Journal of NeuroVirology最新文献

Background: HIV-associated neurocognitive impairment (HAND) is a common complication of HIV-1 infection, which can be exacerbated by exposure to cigarette smoke (CS). Tight junction proteins (TJPs) of the blood-brain barrier (BBB) play a crucial role in maintaining BBB integrity and preventing the entry of circulating toxic factors, including those resulting from HIV-1 infection, into the central nervous system. Both CS exposure and HIV-1 infection can independently disrupt TJPs and compromise BBB integrity; however, the combined or individual effects of these factors on BBB TJPs remain poorly understood.

Methods: An in vitro BBB comprised of Sprague-Dawley rat brain microvascular endothelial cell (RBMVEC) transwell cultures was exposed to wild-type (WT) and HIV-1 transgenic (TG) rat sera, alone or in combination with cigarette smoke extract (CSE) and analyzed for trans-endothelial electrical resistance (TEER) and paracellular permeability to 10 kDa fluorescein isothiocyanate (FITC)-dextran. Immunofluorescence staining was performed to assess the effects of treatment on the cellular localization and expression of the TJPs, "zonula occludens-1 (ZO-1) and claudin-5.

Results: Pretreatment TEER measures were significantly higher for cultures treated with WT serum alone compared to those treated with TG serum or with CSE. Compared to pretreatment, TEER measures were significantly reduced by treatment with WT serum alone, CSE alone, WT serum + CSE, and TG serum + CSE. TG serum alone or TG serum + CSE resulted in statistically significant increased permeability compared to WT serum. All treatments decreased TJP staining intensity, and, in some cases, altered TJP localization. These effects were most prominent following incubation with either CSE alone, TG serum alone, or TG serum + CSE.

Conclusions: CSE and TG serum induced separate and additive toxic effects on BBB function and integrity, which may underlie mechanisms that are associated with more severe HAND among HIV+ cigarette smokers.

Human herpesviruses (HHVs) cause central nervous system (CNS) infections; however, the role of neural autoantibodies remains unclear. We aimed to assess the presence of anti-N-methyl-D-aspartate receptor (anti-NMDAR) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in HHV-associated CNS infections. Seventeen adults with HHV DNA in the cerebrospinal fluid were tested using flow cytometry-based assays. None of the patients tested positive for anti-NMDAR antibodies. Anti-MOG antibodies were detected in two patients with VZV-associated CNS infection, one appearing after deterioration and the other at onset. Both patients recovered without sequelae. Anti-MOG antibodies may arise in VZV-associated CNS infections, warranting the consideration of autoimmune mechanisms.

Drugs inhibiting the cyclin-dependent kinases (CDK) 4 and 6 are widely used for the treatment of luminal breast cancer, in the adjuvant and in the metastatic setting, and adverse events are well-known. Progressive multifocal leukoencephalopathy (PML) is classically linked to immunosuppression. We present a case of progressive multifocal leukoencephalopathy that developed during adjuvant abemaciclib therapy in a seventy-year-old woman diagnosed with locally advanced ductal carcinoma of the breast. Neurological impairment developed after 18 months of initiating abemaciclib and in imaging tests a left frontal brain lesion appeared. Metastasis was excluded and the evidence of the John Cunningham polyomavirus (JCPyV) genome, both in the blood and in the cerebrospinal fluid, supported the diagnosis of PML. We did not identify significant immune blood cell counts alterations, nor other causes of immunosuppression; the patient was not treated with other immunosuppressive drugs. We speculate that different immune mechanism alterations related to abemaciclib, which has a high penetration rate in the brain, may be involved in an increased risk of JCPyV reactivation and consequently PML development.

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.