HSV-1 Virus Research Articles

Reactivation of HSV-1 following explant of tree shrew brain.

Herpes Simplex Virus type I (HSV-1) latently infects peripheral nervous system (PNS) sensory neurons, and its reactivation leads to recurring cold sores. The reactivated HSV-1 can travel retrograde from the PNS into the central nervous system (CNS) and is known to be causative of Herpes Simplex viral encephalitis. HSV-1 infection in the PNS is well documented, but little is known on the fate of HSV-1 once it enters the CNS. In the murine model, HSV-1 genome persists in the CNS once infected through an ocular route. To gain more details of HSV-1 infection in the CNS, we characterized HSV-1 infection of the tree shrew (Tupaia belangeri chinensis) brain following ocular inoculation. Here, we report that HSV-1 enters the tree shrew brain following ocular inoculation and HSV-1 transcripts, ICP0, ICP4, and LAT can be detected at 5 days post-infection (p.i.), peaking at 10 days p.i. After 2 weeks, ICP4 and ICP0 transcripts are reduced to a basal level, but the LAT intron region continues to be expressed. Live virus could be recovered from the olfactory bulb and brain stem tissue. Viral proteins could be detected using anti-HSV-1 antibodies and anti-ICP4 antibody, during the acute stage but not beyond. In situ hybridization could detect LAT during acute infection in most brain regions and in olfactory bulb and brain stem tissue well beyond the acute stage. Using a homogenate from these tissues’ post-acute infection, we did not recover live HSV-1 virus, supporting a latent infection, but using a modified explant cocultivation technique, we were able to recover reactivated virus from these tissues, suggesting that the HSV-1 virus latently infects the tree shrew CNS. Compared to mouse, the CNS acute infection of the tree shrew is delayed and the olfactory bulb contains most latent virus. During the acute stage, a portion of the infected tree shrews exhibit symptoms similar to human viral encephalitis. These findings, together with the fact that tree shrews are closely related to primates, provided a valuable alternative model to study HSV-1 infection and pathogenesis in the CNS.

Harmine blocks herpes simplex virus infection through downregulating cellular NF-κB and MAPK pathways induced by oxidative stress

Herpes simplex virus types 1 and 2 (HSV-1 and -2) are highly prevalent in many populations and therapeutic options are limited. Both viruses can establish latency by maintaining viral genomes in neurons of sensory ganglia. Primary or recurrent HSV infections may lead to deleterious outcomes: HSV-1 infection may result in corneal blindness and encephalitis and HSV-2 infection leads to herpes genitalis. While no effective vaccine is available, acyclovir is widely used for therapy, which targets and inhibits viral DNA polymerase. Although acyclovir is of low toxicity, resistant strains arise due to persistent use, mainly in immune compromised patients. In our effort to identify new HSV inhibitory molecules, harmine was found to potently inhibit HSV infection. Harmine, a beta-carbon alkaloid with an indole core structure and a pyridine ring, is widely distributed in plants. Earlier studies showed that harmine exhibited pharmacological activities such as antifungal, antimicrobial, antitumor, antiplasmodial and antioxidants. In the current study, we showed that harmine was a potent inhibitor of HSV-2 infection in vitro assays with EC50 value at around 1.47μM and CC50 value at around 337.10μM. The HSV RNA transcription, protein synthesis, and virus titers were reduced by the presence of harmine in a dose dependent manner. Further study on the mechanism of the anti-HSV activity showed that harmine blocked HSV-induced ROS production and the upregulated cytokine/chemokine expression, but our evidence showed that the inhibition of viral replication was unlikely mediated by the blocking of ROS production. We demonstrated that harmine significantly reduced HSV-2-induced NF-κB activation, as well as IκB-α degradation and p65 nuclear translocation. We found that harmine also inhibited HSV-2-mediated p38 kinase and c-Jun N-terminal kinases (JNK) phosphorylation.

Superior Versus Inferior Vestibular Neuritis: Are There Intrinsic Differences in Infection, Reactivation, or Production of Infectious Particles Between the Vestibular Ganglia?

Intrinsic differences in neurons of the vestibular ganglia result in the increased likelihood of superior vestibular ganglion involvement in vestibular neuritis. Vestibular neuritis is hypothesized to result from herpes simplex type I (HSV1) infection or reactivation in vestibular ganglia. Involvement of the inferior vestibular ganglion is extremely rare in patients with vestibular neuritis. Primary cultures of rat superior and inferior vestibular ganglion neurons (VGNs) were cultivated separately. Neurons were lytically and latently infected with HSV1 with a US11-green fluorescent protein (GFP) chimera. Percentage lytic infection and baseline reactivation was assessed by microscopy for GFP fluorescence. Trichostatin-A (TSA) was used to stimulate HSV1 reactivation. Virion production was assessed by viral titers. Relative numbers of latency-associated (LAT) transcripts were determined by real-time reverse-transcription polymerase chain reaction (real-time RT-PCR). Lytic infection rates were equivalent between the two ganglia (p > 0.05). Lytic infections yielded similar amounts of plaque-forming units (p > 0.05). Relative amounts of LAT transcripts did not differ between latently infected superior and inferior VGNs. Latently infected cultures showed no differences in rates of baseline and TSA-induced HSV1 reactivation (p > 0.05). Production of virions was not significantly different between reactivated, latently infected superior versus inferior VGNs (p = 0.45). Differences in prevalence of superior and inferior vestibular neuritis do not result from intrinsic differences in HSV1 infection or virion production of these neurons. Other factors, such as the length and width of the bony canal containing the ganglia and nerves, account for the greater involvement of the superior vestibular ganglion in vestibular neuritis.

