A woman in her 50s receiving paclitaxel, carboplatin, and pembrolizumab for recurrent cervical cancer developed herpes zoster and received antiviral therapy. 18F-FDG PET/CT performed 22 days after zoster onset, when the skin lesions had crusted, demonstrated continuous uptake extending from the left L5 dorsal root ganglion to the sciatic nerve. To our knowledge, this is the first reported case of FDG PET findings indicating ganglioneuritis extending from the dorsal root ganglion to a peripheral nerve after herpes zoster. Recognition of this pattern is important in patients receiving chemoimmunotherapy because it may mimic immune-related neuritis or perineural tumor spread.

Cells sense infection through dedicated receptors, yet these surveillance pathways are often subverted by pathogen-encoded virulence factors. Guard immunity provides complementary defense by rapidly killing infected cells in response to infection induced stress. However, the symptoms of infection frequently resemble noninfectious stress, raising the question of how they are distinguished. Using quantitative transcriptomics, proteomics, and global translation measurements during viral infections in vitro and in vivo, we show that infection globally suppresses host gene expression and prevents direct antiviral responses. However, the resulting proteostatic stress does not activate guard immunity unless tumor necrosis factor-α (TNFα) is present. We identify the anti-apoptotic protein c-FLIP as a guard for gene expression integrity: its loss sensitizes cells to TNFα, triggering cell death and limiting viral spread. Modeling demonstrates that TNFα and c-FLIP loss function as a biological AND-gate, providing specificity and speed. These findings show how cells integrate internal stress signals with external inflammatory cues to improve the fidelity of death decisions, and how this circuitry may misfire during noninfectious inflammation.

Encephalitis guidelines recommend repeating a lumbar puncture (LP) 3-7 days after an initial negative cerebrospinal fluid (CSF) herpes simplex virus (HSV) polymerase chain reaction (PCR) test in patients with high suspicion for HSV or varicella zoster virus (VZV), but this subgroup has not been specified. Retrospective observational study of 602 adults with encephalitis from 2002 to 2023 from two large U.S. healthcare systems. Multivariate logistic regression models were developed and internally validated to identify clinically relevant and statistically significant features predicting HSV, VZV, and combined HSV/VZV encephalitis. HSV and VZV encephalitis were diagnosed in 103 (17.1%) and 43 (7.14%), respectively. Independent predictors for HSV acute presentation, new temporal lobe abnormalities on MRI, and hemorrhage on brain MRI. For VZV, predictors were immunosuppression, Charles Comorbidity Index > 2, and absence of seizures on presentation. For HSV/VZV, predictors included age ≥ 50 years, immunocompromise, acute presentation, CSF lymphocytosis, new temporal lobe abnormalities on MRI, hemorrhage on brain MRI, and Glasgow Coma Scale (GCS) ≥ 13 (P < 0.05). Patients were classified into 3 categories: low-risk (0 points), intermediate-risk (1 point), and high-risk (≥ 2 points). The area under the receiver operating curve was 0.675, 0.734, and 0.583 for the HSV, VZV, and HSV/VZV models, respectively. The risk score can help identify patients with an initial negative PCR who would benefit from a repeat LP (intermediate- or high-risk) and may support discontinuing acyclovir in low-risk patients.

