalytic effector functions of TRM CD8+ T cells in the tissue context of human HSV-2 infection. We highlight recent insights into the intricate overlaps between intrinsic resistance, innate defense, and adaptive immunity in the tissue microenvironment and discuss how rapid virus-host dynamics at the skin and mucosal level influence clinical outcomes of genital herpes diseases.

Asunto(s)

Linfocitos T CD8-positivos , Herpes Genital , Herpesvirus Humano 2 , Activación Viral , Latencia del Virus , Humanos , Herpes Genital/inmunología , Herpes Genital/virología , Activación Viral/inmunología , Herpesvirus Humano 2/inmunología , Herpesvirus Humano 2/fisiología , Linfocitos T CD8-positivos/inmunología , Latencia del Virus/inmunología , Memoria Inmunológica , Inmunidad Adaptativa , Piel/inmunología , Piel/virología , Inmunidad Innata , Animales

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Introduction: Elsberg syndrome (ES) presents with bowel and bladder dysfunction, resembling cauda equina syndrome, and is classified as a clinicoradiographic syndrome most commonly associated with HSV-2 reactivation. Most cases reveal smooth and continuous nerve enhancement on imaging. Case Description: We present a unique case of ES that presented as several nodular, ring enhancing soft tissue masses along the cauda equina. An 81-year-old woman presented with several weeks of sacral sensory impairment. MRI of the lumbar spine at presentation showed several nodular, ring enhancing soft tissue masses within the thecal sac along the cauda equina, concerning for leptomeningeal carcinomatosis from an unknown primary source. Cerebrospinal fluid (CSF) analysis was notable for lymphocyte predominant pleocytosis and protein elevation, which was nonspecific but suggestive of leptomeningeal carcinomatosis. CSF rapid meningitis panel was positive for HSV2 which was confirmed on HSV2 PCR. The patient was briefly on on acyclovir and was stopped due to lack of meningioencephalitis symptoms. Malignancy workup with cytological analysis and systemic imaging were negative. Given the absence of malignancy and positive HSV2 PCR, the patient was diagnosed with HSV-2 sacral radiculitis and subsequently treated with a full course of intravenous acyclovir with gradual clinical and radiographic improvement. Discussion: Ring-enhancing lesions along the cauda equina are most suggestive of LC. Our case highlights an as of yet unreported presentation of ES which may be valuable for neurologists to be aware of as to avoid any potential diagnostic dilemma, minimize unnecessary and costly testing, and not delay effective treatment.

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Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are widespread human pathogens that establish chronic latent infections leading to recurrent episodes. Current treatments are limited, necessitating the development of novel antiviral strategies. This study aimed to assess the antiviral efficacy of novel topical formulations containing interferon alpha-2b (IFN α-2b) against HSV-1 and HSV-2. The formulations, Oftalmoferon® forte (eye drops) and Interferon Vaginal Tablets, demonstrated potent antiviral effects against HSV-1 and HSV-2 in Vero cells, respectively, with concentration-dependent inhibition of viral replication. Subsequently, their efficacy was tested in animal models: HSV-1 keratitis in the rabbit eye model and HSV-2 genital herpes in mice. Oftalmoferon® forte effectively treated HSV-1 keratitis, reducing clinical symptoms and ulcerations compared to virus control. Interferon Vaginal Tablets showed promising results in controlling HSV-2 genital herpes in mice, improving survival rates, reducing clinical signs, weight loss and viral replication. The novel IFN α-2b formulations exhibited significant antiviral activity against HSV infections in cell culture and animal models. These findings suggest the potential of these formulations as alternative treatments for HSV infections, particularly in cases resistant to current therapies. Further studies are warranted to optimize treatment regimens and assess clinical efficacy in humans.

Asunto(s)

Antivirales , Modelos Animales de Enfermedad , Herpes Genital , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Queratitis Herpética , Animales , Conejos , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Antivirales/administración & dosificación , Antivirales/farmacología , Antivirales/uso terapéutico , Ratones , Herpes Genital/tratamiento farmacológico , Herpes Genital/virología , Queratitis Herpética/tratamiento farmacológico , Queratitis Herpética/virología , Chlorocebus aethiops , Femenino , Células Vero , Interferón alfa-2/administración & dosificación , Interferón alfa-2/uso terapéutico , Replicación Viral/efectos de los fármacos , Administración Tópica , Soluciones Oftálmicas , Interferón-alfa/administración & dosificación , Humanos