Icacinlactone H and Icacintrichantholide from the Tuber of Icacina trichantha.

The 17-norpimarane diterpene is a small group of natural products. A new member, icacinlactone H (1), and a new rearranged 17-norpimarane with an unprecedented carbon skeleton, icacintrichantholide (2), were isolated from Icacina trichantha. Their structures including the absolute configuration were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism analysis. A plausible biogenetic pathway for 1 and 2 is proposed. Both 1 and 2 showed no significant activity against herpes simplex viruses HSV-1 and HSV-2 as well as the Epstein-Barr virus at 50 μM.

Innate lymphotoxin receptor mediated signaling promotes HSV-1 associated neuroinflammation and viral replication

Host anti-viral innate immunity plays important roles in the defense against HSV-1 infection. In this study, we find an unexpected role for innate LT/LIGHT signaling in promoting HSV-1 replication and virus induced inflammation in immunocompromised mice. Using a model of footpad HSV-1 infection in Rag1–/– mice, we observed that blocking LT/LIGHT signaling with LTβR-Ig could significantly delay disease progression and extend the survival of infected mice. LTβR-Ig treatment reduced late proinflammatory cytokine release in the serum and nervous tissue, and inhibited chemokine expression and inflammatory cells infiltration in the dorsal root ganglia (DRG). Intriguingly, LTβR-Ig treatment restricted HSV-1 replication in the DRG but not the footpad. These findings demonstrate a critical role for LT/LIGHT signaling in modulating innate inflammation and promoting HSV-1 replication in the nervous system, and suggest a new target for treatment of virus-induced adverse immune response and control of severe HSV-1 infection.

Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues

A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9μM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45–58μM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45–73μM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1–19μM range.

Partial and total C-6 oxidation of gelling carrageenans. Modulation of the antiviral activity with the anionic character

The optimal conditions for the full C-6 oxidation of κ- and ι-carrageenans using (2,2,6,6-tetramethylpiperidinyl)oxy (TEMPO) in the presence of sodium hypochlorite and sodium bromide were assessed. The fully oxidized products were characterized by NMR spectroscopy. Partially oxidized products were also obtained and analyzed by chemical and spectroscopical methods. The antiviral activity of carrageenans against herpes simplex virus HSV-1 and HSV-2 determined by plaque reduction assay, was not largely affected by full oxidation of the polysaccharides, but an increase in activity was detected by partial oxidation. A specific overoxidation on C-2 of the 3,6-anhydrogalactose moiety of κ-carrageenan was identified, solved experimentally and rationalized through the application of molecular modeling.

Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives

Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a–3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H-imidazolidine-2-imines (1a–1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R1 are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4-methyl and 4-chloro substitution is tolerated as R1, whereas 4-chloro and 2-methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds.

Docking and antiherpetic activity of 2-aminobenzo[de]-isoquinoline-1,3-diones.

As part of our search for new compounds having antiviral effects, the prepared 2-aminonaphthalimide series was examined for its activity against the herpes simplex viruses HSV-1 and HSV-2. This represents the first study of the antiviral effects of this class of compounds. The new series of 2-amino-1H-benzo[de]isoquinoline-1,3-diones was examined against HSV-1 and HSV-2 using a cytopathic effect inhibition assay. In terms of effective concentration (EC50), furaldehyde, thiophene aldehyde and allyl isothiocyanide derivatives 14‒16 showed potent activity against HSV-1 (EC50 = 19.6, 16.2 and 17.8 μg/mL), compared to acyclovir as a reference drug (EC50 = 1.8 μg/mL). Moreover, 14 and 15 were found to exhibit valuable activity against HSV-2. Many of the tested compounds demonstrated weak to moderate EC50 values relative to their inactive parent compound (2-amino-1H-benzo[de]isoquinoline-1,3-dione), while compounds 7, 9, 13, 14, 15, 16, 21 and 22 were the most active set of antiviral compounds throughout this study. The cytotoxicity (CC50), EC50, and the selectivity index (SI) values were determined. In a molecular docking study, the ligand-receptor interactions of compounds 1–24 and their parent with the HSV-1 thymidine kinase active site were investigated using the Molegro Virtual Docker (MVD) software. Based on the potent anti-HSV properties of the previous naphthalimide condensate products, further exploration of this series of 2-amino-1H-benzo[de]isoquinoline-1,3-diones is warranted.

