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Host shutoff activity of VHS and SOX-like proteins: role in viral survival and immune evasion.

BACKGROUND: Host shutoff refers to the widespread downregulation of host gene expression and has emerged as a key process that facilitates the reallocation of cellular resources for viral replication and evasion of host antiviral immune responses. MAIN BODY: The Herpesviridae family uses a number of proteins that are responsible for host shutoff by directly targeting messenger RNA (mRNA), including virion host shutoff (VHS) protein and the immediate-early regulatory protein ICP27 of herpes simplex virus types 1 (HSV-1) and the SOX (shutoff and exonuclease) protein and its homologs in Gammaher…

Validation and Characterization of Five Distinct Novel Inhibitors of Human Cytomegalovirus.

The critical consequences of human cytomegalovirus (HCMV) infection in the transplant population and in congenitally infected infants, the l … each compound inhibited a specific stage of HCMV replication. One compound was also active against herpes simplex virus (HSV1 and HSV2), and another compound was active against Epstein-Barr virus (EBV). Drug combination studies revealed that all five compounds were additive with ganciclovir or letermovir. Future studies will focus on optimization of these new a …

Epstein-Barr virus retinitis in an immunocompromised child: A case report.

INTRODUCTION: The Epstein-Barr virus is a rare causative pathogen identified in the posterior segment. The majority of cases were presented … polymerase chain reaction was positive for Epstein-Barr virus DNA but negative for cytomegalovirus, herpes simplex virus and varicella zoster virus DNA. Systemic acyclovir and intravitreal ganciclovir injection were administered. Seven months later, retinitis resolved with remnant retinal fibrosis, and visual acuity improved to 20/500. CONCLUSION: Epstein-Barr …

Astrocyte- and Neuron-Derived CXCL1 Drives Neutrophil Transmigration and Blood-Brain Barrier Permeability in Viral Encephalitis.

Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral r…

Conditional ablation of reactive astrocytes to dissect their roles in spinal cord injury and repair.

Astrocytes become reactive in response to spinal cord injury (SCI) and ultimately form a histologically apparent glial scar at the lesion site. It is controversial whether astrocytic scar is detrimental or beneficial to the axonal regeneration and SCI repair. Therefore, much effort has focused on understanding the functions of reactive astrocytes. Here, we used a lentivirus-mediated herpes simplex thymidine kinase/ganciclovir (HSVtk/GCV) system to selectively kill scar-forming reactive proliferating astrocytes. The suicide gene expression was regulated by human glial fibrillary acidic protein …

Herpetic Anterior Uveitis in a Chinese Referral Center: Clinical Manifestations and Laboratory Test Results.

PURPOSE: To describe and to compare the clinical manifestation and laboratory test results of herpetic anterior uveitis (HAU) caused by Herpes simplex virus (HSV) and varicella-zoster virus (VZV). METHODS: A retrospective, observational study on patients diagnosed with HAU. Etiology, clinical features, ocular complications, and recurrences of the infection were evaluated as main clinical parameters. The aqueous Interleukin-8 (IL-8) level was also measured to assess the intraocular inflammation. RESULTS: Thirty-two eyes (32 patients) were involved. Among all involved cases, 24 had VZV-AU and …

Herpesviral lytic gene functions render the viral genome susceptible to novel editing by CRISPR/Cas9.

Herpes simplex virus (HSV) establishes lifelong latent infection and can cause serious human disease, but current antiviral therapies target lytic but not latent infection. We screened for sgRNAs that cleave HSV-1 DNA sequences efficiently in vitro and used these sgRNAs to observe the first editing of quiescent HSV-1 DNA. The sgRNAs targeted lytic replicating viral DNA genomes more efficiently than quiescent genomes, consistent with the open structure of lytic chromatin. Editing of latent genomes caused short indels while editing of replicating genomes produced indels, linear molecules, and la…

Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis.

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and alt…

Изучение роли запрограммированного клеточного белка смерти 1 и его лиганда 1 в заболеваниях глаз.

Для регулирования как физиологической, так и патологической иммунной реакции необходимы запрограммированные рецептор смерти-1 (PD-1) и его лиганд PD-L1 в качестве негативных взаимостимуляторных молекул. В ходе исследований раковых заболеваний широко изучался способ подачи сигналов с помощью ПД-1/ПД-L1 и стал горячей точкой для биофармацевтики и иммунной терапии. Кроме того, моноколональные антитела для PD-1 только что были утверждены Администрацией США по продуктам питания и лекарствам для лечения определенных видов вредоносных веществ. Недавно проведенные исследования позволили установить тес

Совпадение в аннотации оригинала
Programmed death receptor-1 (PD-1) and its ligand, PD-L1, as negative co-stimulatory molecules, are indispensable for regulating both physio … uveitis, autoimmune dry eye, sympathetic ophthalmia, Graves' ophthalmopathy, diabetic retinopathy, herpes simplex keratitis, and trachoma, with the intent of highlighting the potential of PD-1/PD-L1 as novel therapeutic targets or biomarkers for these ocular diseases.

Diagnosis of congenital/perinatal infections by neonatologists: a national survey.