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BACKGROUND: The clinical severity of genital HSV-2 infection varies widely among infected persons with some experiencing frequent genital lesions while others are asymptomatic. The viral genital shedding rate is closely associated with and has been established as a surrogate marker of clinical severity. METHODS: To assess the relationship between viral genetics and shedding, we assembled a set of 145 persons who had the severity of their genital herpes quantified through determination of their HSV genital shedding rate. An HSV-2 sample from each person was sequenced and biallelic variants among these genomes were identified. RESULTS: We found no association between metrics of genome-wide variation in HSV-2 and shedding rate. A viral genome-wide association study (vGWAS) identified the minor alleles of three individual unlinked variants as significantly associated with higher shedding rate (p<8.4x10-5): C44973T (A512T), a non-synonymous variant in UL22 (glycoprotein H); A74534G, a synonymous variant in UL36 (large tegument protein); and T119283C, an intergenic variant. We also found an association between the total number of minor alleles for the significant variants and shedding rate (p=6.6x10-7). CONCLUSIONS: These results add to a growing body of literature for HSV suggesting a connection between viral genetic variation and clinically important phenotypes of infection.

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Alzheimer's disease (AD) is a real and current scientific and societal challenge. Alzheimer's disease is characterised by a neurodegenerative neuroinflammatory process, but the etiopathogenetic mechanisms are still unclear. The possible infectious aetiology and potential involvement of Herpes viruses as triggers for the formation of extracellular deposits of amyloid beta (Aß) peptide (amyloid plaques) and intraneuronal aggregates of hyperphosphorylated and misfold could be a possible explanation. In fact, the possible genetic interference of Herpes viruses with the genome of the host neuronal cell or the stimulation of the infection to a continuous immune response with a consequent chronic inflammation could constitute those mechanisms underlying the development of AD, with possible implications in the understanding and management of the disease. Herpes viruses could be significantly involved in the pathogenesis of AD and in particular, their ability to reactivate in particular conditions such as immunocompromise and immunosenescence, could explain the neurological damage characteristic of AD. Our review aims to evaluate the state of the art of knowledge and perspectives regarding the potential relationship between Herpes viruses and AD, in order to be able to identify the possible etiopathogenetic mechanisms and the possible therapeutic implications.

Asunto(s)

Enfermedad de Alzheimer , Infecciones por Herpesviridae , Herpesviridae , Humanos , Enfermedad de Alzheimer/virología , Enfermedad de Alzheimer/inmunología , Herpesviridae/patogenicidad , Herpesviridae/genética , Herpesviridae/fisiología , Infecciones por Herpesviridae/virología , Infecciones por Herpesviridae/inmunología , Péptidos beta-Amiloides/metabolismo , Animales

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Herpes simplex virus (HSV) infections are one of the most common and stigmatized infections of humankind, affecting more than 4 billion people around the world and more than 100 million Americans. Yet, most people do not know their infection status, and antibody testing is not recommended, partly due to poor test performance. Here, we compared the test performance of the Roche Elecsys HSV-1 IgG and HSV-2 IgG, DiaSorin LIAISON HSV-1/2 IgG, and Bio-Rad BioPlex 2200 HSV-1 and HSV-2 IgG assays with the gold-standard HSV western blot in 1,994 persons, including 1,017 persons with PCR or culture-confirmed HSV-1 and/or HSV-2 infection. Across all samples, the Bio-Rad and Roche assays had similar performance metrics with low sensitivity (<85%) but high specificity (>97%) for detecting HSV-1 IgG and both high sensitivity (>97%) and high specificity (>98%) for detecting HSV-2 IgG. The DiaSorin assay had a higher sensitivity (92.1%) but much lower specificity (88.7%) for detecting HSV-1 IgG and comparatively poor sensitivity (94.5%) and specificity (94.2%) for detecting HSV-2 IgG. The DiaSorin assay performed poorly at low-positive index values with 60.9% of DiaSorin HSV-1 results and 20.8% of DiaSorin HSV-2 results with positive index values <3.0 yielding false positive results. Based on an estimated HSV-2 seroprevalence of 12% in the United States, positive predictive values for HSV-2 IgG were 96.1% for Roche, 87.4% for Bio-Rad, and 69.0% for DiaSorin, meaning nearly one of every three positive DiaSorin HSV-2 IgG results would be falsely positive. Further development in HSV antibody diagnostics is needed to provide appropriate patient care.IMPORTANCESerological screening for HSV infections is currently not recommended in part due to the poor performance metrics of widely used commercial HSV-1 and HSV-2 IgG assays. Here, we compare three Food and Drug Administration (FDA)-cleared automated HSV-1 and HSV-2 IgG assays to the gold-standard western blot across nearly 2,000 samples. We find that not all commercially available HSV assays are created equal, with comparably low sensitivities for HSV-1 IgG across platforms and high false positivity rates for DiaSorin on HSV-2 IgG. This study is the first large-scale comparison of performance metrics for the Bio-Rad and Roche assays in over 10 years. Our study confirms that there remains room for improvement in HSV serological diagnostic testing-especially in regard to low sensitivities for HSV-1 IgG detection-and highlights that some previously less-studied assays may have better performance metrics than previously considered typical of commercially available HSV-2 IgG assays.

