Search Results (1,252)

Background Cytomegalovirus (CMV) infection is a major contributor to morbidity and mortality in recipients of hematopoietic stem cell transplant (HSCT), solid organ transplant (SOT), and chimeric antigen receptor T-cell (CAR-T) therapy. While antiviral agents remain the cornerstone of treatment, CMV-specific immunoglobulins (CMVIG) have been utilized as adjunct therapy with variable outcomes. This study aims to evaluate the virological response and tolerability of CMVIG in cases of severe or refractory CMV viremia, with or without CMV disease. Methods: We conducted a single-center retrospective case series of adult recipients of SOT, allogeneic HSCT, and/or CAR-T cell therapy who developed CMV viremia or disease and received at least one dose of CMVIG between May 2017 and May 2023 at our center. Virological improvement within 14 days of starting CMVIG and tolerability of CMVIG are the primary outcome of this study. Results: A total of 33 patients were included. Of these, 29 underwent transplantation [SOT: 48.2%, HSCT: 51.7%], and five underwent CAR-T cell therapy (one post-HSCT). High-risk CMV serostatus was present in 12%. CMV viremia was documented in 32 patients (97%), and tissue-invasive disease was present in 11 patients (33.3%). Virological response, was observed in 65.6% of the cohort. The median time to undetectable CMV viral load following CMVIG initiation was 28 days. CMVIG was well-tolerated. All-cause mortality at 90 days remained high (57%). Conclusion: In this case series, CMVIG demonstrated a virological response rate of 65.6% in patients with severe or refractory CMV infection. While CMVIG was well-tolerated with minimal adverse events, the high mortality rate despite virological response suggests that CMVIG may be insufficient for this critically ill population. Our findings should be interpreted as observational data from a small case series, and prospective controlled trials are needed to establish the true benefit of CMVIG in combination with standard antiviral therapy. Full article

Viral infections of the central nervous system produce memory impairment through mechanisms that extend beyond acute neuronal injury. Herpes simplex virus type 1, human immunodeficiency virus, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, influenza, SARS-CoV-2, West Nile virus, and Zika virus each enter or engage the brain through distinct routes, yet converge on four shared molecular pathways that selectively damage hippocampal circuits: mitochondria-associated membrane (MAM) dysfunction, chronic neuroinflammation, blood–brain barrier (BBB) disruption, and impaired CREB-BDNF signaling. These pathways specifically compromise the dentate gyrus, CA3, and CA1 subfields, producing predictable deficits in pattern separation, associative retrieval, and temporal memory binding. Antiretroviral and antiviral therapies suppress viral replication but fail to reverse organelle-level dysfunction, leaving most hippocampal injury unaddressed. Emerging plasma biomarkers, p-tau217, neurofilament light chain, and GFAP, combined with hippocampal subfield MRI, now enable mechanistic stratification before irreversible circuit loss occurs. This review proposes, as a unifying hypothesis, that virus-associated memory impairment represents a convergent hippocampal syndrome driven by shared downstream pathways, and that combination therapies targeting these pathways simultaneously offer greater therapeutic promise than pathogen-specific approaches alone. The evidentiary basis for this framework varies across pathogens and conditions; direct mechanistic evidence, mechanistic analogy, and preclinical data are distinguished throughout. Full article

Background/Objectives: No licensed vaccine against cytomegalovirus (CMV) is currently available, despite the significant risk of mother-to-infant transmission leading to serious neurodevelopmental impairment and the substantial morbidity caused by CMV infection in immunocompromised persons. We report results from a phase 2 trial of the investigational CMV mRNA vaccine mRNA-1647 and a long-term extension study (NCT04232280; NCT04975893). Methods: This randomized, observer-blind, placebo-controlled phase 2 study, conducted at 9 US sites, enrolled participants in two parts. In the first part, healthy adults aged 18–40 years were stratified by baseline CMV status into CMV-seronegative and CMV-seropositive parallel cohorts and randomized 3:1 to receive mRNA-1647 (50, 100, or 150 μg) or placebo. In the second part, healthy female participants aged 18–40 years were randomized 3:1 to receive 100 μg mRNA-1647 or placebo. In both parts, vaccine or placebo was administered at Months 0, 2, and 6. Participants completing the Primary Trial through Month 18 were eligible to enroll in the extension study, wherein safety and immunogenicity were assessed every 6 months until all participants reached Month 48 (interim analysis) and a subset had Month 54 immunogenicity samples available. Primary objectives were to assess safety and neutralizing antibody responses. Results: Solicited adverse reactions were mostly grade 1 or 2 in severity, and no notable dose-related safety trends were identified. Neutralizing antibody and antigen-specific binding IgG responses were induced in CMV-seronegative participants and boosted in CMV-seropositive participants, with durability of responses through Month 48 and up to Month 54. Conclusions: The investigational vaccine mRNA-1647 was generally well tolerated and induced durable humoral immune responses across baseline CMV serostatus, with persistence supported through Month 48 and by available Month 54 data. Full article

