Journal of NeuroVirology最新文献

Rabies virus (RABV) is a highly neurotropic pathogen with near-uniform lethality after symptom onset, yet the molecular mechanisms underlying disease progression in the central nervous system (CNS) remain poorly defined. To address this gap, we performed time-resolved, label-free quantitative proteomics in RABV-infected mouse brains at defined clinical phases of RABV infection (asymptomatic, progressive, terminal). Differential protein expression was analyzed by clustering, enrichment, and protein-protein interaction networks. Machine learning models classified infection stages, and top biomarkers were validated by Western blot. Principal component and clustering analyses separated infection phases robustly, while GO/KEGG and PPI analyses revealed a progression from cytoskeletal/trafficking remodeling (early) to innate immune activation (intermediate) and proteostasis collapse/neurodegeneration-linked pathways (late). A Support Vector Machines classifier discriminated phases with high performance (F1 = 0.88; AUC = 0.79) and SHAP interpretation highlighted LAMP2, IL18 and SNCA among the top phase-specific predictors, and confirmed experimentally. This integrative proteomics-machine learning approach maps dynamic molecular transitions during RABV infection and nominates diagnostic biomarkers relevant to neurovirology. These findings provide mechanistic insights into viral neuropathogenesis and highlight parallels with neurodegeneration.

Parkinson's disease (PD) is the second most prevalent progressive neurological movement condition worldwide. Previous studies have reported aberrant expression of lncRNA MCF2L-AS1 in PD. Therefore, this study aims to investigate the clinical significance of MCF2L-AS1 in PD patients and to explore whether MCF2L-AS1 is involved in the disease progression of PD by regulating miR-28-5p expression. The expression of MCF2L-AS1 was detected by using RT-qPCR. The diagnostic function of MCF2L-AS1 in PD was analyzed via ROC curves. CCK-8 assay was used to measure cell viability, and the apoptosis rate and ROS level were detected by flow cytometry. The targeted binding relationship between MCF2L-AS1 and miR-28-5p was detected using a dual-luciferase reporter gene assay. The concentration of MDA, SOD, and proinflammatory factors (TNF-α, IL-1β, and IL-6) was detected by using ELISA kits. This study found that the expression of MCF2L-AS1 was downregulated in patients with PD, and MCF2L-AS1 had predictive potential in PD. In addition, MCF2L-AS1 regulated MPP⁺-induced cell viability, apoptosis, oxidative stress, and inflammation of SH-SY5Y cells by regulating miR-28-5p expression. Therefore, MCF2L-AS1 may function as a biomarker for the diagnosis and treatment of PD.

Microglia are considered the main human immunodeficiency virus (HIV) reservoirs in the central nervous system (CNS) due to their ability to become productively infected, produce new infectious HIV virions, and support HIV latency. The anatomical location of microglia necessitates the use of in vitro HIV infection models. However, currently available in vitro models are laced with limitations, including their suboptimal HIV infection rates, poor experimental tractability, and low affordability. Therefore, we sought to develop a new in vitro infection model that addresses these concerns. Here, we confirmed that microglia express sterile alpha motif and histidine-aspartic domain-containing protein-1 (SAMHD1), an antiviral mechanism that opposes HIV replication. We show that administration of simian immunodeficiency virus (SIV)-derived Vpx virus-like particles (VLPs) can reduce the levels of SAMHD1, thus allowing for increased infectivity in EcoHIV-infected CHME5 microglial cell line. With this model, we achieved higher initial rates of HIV infection. We could also track the cells using eGFP expression during active replication, latency, and latency reversal. Further, we developed a CHME5-EcoHIV + cell line using fluorescence-activated cell sorting (FACS). Despite high infectivity of HIV in CHME5 cells, we confirmed that limited latency reversal occurs following their exposure to conventional latency reversing agents (LRAs). Our novel microglia infection model saves researchers time and money and, due to its ease of use, can rapidly contribute to curative research in the field.