Herpes simplex esophagitis (HSE) rarely occurs in immunocompetent patients. Eosinophilic esophagitis (EoE) may predispose to herpes simplex virus superinfection through epithelial barrier disruption. We present an immunocompetent woman with previous EoE managed with dietary modifications without pharmacologic therapy who developed severe odynophagia. Endoscopy showed erosive esophagitis mimicking candidiasis and active EoE, histologically consistent with HSE without eosinophilic inflammation or fungal organisms. Empiric antifungals and corticosteroids were discontinued, and intravenous acyclovir was initiated with rapid improvement. Follow-up endoscopy confirmed complete mucosal healing. This case highlights the diagnostic complexity of HSE complicating EoE and the indispensable role of histopathologic evaluation.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease where chronological aging predicts the conversion to progressive MS (PMS), a phase defined by compartmentalized inflammation and accelerated neurodegeneration. While current disease modifying therapies (DMTs) are effective for managing the inflammatory aspect of MS, treatments remain inadequate. It is imperative to understand the biology of aging including an important hallmark of aging, cellular senescence. Cellular senescence is a state of cell cycle arrest where cells remain in their senescent state and produce a distinctive senescence-associated secretory phenotype (SASP), characterized by the release of pro-inflammatory cytokines, chemokines, and growth factors. Growing experimental and clinical evidence suggests that the accumulation of senescent cells and SASP secretion perpetuates a pathological feedback loop linking age-related processes with accelerated neurodegeneration observed in PMS. Whether senescence drives PMS or accompanies it remains unresolved. In this Review, we outline the biology of aging, senescence pathway markers, and SASP components. We evaluate studies of cellular senescence and SASP markers in MS, including immunosenescence, T- and B-cell changes; the contributions of Epstein-Barr virus, cytomegalovirus, and herpes simplex virus-1; and the relationship between senescence burden, brain atrophy, and DMT response. Lastly, we outline the available senotherapeutic approaches aimed at mitigating MS and other neurodegenerative diseases.

Pain and psychological disorders are two common symptom clusters in patients with herpes zoster-related pain (HZ-RP). We utilized functional magnetic resonance imaging (fMRI) to investigate functional characteristics of the brain in HZ-RP patients with different levels of anxiety. Twenty-five HZ-RP patients with high anxiety (HZ-RP with HA) and 26 HZ-RP patients with low anxiety (HZ-RP with LA) were enrolled. Fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo) and functional connectivity (FC) based on the brain regions with significant differences and default mode network were compared between two groups. Multivariate linear regression models were used to investigate impact of clinical characteristics on significant abnormalities, and moderation analysis was used to examine interaction between pain and anxiety. Compared with HZ-RP with LA, HZ-RP with HA resulted in increased fALFF in the right Rolandic operculum (RO) and ReHo in the left middle temporal gyrus (MTG) but decreased ReHo in the right precentral gyrus (PrCG). The left anterior prefrontal cortex showed decreased FC with the left medial superior frontal gyrus, whereas the left occipital cortex showed increased FC with the right fusiform gyrus, right MTG and left precuneus in HZ-RP with HA. Multivariate linear regression models revealed that the degree of pain and anxiety contributed to explaining the variance in the fALFF of the right RO, and anxiety alone correlated with ReHo abnormalities in the right PrCG. Abnormal brain function, particularly in the right PrCG, may underpin anxiety-related pathophysiology in HZ-RP patients, suggesting potential neural targets for intervention.

Including all relevant costs and effects in economic evaluations can be challenging, especially when spillovers in other individuals or sectors are likely. Previous literature has highlighted that the combination of relevant spillovers is evaluation and context specific. This emphasises the importance of identifying (the evidence on) relevant spillovers systematically. Spillovers are defined here as "all impacts from an intervention on all parties or entities other than the users of the intervention under evaluation". In this study, we evaluate the feasibility of applying the recently introduced Expanded Impact Inventory to identify (evidence on) potentially relevant spillovers. If feasible, this approach can help to determine the analytical scope of health economic evaluations and to identify the available knowledge (gaps). As an illustration, we use two case studies: vaccination against acute respiratory diseases and herpes zoster. Using the inventory to guide a rapid review of economic studies in these disease areas, we found that commonly considered spillovers are patient healthcare and productivity costs-in so far these are borne by others than the patient-, as well as caregiving time costs. Spillover impacts on health, broader quality of life, and productivity of others, especially caregivers, were often highlighted as important, though evidence remains limited. This application demonstrates that using the Expanded Impact Inventory to identify (evidence on) potentially relevant spillovers and delineate the scope of economic evaluations is feasible. Using this framework across various interventions and disease areas can promote the systematic consideration of broader impacts in economic evaluations, strengthening the evidence base for spillovers and improving the comprehensiveness and comparability of economic evaluations.