Background: Cytomegalovirus (CMV) viral load monitoring forms the basis of preemptive treatment strategies in patients undergoing solid organ and hematopoietic stem cell transplantation. This study aimed to evaluate the analytical performance and inter-method agreement of a laboratory-developed CMV real-time PCR (qPCR) test compared to a commercial reference method using plasma samples. Methods: A total of 100 EDTA plasma samples were analyzed in parallel using a laboratory-developed CMV qPCR test and the reference method (Roche Cobas^® CMV). Analytical sensitivity was determined us-ing synthetic DNA cloned into the pUC57 plasmid backbone containing the US17 region of the CMV genome, and the limit of detection (LoD₉₅) was calculated using probit regression analysis. The relationship between the quantitative results obtained from clinical samples was evaluated using the Spearman rank correlation coefficient, while inter-method clinical agreement was assessed using the Bland–Altman method. Results: The limit of detection (LoD₉₅) of the laboratory-developed CMV qPCR test, as determined by probit regression analysis, was 63.8 copies/µL. A weak and statistically non-significant correlation was ob-served between the laboratory-developed CMV qPCR test and the reference method in Spearman rank correlation analysis of samples for which numerical quantitative results were available from both methods (ρ = 0.32; p = 0.22; n = 16). Bland–Altman analysis showed a mean difference of −0.48 log₁₀ units, with the vast majority of measurements falling within the 95% limits of agreement. Conclusions: The assay demonstrated measurable analytical performance and inter-method agreement; however, its use for quantitative viral load monitoring, particularly at low CMV DNA levels, should be interpreted with caution. Full article

Human cytomegalovirus (HCMV) remains an important medical problem in multiple patient settings despite the availability of antivirals. In part, this is linked to resistance, cost and restrictions on use in several patient settings. More generally, it remains attractive to increase our arsenal of anti-viral approaches to target HCMV. We previously characterized a potent inhibitor of HCMV infection, DIDS, that displays cysteine reactivity, allowing it to bind virions and neutralize HCMV infection of fibroblasts. We now show that DIDS is inhibitory to cell-free and cell-associated infection of multiple cell types, including cells of the haematopoietic lineage—cells important for latency and dissemination. Consistent with this broad activity, DIDS partially inhibited gB (but not SARS-CoV-2 spike) fusion activity. Intriguingly, further characterization of DIDS activity in myeloid cells revealed that, unlike in all other cell types, DIDS blocked a post-entry event in CD14+ monocytes and also dendritic cell derivatives. Despite viral entry, entry was largely silent, with a failure to activate innate immunity and cell survival pathways known to be activated by HCMV. In contrast, HCMV infection was observed to activate host miRNA expression in CD14+ cells, suggesting a DIDS-insensitive viral function was responsible or, alternatively, that host miRNA expression is a potential anti-viral response to viral internalization. Thus, we report the further characterization of a broad-acting inhibitor of HCMV infection, which may also prove a useful tool to study unique events for the infection of monocytic cells by HCMV—a cell type that is crucial for HCMV dissemination and pathogenesis in vivo. Full article