Severe Acute Respiratory Syndrome Coronavirus-2 infection has been associated to neurological symptoms characteristic of long-lasting post-acute coronavirus disease. However, the complex mechanisms involved in these clinical manifestations are still unclear. Glial cells are key to inflammation and neurodegeneration in response to central nervous system infection. To investigate this pathway, induced pluripotent stem cells human astrocytes and human microglial HMC3 cells were infected with SARS-CoV-2. Astrocytes showed to be prone to infection, while HMC3 supported only marginal virus replication. A significant IFN-β response was induced in astrocytes, while both cell types showed some level of chemoattractant production. Interestingly, both glial cells showed signs of senescence and activation of the pro-inflammatory cGAS-STING pathway. To investigate if glial cells infection could impair the function of neuronal networks, primary rat cortical cultures seeded on multi-electrode arrays were used to monitor the electrical activity after exposure to SARS-CoV-2. Effective SARS-CoV-2 infection of the glia led to a major loss of synaptic connections, an increase expression and production of pro-inflammatory cytokines and chemokines, and an increase of DNA damage foci. Intriguingly, the pro-inflammatory response was cGAS-STING dependent. Finally, an antagonist of the cGAS-STING pathway was able to ameliorate the decrease in electrical activity early post-infection. These data point to SARS-CoV-2 infection of the glia as a culprit for neurological complications during COVID-19.

Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV) reactivation in the setting of impaired cellular immunity. While commonly associated with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and immunosuppressive therapies, PML can also arise in primary immunodeficiency disorders. We report a case of PML in a young adult with autosomal recessive hyper-IgE syndrome (AR-HIES) due to DOCK8 deficiency, highlighting the importance of considering genetic immunodeficiencies in cases of JCV-PML without known iatrogenic or acquired causes.

Virus-induced accelerated aging has been proposed as a potential mechanism underlying the persistence of HIV-associated brain injury (HABI) despite advances in access and adherence to combination antiretroviral therapies (cART). While some studies have demonstrated evidence of accelerated aging in PLWH, studies examining the effects of cART intervention are limited, with most studies being in vitro or utilizing small animal models. Here, we utilized archival FFPE tissues from Simian immunodeficiency virus (SIV) infected rhesus macaques to assess the levels of two proteins commonly associated with aging - the cellular senescence marker p16^INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Our central hypothesis was that SIV infection induces accelerated aging phenotypes in the brain characterized by increased expression of p16 and SIRT1 that correlate with increased neurodegeneration, and that cART inhibits this process. We found that SIV infection induced increased GFAP, p16, SIRT1, and neurodegeneration in multiple brain regions. Importantly, cART reduced SIV-induced accelerated aging (p16 and SIRT1) in the hippocampus and neurodegeneration and GFAP expression in the frontal lobe. Combined, these data suggest that cART is both safe and effective in reducing neuroinflammation and age-associated alterations in astrocytes that contribute to neurodegeneration, providing possible therapeutic targets in the treatment of HABI.

