Acute-Onset Lower Extremity Weakness and Urinary Retention in a Chronically Immunosuppressed Patient: Diagnosis and Management of Herpes Simplex Virus Type 2 Myelitis.

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.

Differential Contributions of Interferon Classes to Host Inflammatory Responses and Restricting Virus Progeny Production.

Fundamental to mammalian intrinsic and innate immune defenses against pathogens is the production of Type I and Type II interferons, such as IFN-ß and IFN-γ, respectively. The comparative effects of IFN classes on the cellular proteome, protein interactions, and virus restriction within cell types that differentially contribute to immune defenses are needed for understanding immune signaling. Here, a multilayered proteomic analysis, paired with biochemical and molecular virology assays, allows distinguishing host responses to IFN-ß and IFN-γ and associated antiviral impacts during infection with several ubiquitous human viruses. In differentiated macrophage-like monocytic cells, we classified proteins upregulated by IFN-ß, IFN-γ, or pro-inflammatory LPS. Using parallel reaction monitoring, we developed a proteotypic peptide library for shared and unique ISG signatures of each IFN class, enabling orthogonal confirmation of protein alterations. Thermal proximity coaggregation analysis identified the assembly and maintenance of IFN-induced protein interactions. Comparative proteomics and cytokine responses in macrophage-like monocytic cells and primary keratinocytes provided contextualization of their relative capacities to restrict virus production during infection with herpes simplex virus type-1, adenovirus, and human cytomegalovirus. Our findings demonstrate how IFN classes induce distinct ISG abundance and interaction profiles that drive antiviral defenses within cell types that differentially coordinate mammalian immune responses.

Antiviral and synergistic effects of photo-energy with acyclovir on herpes simplex virus type 1 infection.

This experimental study aimed to evaluate the antiviral and synergistic effects of photoenergy irradiation on human herpes simplex virus type I (HSV-1) infection. We assessed viral replication, plaque formation, and relevant viral gene expression to examine the antiviral and synergistic effects of blue light (BL) with acyclovir treatment. Our results showed that daily BL (10 J/cm2) irradiation inhibited plaque-forming ability and decreased viral copy numbers in HSV-1-infected monkey kidney epithelial Vero cells and primary human oral keratinocyte (HOK) cells. Combined treatment with the antiviral agent acyclovir and BL irradiation increased anti-viral activity, reducing viral titers and copy numbers. In particular, accumulated BL irradiation suppressed characteristic viral genes including UL19 and US6, and viral DNA replication-essential genes including UL9, UL30, UL42, and UL52 in HOK cells. Our results suggest that BL irradiation has anti-viral and synergistic properties, making it a promising therapeutic candidate for suppressing viral infections in clinical trials.

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

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

Serological Screening of TORCH Pathogen Infections in Infertile Women of Childbearing Age in Northwest China.

Serological screening for TORCH(Toxoplasma gondii [TOX], Rubella virus [RV], Cytomegalovirus [CMV], and Herpes simplex virus [HSV]) infections is an effective method for preventing congenital infections caused by TORCH pathogens.In this study, we retrospectively analyzed the characteristics of TORCH infections in 17,807 infertile women of childbearing age in northwest China.We conducted serological detection of TORCH-pathogen-specific IgM and IgG antibodies. The seroprevalence of TORCH infections was statistically analyzed by applying χ2 and Fisher exact-probability tests to evaluate the differences among ages and across quarters of the year. The overall IgM/IgG seroprevalences of TOX, RV, CMV, HSV-1, and HSV-2 were 0.46/3.4%, 0.77/84.93%, 0.68/97.54%, 1.2/82.83%, and 0.62/10.04%, respectively. The positive rates for RV-IgM in women ≥ 40 years old were significantly higher than those for women 25-39 (P < 0.05) years of age. The seroprevalence of HSV1-IgM was higher in the third and fourth quarters of the year (seasons) (P < 0.001), and the seroprevalence of CMV-IgG was statistically significant between differences quarters (P = 0.017), and the seroprevalence of CMV-IgG in the first quarter was lower than that in the third and fourth quarters (Bonferroni correction, P = 0.009 > 0.0083), suggesting no statistically significant difference between the latter two groups. This study showed that in northwestern China the risk of acquiring primary infection by a TORCH pathogen among infertile women of childbearing age were still high, especially Toxoplasma gondii and Herpesvirus type 2 infection. Therefore, effective prevention strategies that include serological screening for TORCH should be implemented.