Background: Emerging evidence suggests that antiviral treatment targeting human cytomegalovirus (HCMV) may improve outcomes in patients with glioblastoma (GBM). In this study, we analyzed serological data from the placebo-controlled VIGAS1 trial (Eudra number 2006-002022-29), which assessed the effect of valganciclovir (VGCV) on GBM progression in 42 patients, for impact of VGCV in preventing HCMV reactivation. Methods: VIGAS1 patients had undergone radical surgery and were randomized to receive either VGCV (n = 22) or placebo (n = 20) alongside standard radiochemotherapy. Blood was prospectively collected at baseline and 3-, 12- and 24-week follow-up visits. GBM cell lines and a cytomegalovirus-infected murine brain cancer model were used to validate the clinical findings. Results: Over the 24-week study period, we found that HCMV reactivation, as inferred from IgM seropositivity, occurred in 58.3% of patients in the placebo group, whereas this was completely prevented in the VGCV-treated group except for one patient with no treatment compliance (p = 0.0005). HCMV reactivation was linked to early recurrence. IgG-positive patients treated with VGCV showed a significantly longer time to progression (TTP) than those receiving placebo (6.7 vs. 3.7 months, p = 0.0408). We found a significant association between higher steroid doses and enhanced reactivation in the placebo group. In vitro and murine studies confirmed that corticosteroids, combined with radiation therapy, enhanced cytomegalovirus reactivation, which was mitigated by antiviral treatment. Conclusions: These findings suggest that preventing HCMV reactivation with antiviral therapy may improve patient outcomes, especially in HCMV-seropositive GBM patients, and further support the hypothesis that HCMV is a tumor-promoting virus. Full article

Background: Congenital cytomegalovirus (CMV) infection is the most common congenital infection worldwide and a leading cause of neurodevelopment impairment. Prenatal imaging plays a central role in diagnosis and prognostic assessment. Methods: We conducted a systematic review of studies evaluating the role of ultrasound, including dedicated fetal neurosonography and magnetic resonance imaging (MRI) in the prenatal detection and assessment of CMV infection. PubMed, Web of Science, and Scopus were searched for relevant studies, and data were synthesized focusing on detected abnormalities and the incremental diagnostic value of MRI. Results: Fifty-nine studies were included. Dedicated neurosonography (NSG) was the primary modality for detecting CMV-related fetal brain abnormalities, particularly ventriculomegaly and cortical malformations. Fetal MRI provided additional diagnostic information, mainly through improved visualization of the brain parenchyma, allowing better detection of white matter abnormalities, migrational disorders and posterior fossa involvement, especially when performed later in gestation. Conclusions: Dedicated neurosonography remains the cornerstone for the evaluation of suspected congenital fetal CMV infection. Fetal MRI represents a complementary tool that can confirm, refine or extend ultrasound findings and may improve prognostic assessment when additional or subtle brain abnormalities are suspected. Full article

Background: Post-transplant immune heterogeneity may influence kidney allograft outcomes, yet the clinical relevance of circulating T-cell phenotypes remains incompletely defined. We aimed to identify 12-month post-transplant data-driven T-cell clusters and examine their relation to graft-function patterns during the first post-transplant year. Methods: Peripheral blood T-cell subpopulations were analyzed in 112 kidney transplant recipients at 12 months post-transplantation using flow cytometry. Standardized subpopulation frequencies underwent unsupervised hierarchical clustering, with principal component analysis used for visualization. Longitudinal graft function trajectories (eGFR and serum creatinine at 1, 3, 6, and 12 months) were analyzed using generalized estimating equation models, including time-by-cluster interactions. Results: Three recipient clusters were identified: a CD8-skewed cytotoxic/senescent cluster, an innate-like cytotoxic cluster, and a CD4-dominant cluster. Cluster robustness was supported by complementary k-means analysis. Older recipient age and baseline cytomegalovirus seropositivity were associated with the CD8-skewed cluster. Recipients assigned to different T12 clusters showed differences in serum creatinine levels and graft function trajectories, although some associations were attenuated after additional adjustment for transplant-related factors. Conclusions: In this cohort, unsupervised clustering identified distinct post-transplant T-cell profiles associated with early graft function patterns. These findings are hypothesis-generating and require longitudinal and external validation. Full article