Asunto(s)

Anticuerpos Antivirales , Herpes Simple , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Inmunoglobulina G , Sensibilidad y Especificidad , Humanos , Inmunoglobulina G/sangre , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 2/inmunología , Herpesvirus Humano 2/aislamiento & purificación , Anticuerpos Antivirales/sangre , Herpes Simple/diagnóstico , Herpes Simple/virología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Adulto Joven , Anciano , Automatización de Laboratorios , Niño , Anciano de 80 o más Años , Inmunoensayo/métodos , Preescolar

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A 34-year-old immunosuppressed male presented with worsening bilateral lower extremity weakness and urinary retention accompanied by a painless clean-based chancre on his glans penis. Physical examination revealed symmetrically diminished lower extremity weakness most pronounced with hip flexion and knee extension and absent Achilles reflexes. Full MRI spine without contrast was noncontributory. Lumbar puncture showed elevated protein and total nucleated cells with lymphocytic predominance. Both CSF and serum polymerase chain reaction were positive for herpes simplex virus type 2. He received IV methylprednisolone and acyclovir and underwent four months of physical therapy with complete resolution of his neurologic deficits.

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Helicase-primase is an interesting target for the therapy of herpes simplex virus (HSV) infections. Since amenamevir is already approved for varicella-zoster virus (VZV) and HSV in Japan and pritelivir has received breakthrough therapy status for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in me-too approaches. Here, we describe the attempt to improve nervous tissue penetration in Phaeno Therapeutics drug candidate HN0037 to target the latent reservoir of HSV by installing less polar moieties, mainly a difluorophenyl instead of a pyridyl group, and replacing the primary sulfonamide with a methyl sulfoximine moiety. However, all obtained stereoisomers exhibited a weaker inhibitory activity on HSV-1 and HSV-2.

Asunto(s)

Antivirales , ADN Primasa , Sulfonamidas , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , ADN Primasa/antagonistas & inhibidores , ADN Primasa/metabolismo , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , ADN Helicasas/antagonistas & inhibidores , ADN Helicasas/metabolismo , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Humanos , Estructura Molecular , Pruebas de Sensibilidad Microbiana , Relación Dosis-Respuesta a Droga , Iminas/química , Iminas/farmacología , Iminas/síntesis química