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

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

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.

Management strategies for common viral infections in pediatric renal transplant recipients.

Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort. Children are at high risk of acquiring virus-related complications due to immunological immaturity and the enhanced alloreactivity risk that led to maintenance of high immunosuppressive regimes. Hence, prevention, early detection, and prompt treatment of such infe ctions are of paramount importance. Among all viral infections, herpes viruses (herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus), hepatitis B and C viruses, BK polyomavirus, and respiratory viruses (respiratory syncytial virus, parainfluenza virus, influenza virus and adenovirus) are common in kidney transplant recipients. These viruses can cause systemic disease or allograft dysfunction affecting the clinical outcome. Recent advances in tech nology and antiviral therapy have improved management strategies in screening, monitoring, adoption of prophylactic or preemptive therapy and precise trea tment in the immunocompromised host, with significant impact on the outcome. This review discusses the etiology, screening and monitoring, diagnosis, pre vention, and treatment of common viral infections in pediatric renal transplant recipients.

Comparative analysis of microbial composition and functional characteristics in dental plaque and saliva of oral cancer patients.

BACKGROUND: The oral cavity is home to various ecological niches, each with its own unique microbial composition. Understanding the microbial communities and gene composition in different ecological niches within the oral cavity of oral cancer (OC) patients is crucial for determining how these microbial populations contribute to disease progression. METHODS: In this study, saliva and dental plaque samples were collected from patients with OC. Metagenomic sequencing was employed to analyze the microbial community classification and functional composition of the different sample groups. RESULTS: The results of the study revealed significant differences in both the function and classification of microbial communities between saliva and dental plaque samples. The diversity of microbial species in saliva was found to be higher compared to  that in plaque samples. Notably, Actinobacteria were enriched in the dental plaque of OC patients. Furthermore, the study identified several inter-group differential marker species, including Prevotella intermedia, Haemophilus parahaemolyticus, Actinomyces radius, Corynebacterium matruchitii, and Veillonella atypica. Additionally, 1,353 differential genes were annotated into 23 functional pathways. Interestingly, a significant correlation was observed between differentially labeled species and Herpes simplex virus 1 (HSV-1) infection, which may be related to the occurrence and development of cancer. CONCLUSIONS: Significant differences in the microbial and genetic composition of saliva and dental plaque samples were observed in OC patients. Furthermore, pathogenic bacteria associated with oral diseases were predominantly enriched in saliva. The identification of inter-group differential biomarkers and pathways provide insights into the relationship between oral microbiota and the occurrence and development of OC.

HSV-1 employs UL56 to antagonize expression and function of cGAMP channels.

DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.

Herpes simplex keratitis: A brief clinical overview.

The aim of our minireview is to provide a brief overview of the diagnosis, clinical aspects, treatment options, management, and current literature available regarding herpes simplex keratitis (HSK). This type of corneal viral infection is caused by the herpes simplex virus (HSV), which can affect several tissues, including the cornea. One significant aspect of HSK is its potential to cause recurrent episodes of inflammation and damage to the cornea. After the initial infection, the HSV can establish a latent infection in the trigeminal ganglion, a nerve cluster near the eye. The virus may remain dormant for extended periods. Periodic reactivation of the virus can occur, leading to recurrent episodes of HSK. Factors triggering reactivation include stress, illness, immunosuppression, or trauma. Recurrent episodes can manifest in different clinical patterns, ranging from mild epithelial involvement to more severe stromal or endothelial disease. The severity and frequency of recurrences vary among individuals. Severe cases of HSK, especially those involving the stroma and leading to scarring, can result in vision impairment or even blindness in extreme cases. The cornea's clarity is crucial for good vision, and scarring can compromise this, potentially leading to visual impairment. The management of HSK involves not only treating acute episodes but also implementing long-term strategies to prevent recurrences and attempt repairs of corneal nerve endings via neurotization. Antiviral medications, such as oral Acyclovir or topical Ganciclovir, may be prescribed for prophylaxis. The immune response to the virus can contribute to corneal damage. Inflammation, caused by the body's attempt to control the infection, may inadvertently harm the corneal tissues. Clinicians should be informed about triggers and advised on measures to minimize the risk of reactivation. In summary, the recurrent nature of HSK underscores the importance of both acute and long-term management strategies to preserve corneal health and maintain optimal visual function.