Hepatocellular carcinoma (HCC) develops in a chronically injured and immunologically specialized organ that is both the treatment target and a major determinant of viral clearance and toxicity. Oncolytic viruses (OVs) can couple tumor-selective infection with immunogenic lysis, innate sensing, antigen presentation, and adaptive immune recruitment, but the clinical consequences of these processes depend on viral platform, delivery route, liver-resident cell handling, spatial disease distribution, and hepatic reserve. This review synthesizes HCC OV biology across four linked levels: platform-specific tumor-cell susceptibility; replication and interferon restriction; regulation by Kupffer cells, liver sinusoidal endothelial cells, dendritic-cell subsets, hepatic stellate cells, fibroblasts, and resident lymphoid populations; and spatial pharmacodynamics across injected tumors, non-injected intrahepatic lesions, cirrhotic parenchyma, and extrahepatic disease. We compare adenovirus, vaccinia virus, herpes simplex virus, and candidate RNA viruses using route- and assay-matched criteria and interpret clinical evidence according to study design, biological context, and permissible inference. Early Pexa-Vec studies established biological activity, whereas PHOCUS defined a negative boundary for Pexa-Vec followed by sorafenib in an unselected first-line population. H101 plus nivolumab and VG161 support early feasibility and pharmacodynamic investigation, while integrated human pharmacodynamic and diseased-liver HCC-model reovirus data highlight schedule-dependent immune effects and potential off-tumor liver inflammation. VIRAL-HCC is used only as a non-scored organizational matrix for prospective trial design and biomarker interpretation. Future development should link tumor exposure and productive infection or payload expression to compartment-resolved immune effects, clinically relevant tumor control, and preservation of hepatic reserve.

Immunotherapy with oncolytic Herpes simplex virus type 1 (oHSV-1) shows promise for glioblastoma; however, clinical benefit remains uncommon due to tumour- and host-mediated immunosuppression, which limits immune targeting of residual glioblastoma stem-like cells (GSCs). To address this barrier, extracellular vesicles (EVs) harvested from oHSV-1-infected GSCs (EVOV) were evaluated for their immunomodulatory capacity by priming peripheral blood mononuclear cells (PBMCs) ex vivo and in vivo. In GSC-PBMC organoids analysed by single-cell RNA sequencing, IFN-response and antigen-presentation programs were induced in both immune and tumour compartments, despite the GSC state. EVOV organoid transcriptome associated with patient tumour antigen-processing programs linked to improved clinical outcome, and EVOV immunopeptidomics identified candidate biomarker peptides that were also detected in patient immunopeptidomes from the clinical-trial cohort. In PBMC-engrafted NOD scid gamma mice bearing intracranial GSC xenografts, EVOV delivery increased circulating interferon (IFN) levels and enhanced systemic activation of T-cell subsets, while spatial transcriptomics revealed recruitment of peripheral immune cells to the tumour, accompanied by reprogramming of GSC states. Blocking vesicle-associated major histocompatibility complex I (MHC-I) attenuated EVOV-driven PBMC cytotoxicity against GSCs, supporting an MHC-I peptide-dependent mechanism of immune priming and a vaccine- or adjuvant-like, non-infectious, vesicle-based immunotherapeutic strategy.

Viral infections of the central nervous system (CNS) pose a significant risk for seizures, and in some cases, long-term epileptogenesis. Seizure development following viral infection involves diverse CNS mechanisms, with emerging evidence that peripheral factors, including gut microbiome composition and immune-inflammatory responses, also contribute. The gut microbiome is a multifaceted ecosystem with important roles in CNS health, and advances in sequencing have enabled investigation of host and microbial genomic changes associated with seizure development. While both animal and human studies link gut dysbiosis to epilepsy, including infection-induced epilepsy, the specific effects of viral-induced seizures on the gut microbiome remain unclear. Moreover, the influence of virus-triggered epileptogenesis is not well understood. This review summarizes current knowledge on viral infections linked to seizures and highlights the limited but growing evidence for gut microbial changes in this context. We focus on Zika virus (ZIKV), West Nile virus (WNV), and herpes simplex virus-1 (HSV-1), all implicated in human epileptogenesis, though direct microbiome-seizure connections are still limited. We also discuss severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes neurological symptoms without consistently inducing seizures in rodent models despite neurological involvement, and Theiler's murine encephalomyelitis virus (TMEV), a murine virus widely used as a model of infection-induced seizures because it induces strain-dependent seizures in mice. Current evidence suggests associations among viral infections, gut microbiome alterations, and seizure occurrence; however, further causative studies are needed to define their roles and elucidate underlying mechanisms.