Cytomegalovirus (CMV) establishes lifelong latency following primary infection and can reactivate to cause severe illness in immunocompromised hosts. CMV DNAemia in non-HIV-infected, non-solid organ/bone marrow transplant (NHNT) hosts is poorly characterized, with limited clinical insights. We aim to describe the clinical presentation, prognostic indicators, and outcomes of CMV DNAemia among NHNT patients. We used the TriNetX international patient database to identify adult patients diagnosed with CMV DNAemia from 2016 until March 2023. We evaluated hospitalization, intensive care unit (ICU) level care, and all-cause mortality at 30 days and 1 year. We also completed a post-propensity score analysis comparing clinical characteristics of survivors versus non-survivors at 90 days. We identified 1123 NHNT patients with CMV DNAemia, most of whom had neoplasms (63%). Venous thromboembolism occurred in 31% of the population. The 30-day hospitalization and all-cause mortality rates were 35% and 14%, respectively. After propensity score matching and Bonferroni correction, weakness, purpura, acute respiratory failure, malnutrition, encephalopathy, and hypotension were associated with increased 90-day all-cause mortality. NHNT patients with CMV DNAemia carry a substantial morbidity and all-cause mortality. Further studies are warranted to clarify whether CMV DNAemia is a causative factor or an incidental finding in this population. Full article

Adenoviruses have been implicated in childhood cancers, primarily leukemia, yet prior neonatal investigations have rarely examined other pediatric tumor types. This study evaluated whether adenoviral early region (E1A) sequences can be detected in archival neonatal Guthrie cards from children who later developed diverse pediatric tumors and in corresponding paraffin-embedded tissues. DNA extraction was optimized for long-stored dried blood spots, and PCR conditions were refined for both Guthrie card and paraffin-derived DNA. Adenoviral E1A was analyzed using conventional and nested PCR, and sequencing of representative amplicons confirmed correspondence to human adenovirus species C. E1A PCR positivity was found in 43% of Guthrie cards from cases (n = 54) and 34% of controls (n = 32), and in 41% of tumor tissues (n = 75) compared with 5% of non-tumor paraffin controls (n = 20). Detection occurred across multiple tumor categories without a clear association with tumor type. Partial concordance was observed between paired neonatal and tumor samples, and cytomegalovirus markers were detected in a subset of E1A-positive specimens. These findings confirm the suitability of Guthrie cards for retrospective viral DNA detection and extend previous leukemia-focused neonatal studies to broader pediatric tumors. The data suggest a potential association between birth-stage adenoviral detection and childhood cancer, though a causal link remains unproven and requires further longitudinal investigation. Full article

The rectal mucosa houses a large number of viruses with important roles in shaping the local microbial communities and modulating immune responses, which could influence host susceptibility to infection and other diseases. Unique composition of the gut microbiome, including the predominance of clinically significant eukaryotic viruses like herpesviruses, cytomegalovirus, and human papillomavirus, has been described in both people with HIV (PWH) and men who have sex with men (MSM) vulnerable to HIV. Despite these insights, the rectal virome and the clinical implications of virome–bacteriome–immune interactions in the rectal mucosa remain poorly understood. In this review, we synthesize existing data on the composition of the rectal virome, its interactions with the bacteriome and the immune system, and implications on clinical outcomes in people living with or vulnerable to HIV. We also highlight the gaps and research needed to further explore and unravel these relationships. Full article

Background/Objectives: Maternal valaciclovir therapy is increasingly used to reduce fetal viral replication in cases of primary cytomegalovirus (CMV) infection during pregnancy. However, data on its impact on early neurodevelopmental outcomes remain limited. This study aimed to evaluate the association between prenatal valaciclovir exposure and early neurodevelopment in infants with confirmed congenital CMV infection (cCMV). Methods: In this retrospective monocentric cohort study, 30 infants with PCR-confirmed cCMV infection were assessed at 4–8 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants were stratified according to prenatal exposure to maternal valaciclovir. Univariate analyses and multivariable linear regression models were performed to evaluate the association between prenatal antiviral exposure and cognitive outcome, adjusting for brain MRI findings and selected clinical variables. Results: Fifteen infants (50%) were exposed to prenatal valaciclovir. Exposed infants demonstrated higher cognitive composite scores compared with unexposed infants (median 105 [IQR 100–110] vs. 90 [85–110]; p = 0.030). In multivariable analysis, prenatal valaciclovir exposure remained significantly associated with higher cognitive scores (β = 11.89, 95% CI 2.86–20.92; p = 0.012), while neonatal MRI abnormalities were not independently associated with outcome. No significant differences were observed in language or motor domains. The final model explained 30% of the variance in cognitive scores (R² = 0.30). Conclusions: Prenatal valaciclovir exposure was associated with higher cognitive composite scores after adjustment for selected covariates. Although causality cannot be inferred, these findings suggest a potential association with early neurodevelopmental outcomes and support the inclusion of functional neurodevelopmental endpoints in future prospective studies. These results should be considered exploratory and hypothesis-generating Full article