Replacement of sulfonamide by sulfoximine within a helicase-primase inhibitor with restricted flexibility.

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.

Combination of ganciclovir and trifluridine prevents drug-resistance emergence in HSV-1.

Ocular herpes simplex virus 1 (HSV-1) infections can lead to visual impairment. Long-term acyclovir (ACV) prophylaxis reduces the frequency of recurrences but is associated with drug resistance. Novel therapies are needed to treat drug-resistant HSV-1 infections. Here, we describe the effects of trifluridine (TFT) in combination with ACV or ganciclovir (GCV) on HSV-1 replication and drug-resistance emergence. Wild-type HSV-1 was grown under increasing doses of one antiviral (ACV, GCV, or TFT) or combinations thereof (ACV + TFT or GCV + TFT). Virus cultures were analyzed by Sanger sequencing and deep sequencing of the UL23 [thymidine kinase (TK)] and UL30 [DNA polymerase (DP)] genes. The phenotypes of novel mutations were determined by cytopathic effect reduction assays. TFT showed overall additive anti-HSV-1 activity with ACV and GCV. Five passages under ACV, GCV, or TFT drug pressure gave rise to resistance mutations, primarily in the TK. ACV + TFT and GCV + TFT combinatory pressure induced mutations in the TK and DP. The DP mutations were mainly located in terminal regions, outside segments that typically carry resistance mutations. TK mutations (R163H, A167T, and M231I) conferring resistance to all three nucleoside analogs (ACV, TFT, and GCV) emerged under ACV, TFT, ACV + TFT pressure and under GCV + TFT pressure initiated from suboptimal drug concentrations. However, higher doses of GCV and TFT prevented drug resistance in the resistance selection experiments. In summary, we identified novel mutations conferring resistance to nucleoside analogs, including TFT, and proposed that GCV + TFT combination therapy may be an effective strategy to prevent the development of drug resistance.

Emerging drugs for the treatment of herpetic keratitis.

INTRODUCTION: Herpes simplex keratitis stands as a prominent factor contributing to infectious blindness among developed nations. On a global scale, over 60% of the population tests positive for herpes simplex virus type-1 (HSV-1). Despite these statistics, there is currently no vaccine available for the virus. Moreover, the conventional nucleoside drugs prescribed to patients are proving ineffective in addressing issues related to drug resistance, recurrence, latency, and the escalating risk of vision loss. Hence, it is imperative to continually explore all potential avenues to restrict the virus. This review article centers on the present treatment methods for HSV-1 keratitis (HSK), highlighting the ongoing clinical trials. It delves into the emerging drugs, their mode-of-action and future therapeutics. AREAS COVERED: The review focuses on the significance of a variety of small molecules targeting HSV-1 lifecycle at multiple steps. Peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase, and clinical trial websites. EXPERT OPINION: The exploration of small molecules that target specific pathways within the herpes lifecycle holds the potential for substantial impact on the antiviral pharmaceutical market. Simultaneously, the pursuit of disease-specific biomarkers has the capacity to usher in a transformative era in diagnostics within the field.

Oncolytic virotherapy stimulates anti­tumor immune response and demonstrates activity in advanced sarcoma: Report of two cases.

Sarcoma is derived from mesenchymal neoplasms and has numerous subtypes, accounting for 1% of all adult malignancies and 15% of childhood malignancies. The prognosis of metastatic or recurrent sarcoma remains poor. The current study presents two cases of sarcoma enrolled in a phase I dose escalation trial for solid tumor, who had previously failed all standard therapies. These patients were treated with VG161, an immune-stimulating herpes simplex virus type 1 oncolytic virus with payloads of IL-12, IL-15 and IL-15 receptor α unit, and a programmed cell death 1 (PD-1)/PD-1 ligand 1 blocking peptide. Both cases demonstrated stable disease as the best response, accompanied by a noteworthy prolongation of progression-free survival (11.8 months for chondrosarcoma and 11.9 months for soft tissue sarcoma, respectively) at a dose of 2.5×108 PFU/cycle. In addition, the treatment led to the activation of anti-cancer immunity, as evident from cytokine, lymphocyte subset and related pathway analyses of peripheral blood and/or tumor biopsy samples. These promising results suggest that VG161 monotherapy holds promise as an effective treatment for sarcoma and warrants further investigation through clinical trials. The two reported patients were part of a phase I clinical trial conducted and registered on the Australian New Zealand Clinical Trials Registry in Australia (registration no. ACTRN12620000244909; registration date, 26 February, 2020).

