Journal of NeuroVirology最新文献

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.

COVID-19 is a systemic infection that causes endothelial dysfunction, contributing to severe cases. While vascular complications are well-documented, their impact on vascular structure, function, and cognition remains unclear. This cross-sectional study explored vascular and cognitive differences across patients with mild, moderate, and severe COVID-19, examining correlations between global cognitive performance and vascular parameters. This study included 83 working-age patients (30-65 years, both sexes) who recovered from COVID-19 within 6-12 months. They were grouped by severity: mild (outpatients, no oxygen support), moderate (hospitalized, conventional oxygen therapy), and severe (hospitalized, advanced oxygen therapy). Exclusions included pre-existing cognitive or neurological conditions, significant atherosclerosis, malignancies, and prior COVID-19 vaccination. Global cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) test, while vascular parameters - carotid intima-media thickness (IMT), beta stiffness index (β index), mean flow velocity (MVs), maximum velocity after breath-holding (MV-BH), and breath-holding index (BHI) - were evaluated using duplex ultrasound and transcranial Doppler. Patients with severe COVID-19 had the highest carotid stiffness and poorest cerebrovascular reactivity. While MoCA scores showed no significant group differences, 23-40% had mild cognitive impairment. MoCA scores negatively correlated with β index in mild group (ρ=--0.453; p = 0.034), while MVs positively correlated with MoCA in severe cases (ρ = 0.414; p = 0.028). The association between arterial stiffness and cognitive impairment in mild cases, suggests lasting effects of SARS-CoV-2 rather than pre-existing conditions. These findings highlight carotid stiffness as a key factor in post-COVID-19 cognitive impairment, emphasizing early risk identification for timely intervention.

Angiotensin-converting enzyme 2 (ACE2), a key regulator of the renin-angiotensin system (RAS), maintains central nervous system (CNS) homeostasis by metabolizing neuroinflammatory peptides like angiotensin II (Ang II) and apelin-13, thereby exerting neuroprotective effects. Recent evidence underscores ACE2's paradoxical roles in neurodegeneration: its loss of function due to SARS-CoV-2 spike protein binding exacerbates neuroinflammation and cognitive decline, while its upregulation may mitigate AD pathology by reducing amyloid-β (Aβ) accumulation and tau hyperphosphorylation. The COVID-19 pandemic has further highlighted ACE2 axis dysregulation as a potential accelerator of AD progression, with studies reporting elevated biomarkers of neurodegeneration in post-COVID patients. Therefore, in this review, we highlight the emerging insights into ACE2's dual role in AD and other neurodegenerative diseases, emphasizing its interactions with microglial activation, blood-brain barrier integrity, and mitochondrial dysfunction. We also critically evaluate novel therapeutic strategies, including recombinant ACE2, ACE2-derived peptides, and gene therapy approaches designed to restore RAS balance without compromising viral defense mechanisms. By integrating mechanistic and clinical insights, this work highlights ACE2 as a promising target for neurodegenerative disease interventions.

Alphaherpesviruses such as Herpes Simplex Virus 1 (HSV-1) and Pseudorabies virus (PrV) invade the central nervous system (CNS) via peripheral nerves. While olfactory and trigeminal pathways are well-known, additional cranial routes remain underexplored. Using a PrV-∆UL21gfp/US3∆kin mutant in CD1 mice, we mapped early neuroinvasion (4-96 hpi) by immunofluorescence and RNA in situ hybridization. Viral antigen and lytic viral gene expression (UL19 RNA) were detected in the olfactory epithelium, vomeronasal organ, incisors, palate, olfactory bulb, and brainstem. These results indicate multineural CNS access involving olfactory (I), trigeminal (V), glossopharyngeal (IX), and hypoglossal (XII) nerves, highlighting this model's value for studying early alphaherpesvirus spread.