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Objective: Genital herpes, primarily caused by HSV-2 infection, remains a widespread sexually transmitted ailment. Extracellular vesicles play a pivotal role in host-virus confrontation. Recent research underscores the influence of Chinese herbal prescriptions on extracellular vesicle production and composition. This study aims to probe the impact of JieZe-1 (JZ-1) on extracellular vesicle components, elucidating its mechanisms against HSV-2 infection via extracellular vesicles. Methods: The JZ-1's anti-HSV-2 effects were assessed using CCK-8 assay. Extracellular vesicles were precisely isolated utilizing ultracentrifugation and subsequently characterized through TEM, NTA, and Western Blot analyses. The anti-HSV-2 activity of extracellular vesicles was gauged using CCK-8, Western Blot, and immunofluorescence. Additionally, high-throughput sequencing was employed to detect miRNAs from extracellular vesicles, unraveling the potential antiviral mechanisms of JZ-1. Results: Antiviral efficacy of JZ-1 was shown in VK2/E6E7, HeLa, and Vero cells. The samples extracted from cell supernatant by ultracentrifugation were identified as extracellular vesicles. In VK2/E6E7 cells, extracellular vesicles from JZ-1 group enhanced cell survival rates and diminished the expression of intracellular viral protein gD, contrasting with the inert effect of control group vesicles. Extracellular vesicles from JZ-1 treated Vero cells demonstrated a weaker yet discernible anti-HSV-2 effect. Conversely, extracellular vesicles of HeLa cells exhibited no anti-HSV-2 effect from either group. High-throughput sequencing of VK2/E6E7 cell extracellular vesicles unveiled significant upregulation of miRNA-101, miRNA-29a, miRNA-29b, miRNA-29c, and miRNA-637 in JZ-1 group vesicles. KEGG pathway analysis suggested that these miRNAs may inhibit PI3K/AKT/mTOR signaling pathway and induce autophagy of host cells to protect against HSV-2. Western blot confirmed the induction of autophagy and inhibition of AKT/mTOR in VK2/E6E7 cells with JZ-1 group extracellular vesicles treatment. Conclusion: JZ-1 had an anti-HSV-2 efficacy. After JZ-1 stimulation, VK2/E6E7 cells secreted extracellular vesicles which protect host cells from HSV-2 infection. High-throughput sequencing showed that these extracellular vesicles contained a large number of miRNAs targeting PI3K/AKT/mTOR pathway. JZ-1 group extracellular vesicles could inhibit the activation of AKT/mTOR pathway and induce the host cells autophagy.

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Coleus forskohlii (Willd.) Briq. is a medicinal herb of the Lamiaceae family. It is native to India and widely present in the tropical and sub-tropical regions of Egypt, China, Ethiopia, and Pakistan. The roots of C. forskohlii are edible, rich with pharmaceutically bioactive compounds, and traditionally reported to treat a variety of diseases, including inflammation, respiratory disorders, obesity, and viral ailments. Notably, the emergence of viral diseases is expected to quickly spread; consequently, these data impose a need for various approaches to develop broad active therapeutics for utilization in the management of future viral infectious outbreaks. In this study, the naturally occurring labdane diterpenoid derivative, Forskolin, was obtained from Coleus forskohlii. Additionally, we evaluated the antiviral potential of Forskolin towards three viruses, namely the herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), hepatitis A virus (HAV), and coxsackievirus B4 (COX-B4). We observed that Forskolin displayed antiviral activity against HAV, COX-B4, HSV-1, and HSV-2 with IC50 values of 62.9, 73.1, 99.0, and 106.0 µg/mL, respectively. Furthermore, we explored the Forskolin's potential antiviral target using PharmMapper, a pharmacophore-based virtual screening platform. Forskolin's modeled structure was analyzed to identify potential protein targets linked to its antiviral activity, with results ranked based on Fit scores. Cathepsin L (PDB ID: 3BC3) emerged as a top-scoring hit, prompting further exploration through molecular docking and MD simulations. Our analysis revealed that Forskolin's binding mode within Cathepsin L's active site, characterized by stable hydrogen bonding and hydrophobic interactions, mirrors that of a co-crystallized inhibitor. These findings, supported by consistent RMSD profiles and similar binding free energies, suggest Forskolin's potential in inhibiting Cathepsin L, highlighting its promise as an antiviral agent.

Asunto(s)

Herpesvirus Humano 1 , Colforsina/farmacología , Colforsina/química , Catepsina L , Simulación del Acoplamiento Molecular , Herpesvirus Humano 1/metabolismo , Antivirales/farmacología , Antivirales/química

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A quantitative analysis of the relationship between the structure and inhibitory activity against the herpes simplex virus thymidine kinase (HSV-TK) was performed for the series of 5-ethyluridine, N2-guanine, and 6-oxopurines derivatives with pronounced anti-herpetic activity (IC50 = 0.09 ÷ 160,000 µmol/L) using the GUSAR 2019 software. On the basis of the MNA and QNA descriptors and whole-molecule descriptors using the self-consistent regression, 12 statistically significant consensus models for predicting numerical pIC50 values were constructed. These models demonstrated high predictive accuracy for the training and test sets. Molecular fragments of HSV-1 and HSV-2 TK inhibitors that enhance or diminish the anti-herpetic activity are considered. Virtual screening of the ChEMBL database using the developed QSAR models revealed 42 new effective HSV-1 and HSV-2 TK inhibitors. These compounds are promising for further research. The obtained data open up new opportunities for developing novel effective inhibitors of TK.