Seroprevalence of sexually transmitted infections over 44 years - A cross-sectional study in Sweden.

BACKGROUND: Sexually transmitted infections (STIs) may cause substantial individual suffering and a large economic burden for society. This study examined the seroprevalence of Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus (HSV) types 1 and 2, and several human papillomaviruses (HPV) in the Swedish population over time. METHODS: The study population consisted of 30-year-old women attending maternity care, and 50 year-old men and women attending health check-ups, from 1975 to 2018. Antibody status was determined by multiplex serology and quantified using median reporter fluorescence intensity (MFI). RESULTS: A total of 891 samples were analysed (519 from 30-year-old women, 186 from 50 year-old women and 186 from 50 year-old men). Of these, 41.5% showed seropositivity for Chlamydia trachomatis, 16.7% for Mycoplasma genitalium, 70.5% for HSV-1, 14.9% for HSV-2, 13.2% for high-risk HPV, and 8.3% for low-risk HPV. Seropositivity for Mycoplasma genitalium, HSV-1 and especially Chlamydia trachomatis decreased over time. CONCLUSIONS: There was a decrease over time in Chlamydia trachomatis seroprevalence, probably due to contact tracing, testing and early treatment; this might also have affected Mycoplasma genitalium seroprevalence. Despite the reduction, seroprevalences are still high, so continued and new efforts to reduce STI incidence are essential.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Serious neurological adverse events in immunocompetent children and adolescents caused by viral reactivation in the years following varicella vaccination.

Serious adverse events following vaccination include medical complications that require hospitalisation. The live varicella vaccine that was approved by the Food and Drug Administration in the United States in 1995 has an excellent safety record. Since the vaccine is a live virus, adverse events are more common in immunocompromised children who are vaccinated inadvertently. This review includes only serious adverse events in children considered to be immunocompetent. The serious adverse event called varicella vaccine meningitis was first reported in a hospitalised immunocompetent child in 2008. When we carried out a literature search, we found 15 cases of immunocompetent children and adolescents with varicella vaccine meningitis; the median age was 11 years. Eight of the children had received two varicella vaccinations. Most of the children also had a concomitant herpes zoster rash, although three did not. The children lived in the United States, Greece, Germany, Switzerland, and Japan. During our literature search, we found five additional cases of serious neurological events in immunocompetent children; these included 4 cases of progressive herpes zoster and one case of acute retinitis. Pulses of enteral corticosteroids as well as a lack of herpes simplex virus antibody may be risk factors for reactivation in immunocompetent children. All 20 children with adverse events were treated with acyclovir and recovered; 19 were hospitalised and one child was managed as an outpatient. Even though the number of neurological adverse events remains exceedingly low following varicella vaccination, we recommend documentation of those caused by the vaccine virus.

Navigating diagnostic challenges: imaging strategies for herpes simplex encephalitis in resource limited settings: A case report.

Encephalitis refers to the inflammatory condition affecting the brain parenchyma, leading to various neurological impairments. It can have various causes: infectious, postinfectious, and noninfectious origins. In this case, we present a 76-year-old man who presented to the emergency room with complaints of headache and behavioral changes. Initially, a Computed Tomography (CT) scan raised suspicion of herpes simplex encephalitis and prompted the initiation of treatment. Subsequently, Magnetic Resonance Imaging (MRI) and Cerebrospinal fluid (CSF) culture confirmed the diagnosis. However, despite medical intervention, the patient's condition unexpectedly deteriorated, and he unfortunately passed away after spending 2 weeks in the Intensive Care Unit (ICU). Possible factors contributing to this outcome include delayed presentation to medical care, viral resistance, or the inherent nature of the infection itself, particularly in elderly patients.