OBJECTIVE: To describe the clinical approach used by neonatologists for diagnosis of congenital/perinatal infections (CPI); no such data currently exist. STUDY DESIGN: A national survey regarding the diagnosis of toxoplasma, syphilis, rubella, cytomegalovirus, and herpes simplex virus (HSV) infection in neonates. RESULT: We received 553 (11%) responses. Central nervous system calcification or hydrocephalus was the commonest trigger to pursue a CPI diagnosis (98%); maternal history was the least frequent (67%). Four hundred twenty-two (76%) used general screening such as "TORCH titer screen" …

Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection.

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher …

MxB is an interferon-induced restriction factor of human herpesviruses.

The type I interferon (IFN) system plays an important role in controlling herpesvirus infections, but it is unclear which IFN-mediated effectors interfere with herpesvirus replication. Here we report that human myxovirus resistance protein B (MxB, also designated Mx2) is a potent human herpesvirus restriction factor in the context of IFN. We demonstrate that ectopic MxB expression restricts a range of herpesviruses from the Alphaherpesvirinae and Gammaherpesvirinae, including herpes simplex virus 1 and 2 (HSV-1 and HSV-2), and Kaposi's sarcoma-associated herpesvirus (KSHV). MxB restriction of …

Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human pa…

The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport.

Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process. W…

Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers.

A 65-year-old man with treatment-resistant psoriatic arthritis, hypertension, dyslipidaemia and benign prostatic hyperplasia (BPH) presented with herpes simplex virus (HSV) oral ulcers and a recent 15 lb weight loss due to reduced consumption. Five weeks previously, his methotrexate was tapered and he had begun taking azathioprine. The patient's thiopurine S-methyltransferase (TPMT) activity level was normal prior to starting azathioprine. He was found to have pancytopenia with normal folate levels and azathioprine was discontinued. His pancytopenia worsened, with a nadir 8 days after stopping…

Various patterns of acute alveolar haemorrhage in patients with microscopic polyangiitis: a clinicopathological study of four cases.

It is well known that acute alveolar haemorrhage (AAH) is attributed to capillaritis in most cases with microscopic polyangiitis (MPA). In t … infarct due to aspergillosis, capillaritis due to MPA, vasculitis due to cytomegalovirus (CMV), and herpes simplex virus (HSV) infection. All patients received corticosteroid therapy, and one patient additionally underwent administration of cyclophosphamide. The duration of follow-up ranged from one to 26 months with a mean of eight months. All patients died of …

The use of biologic therapies in uveitis.

PURPOSE: Non-infectious uveitis has been long controlled with the use of corticosteroids with many side effects and poor control in some cas … ers, CME = Cystoid Macular Oedema, CPR = C Protein Reactive, ESR = Erythrocyte Sediment Rate, HSV = Herpes Simplex Virus, ICAM = Intercellular Adhesion Molecules, IMT = Immunomodulatory Therapy, JIA = Juvenile Idiopathic Arthritis, MMP = Matrix Metalloproteinases, MTX = Methotrexate, RA = Rheumatoid Arthritis, TB = Tuberculosis, VCAM = Vascular Adhesion Molecule …

Report of a Myocarditis Outbreak among Pediatric Patients: Human Herpesvirus 7 as a Causative Agent?

BACKGROUND: The etiology of myocarditis in children has not yet been completely elucidated. OBJECTIVE: Medical records of eight pediatric patients diagnosed with acute myocarditis within a 41-day period in a small-town hospital were retrospectively analyzed. METHODS: We examined antibody titers of adenovirus, Epstein-Barr virus, herpes simplex virus, respiratory syncytial virus, varicella-zoster virus and cytomegalovirus in peripheral blood. We used polymerase chain reaction (PCR) amplification to detect genetic sequences from Human herpesvirus (HHV) 7, HHV 6, enterovirus, measles or parvovi…

Bilateral Acute Retinal Necrosis: Clinical Features and Outcomes in a Multicenter Study.

Purpose: To describe clinical features and outcome in bilateral acute retinal necrosis (BARN). Methods: Observational retrospective longitudinal review of ocular findings. Results: Thirty eyes of 15 patients (age 44.1 ± 15.8). Delay of involvement between eyes was 57.2 ± 105.2 months (median 3, range 0.5-360). Herpes simplex virus (HSV)-1 was the most frequent (20 eyes, 66.6%), followed by HSV-2 (five eyes, 16.7%) and varicella zoster virus (VZV, four eyes, 13.3%). Visual acuity worsened in 7 (23%) eyes, improved in 4 (13%), and remained stable in 19 (63%). Major complications included retinal…

Immune Escape via a Transient Gene Expression Program Enables Productive Replication of a Latent Pathogen.

How type I and II interferons prevent periodic reemergence of latent pathogens in tissues of diverse cell types remains unknown. Using homogeneous neuron cultures latently infected with herpes simplex virus 1, we show that extrinsic type I or II interferon acts directly on neurons to induce unique gene expression signatures and inhibit the reactivation-specific burst of viral genome-wide transcription called phase I. Surprisingly, interferons suppressed reactivation only during a limited period early in phase I preceding productive virus growth. Sensitivity to type II interferon was selectivel…