Asunto(s)

Herpesvirus Humano 1 , Relación Estructura-Actividad Cuantitativa , Guanina/química , Timidina Quinasa , Herpesvirus Humano 2 , Simplexvirus , Antivirales/farmacología

RESUMEN

The herpes simplex virus (HSV) is a double-stranded DNA human virus that causes persistent infections with recurrent outbreaks. HSV exists in two forms: HSV-1, responsible for oral herpes, and HSV-2, primarily causing genital herpes. Both types can lead to significant complications, including neurological issues. Conventional treatment, involving acyclovir and its derivatives, faces challenges due to drug resistance. This underscores the imperative for continual research and development of new drugs, with a particular emphasis on exploring the potential of natural antivirals. Flavonoids have demonstrated promise in combating various viruses, including those within the herpesvirus family. This review, delving into recent studies, reveals the intricate mechanisms by which flavonoids decode their antiviral capabilities against HSV. By disrupting key stages of the viral life cycle, such as attachment to host cells, entry, DNA replication, latency, and reactivation, flavonoids emerge as formidable contenders in the ongoing battle against HSV infections.

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Herpes Simple , Herpesvirus Humano 1 , Humanos , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Flavonoides/farmacología , Flavonoides/uso terapéutico , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/fisiología , Estadios del Ciclo de Vida

RESUMEN

PURPOSE: (1) To determine the prevalence of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and cytomegalovirus (CMV) DNA in donor corneas; (2) To evaluate the clinical outcome of the grafts with viral DNA and to compare donors with and without viral DNA. METHODS: We analyzed data from all donors and recipients who underwent penetrating keratoplasty (PK) or Descemet membrane endothelial keratoplasty (DMEK) between September 2022 and March 2023. Donor corneoscleral rims and excised recipients' corneal buttons were tested for the presence of HSV-1, HSV-2, VZV, and CMV DNA by polymerase chain reaction (PCR). The results were known 2-3 days after the surgery. We closely followed up on patients whose grafts tested positive for viral DNA. We compared the medical histories of donors with and without viral DNA. RESULTS: We included 85 corneas from 67 donors. Seven (8.2%) donor corneas tested positive for HSV-1 (n = 3) or VZV (n = 4) DNA. We did not detect any HSV-2 or CMV DNA. In the postoperative follow-up of patients with positive PCR, a graft failure was observed in one and infections in two eyes. Re-operation was necessary in three of these cases (42.9%). Patients without herpes DNA in the donor cornea needed reoperation in 7.7% of the cases. Cultural duration, the cause of the donor's death, and the death-to-explantation interval did not differ significantly between donors with and without viral DNA. Additionally, 3 of the 7 (42.9%) donors with positive PCR were in a septic status at the time of death, compared to 21 of the 78 (26.9%) donors with negative PCR (p = 0.52). CONCLUSIONS: The prevalence of herpes DNA in the donor corneas was 8.2% and thus higher than previously reported. We did not notice any evidence for a donor-to-host transmission, but a higher rate of postoperative complications in recipients of the grafts with viral DNA. The donors with and without herpetic DNA did not differ significantly regarding systemic diagnoses or cultural conditions, but sepsis was more frequent in the group with viral DNA.

RESUMEN

Valacyclovir (VACV) was developed as a prodrug of the most common anti-herpetic drug Acyclovir (ACV), aiming to enhance its bioavailability. Nevertheless, prolonged VACV oral treatment may lead to the development of important side effects. Nanotechnology-based formulations for vaginal administration represent a promising approach to increase the concentration of the drug at the site of infection, limiting systemic drug exposure and reducing systemic toxicity. In this study, VACV-loaded nanodroplet (ND) formulations, optimized for vaginal delivery, were designed. Cell-based assays were then carried out to evaluate the antiviral activity of VACV loaded in the ND system. The chitosan-shelled ND exhibited an average diameter of about 400 nm and a VACV encapsulation efficiency of approximately 91% and was characterized by a prolonged and sustained release of VACV. Moreover, a modification of chitosan shell with an anionic cyclodextrin, sulfobutyl ether ß-cyclodextrin (SBEßCD), as a physical cross-linker, increased the stability and mucoadhesion capability of the nanosystem. Biological experiments showed that SBEßCD-chitosan NDs enhanced VACV antiviral activity against the herpes simplex viruses type 1 and 2, most likely due to the long-term controlled release of VACV loaded in the ND and an improved delivery of the drug in sub-cellular compartments.