Feline calicivirus (FCV) is a major pathogen that threatens feline health worldwide. Its global prevalence, extensive genetic variability, and limited cross-protection among strains present significant challenges for vaccine development. In this study, an infectious clone of the FCV-GDJM202201 strain was constructed using the eukaryotic expression plasmid pcDNA3.1 under the control of the cytomegalovirus (CMV) promoter. The rescued virus, rGDJM-A4822T, exhibited growth kinetics comparable to those of the parental strain in vitro. Subsequently, two recombinant viruses, rGDJM-VP1_JL and rGDJM-VP1_SH, were generated by replacing the VP1 gene in the GDJM202201 backbone with those from heterologous FCV strains. Notably, these recombinant viruses exhibited reduced viral titers compared to rGDJM-A4822T. Finally, neutralization assays revealed differential neutralizing antibody titers among the recombinant FCVs, with rGDJM-A4822T inducing higher neutralizing antibody titers and cross-neutralizing activity. Collectively, this study establishes an FCV infectious clone that can be used to rescue recombinant viruses carrying heterologous VP1 proteins and to evaluate neutralizing antibody responses. Full article

Human cytomegalovirus (HCMV) remains a significant cause of morbidity in immunocompromised patients, necessitating the development of improved antivirals. Using an integrated in silico and in vitro approach, we identified a novel ligand (NL) as a letermovir analog with enhanced binding affinity and reduced cytotoxicity. A pUL56 terminase subunit model generated with AlphaFold 3 was used for the virtual screening of a 15,000-compound library. Among the 73 candidates with structural similarity to letermovir (Tanimoto ≥ 0.6), NL exhibited superior predicted binding affinity (ΔG_bind = −10.7 kcal/mol). In silico toxicity prediction (ProTox 3.0) classified NL as having low toxicity (class 4, LD50 ≈ 1000 mg/kg), which was confirmed in vitro, where NL demonstrated 158-fold less toxic (CC50 = 2.69 mg/mL) in MRC-5 cells than letermovir (0.017 mg/mL). Molecular dynamics simulations over 500 ns revealed that the pUL56-NL complex forms a more thermodynamically stable interaction, with a lower calculated free energy of binding (MMGBSA: −40.89 ± 7.40 kcal/mol vs. −32.76 ± 4.96 kcal/mol) and a narrower free energy landscape. These results establish NL as a promising, low-cytotoxicity candidate with enhanced target engagement, warranting further investigation as a potential anti-HCMV therapeutic. Full article

Polyamines are small, positively charged molecules essential for fundamental cellular processes, including transcription, translation, and membrane fluidity. In the central nervous system (CNS), these molecules serve as homeostatic gatekeepers by modulating neuroreceptors like NMDA and supporting autophagic clearance. While basal polyamine levels are necessary for proper neuronal differentiation and memory formation, their dysregulation is a hallmark of neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases. Neurotropic viruses, including poliovirus, Zika virus, and human cytomegalovirus are significant human pathogens that rely on cellular metabolites for their replication, including polyamines. These pathogens exploit polyamines at multiple stages of their life cycles, relying on them for virion stability, cellular attachment, and the stimulation of viral enzyme activity. Notably, diverse viral families share this dependence, making polyamine biosynthesis a prime target for broad-spectrum antiviral therapies. This review covers the current understanding of polyamine metabolism in virus infection and CNS health and disease, as well as considering antiviral therapies targeting host polyamines to limit neurotropic virus infection. Full article