Persistent intrathecal immune activation and neuronal injury remain common in people with HIV (PWH) despite effective antiretroviral therapy (ART). We examined longitudinal trajectories of cerebrospinal fluid (CSF) neurofilament light (NfL), a marker of axonal injury, together with neuroinflammatory biomarkers following ART initiation. Ninety-nine PWH from the Gothenburg HIV CSF Study Cohort who achieved viral suppression were included, with CSF samples collected before and after treatment initiation. NfL and a panel of biomarkers including YKL-40, sTREM-2, neopterin, and GFAP were analyzed. CSF NfL declined rapidly, from a mean of 673 ng/L at baseline to 592 ng/L after three months and 490 ng/L after twelve months. All inflammatory biomarkers showed parallel and significant decreases. Prior to ART, 25% of participants had elevated NfL levels; this subgroup displayed higher baseline inflammation, and the steepest biomarker declines after treatment initiation. In participants with normal baseline NfL, inflammatory markers decreased while NfL remained stable. Beyond one year, no further reductions were evident. These longitudinal findings demonstrate that ART rapidly and effectively reduces CSF biomarkers of neuronal injury and neuroinflammation in HIV, with the greatest benefit in individuals with baseline axonal damage.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the central nervous system (CNS) caused by reactivation of the John Cunningham (JC) polyomavirus, commonly occurring in immunosuppressed individuals. Comparative data on the clinical and neuroimaging features of PML in human immunodeficiency virus (HIV)-positive and HIV-negative patients from India remain scarce. To compare clinical profiles, neuroimaging characteristics, and outcomes of HIV-positive and HIV-negative PML patients with cerebrospinal fluid (CSF) JC virus polymerase chain reaction (PCR) or brain biopsy PCR confirmation. This single-centre ambispective cohort study included adults (age ≥ 18 years) presenting to a tertiary care hospital in India between January 2019 - July 2025, who were diagnosed with PML. Demographic, clinical, laboratory, imaging and outcome data were collected. These were thereafter compared between the HIV-positive and HIV-negative PML cohorts. We recruited 41 PML patients out of 100 who were screened during the study period. Of these, 29 (70.7%) were HIV-positive and 12 (29.3%) were HIV-negative. HIV positive PML patients were younger [Mean age: (42 ± 10.5 vs 50 ± 13.4 years, p-value = 0.05)] and presented with a shorter symptom duration [4.2 ± 2.2 months vs 7.1 ± 5.3 months (p-value = 0.02)] compared to the HIV-negative cohort. Cognitive impairment (53.6% overall) was the most common symptom overall, with altered sensorium [27.6% vs 16.7% (p = 0.694)] and cerebellar ataxia [41.4% vs 25% (p = 0.480)] observed more commonly in HIV-positive patients and hemiparesis [66.7% vs 44.8% (p = 0.306)] manifesting more frequently in HIV-negative cases. However, these were not statistically significant. Radiologically, multifocal lesions (56.1%) were most commonly seen. Infratentorial involvement [72.3% vs 50% (p-value = 0.491)] and multifocal/diffuse lesions [86.2% vs 75% (p-value = 0.491)] were more common in HIV-positive, although these did not attain statistical significance. The shrimp sign was more common in patients with HIV [37.9% vs 25% (p = 0.003)]. Twenty-six patients (63.4%) showed symptomatic improvement with treatment, while six (14.6%) worsened and nine (22%) succumbed to their illness. Adult HIV-positive PML patients present earlier and tend to have diffuse, infratentorial and deep grey matter involvement. Adult HIV-negative PML patients frequently exhibit focal or punctate lesions. Certain imaging features, such as the shrimp sign in HIV-positive patients and the milky way sign in HIV-negative patients, may provide valuable diagnostic clues, but are not definitive and require confirmation in larger studies. PML patients may show clinical improvement if early therapy for the etiology of PML is provided.

This study aimed to investigate the clinical features of varicella-zoster virus (VZV) meningitis cases diagnosed by polymerase chain reaction (PCR) despite normal routine cerebrospinal fluid (CSF) testing. A retrospective review was performed on hospitalized central nervous system (CNS) infection cases at our institution from 2013 to 2024. VZV meningitis cases were analyzed and divided into two groups: those diagnosed by positive PCR without routine CSF abnormalities (PCR Group) and those with routine CSF abnormalities (Usual Group). PCR methods included conventional techniques and a rapid detection system (FilmArray^®). Among 75 CNS infection cases (49 viral, 13 bacterial, 6 tuberculosis, 2 fungal, and 1 amoebic), 29 VZV meningitis cases were identified. Compared to the Usual Group (n = 25), the PCR Group (n = 4) had significantly lower CSF cell counts (median 1.0 vs. 99.0/µl, p < 0.001) and protein levels (44.0 vs. 70.0 mg/dl, p < 0.001) but similar glucose levels (58.0 vs. 54.0 mg/dl, p = 0.17). All PCR Group cases were female (vs. 52% in the Usual Group), had a trigeminal skin rash (vs. 52%), and presented with headache without meningeal irritation signs (vs. 44.0%) or fever. 50% of cases in the PCR Group were immunocompromised (vs.24%). Other clinical and epidemiological features were similar in both groups. Routine CSF analysis may fail to reveal abnormalities in VZV meningitis, particularly in both immunocompromised and immunocompetent female patients presenting with trigeminal skin rash and headache in the absence of meningeal irritation signs or fever. PCR is recommended to facilitate prompt and accurate diagnosis in such cases.