The bitter side of sweet: the role of Galectin-9 in immunopathogenesis of viral infections.

In recent years, a critical role for β-galactoside-binding protein, Galectin-9 (Gal-9) has emerged in infectious disease, autoimmunity, and cancer. It is a ligand for T cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic viral infections. Gal-9 exerts its pivotal immunomodulatory effects by inducing apoptosis or suppressing effector functions via engagement with its receptor, Tim-3. Recent studies report elevation of circulating Gal-9 in humans infected with different viral infections. Interaction of soluble Gal-9 with Tim-3 expressed on the surface of activated CD4+ T cells renders them less susceptible to HIV-1 infection, while enhanced HIV infection occurs when Gal-9 interacts with a different receptor than Tim-3. This indicates the versatile role of Gal-9 in viral pathogenesis. For instance, higher expression of Tim-3 during chronic viral infection and elevation of plasma Gal-9 may have evolved to limit persistent immune activation and pathogenic T cells activity. In contrast, Gal-9 can suppress the effectiveness of immunity against viral infections. In agreement, Gal-9 knockout mice mount a more robust and vigorous virus-specific immune response in acute and chronic viral infections resulting in rapid viral clearance. In line with this observation, blocking Gal-9 signals to Tim-3-expressing T cells result in improved immune responses. Here we review the biological and immunological properties of Gal-9 in viral infections (HIV, HCV, HBV, HSV, CMV, influenza, and dengue virus). Manipulating Gal-9 signals may have immunotherapeutic potential and could represent an alternative approach for improving immune responses to viral infections/vaccines.

Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease.

Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD(-/+gD-1)). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD(-/+gD1) elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.

Genome wide nucleosome mapping for HSV-1 shows nucleosomes are deposited at preferred positions during lytic infection.

HSV is a large double stranded DNA virus, capable of causing a variety of diseases from the common cold sore to devastating encephalitis. Although DNA within the HSV virion does not contain any histone protein, within 1 h of infecting a cell and entering its nucleus the viral genome acquires some histone protein (nucleosomes). During lytic infection, partial micrococcal nuclease (MNase) digestion does not give the classic ladder band pattern, seen on digestion of cell DNA or latent viral DNA. However, complete digestion does give a mono-nucleosome band, strongly suggesting that there are some nucleosomes present on the viral genome during the lytic infection, but that they are not evenly positioned, with a 200bp repeat pattern, like cell DNA. Where then are the nucleosomes positioned? Here we perform HSV-1 genome wide nucleosome mapping, at a time when viral replication is in full swing (6hr PI), using a microarray consisting of 50mer oligonucleotides, covering the whole viral genome (152kb). Arrays were probed with MNase-protected fragments of DNA from infected cells. Cells were not treated with crosslinking agents, thus we are only mapping tightly bound nucleosomes. The data show that nucleosome deposition is not random. The distribution of signal on the arrays suggest that nucleosomes are located at preferred positions on the genome, and that there are some positions that are not occupied (nucleosome free regions -NFR or Nucleosome depleted regions -NDR), or occupied at frequency below our limit of detection in the population of genomes. Occupancy of only a fraction of the possible sites may explain the lack of a typical MNase partial digestion band ladder pattern for HSV DNA during lytic infection. On average, DNA encoding Immediate Early (IE), Early (E) and Late (L) genes appear to have a similar density of nucleosomes.

Herpes Virus Entry Mediator in Human Corneal Epithelial Cells Modulates the Production of Inflammatory Cytokines in Response to HSV Type 1 Challenge

Aims: To investigate the role of herpes virus entry mediator (HVEM) in viral entry and inflammatory cytokine production in response to herpes simplex virus (HSV) type 1 challenge in human corneal epithelial cells. Methods: HVEM expression in human corneal epithelial cells was determined by immunofluorescence and flow cytometry. The HSV-1 virus expressing β-galactosidase was used to challenge corneal epithelial cells and viral entry assays were performed to ascertain HSV-1 entry into cells. Levels of cytokines TNF-α, IL-6, IFN-γ, IL-12, and IL-18 and chemokines MIP-1α, MIP-1β and MIP-2 were detected in corneal epithelial cells treated with control or HVEM siRNA in response to HSV-1 challenge. Results: Human corneal epithelial cells were positive for HVEM expression and showed high susceptibility to HSV-1 entry. Silencing of HVEM did not alter viral entry dramatically. However, levels of the cytokine IFN-γ and chemokines MIP-1α and MIP-1β were measured to be higher in HVEM siRNA-treated cells than control after HSV-1 challenge. Conclusions: HVEM in human corneal epithelial cells may act to dampen the production of some cytokines and chemokines and thus it may modulate the innate immune response against HSV-1. This may provide a novel mechanism for the pathogenesis of HSV-1 infection in the cornea.

ВОЗМОЖНЫЕ ПУТИ ОПТИМИЗАЦИИ ДИАГНОСТИЧЕСКОЙ ПОМОЩИ БОЛЬНЫМ С СИМПТОМАТИЧЕСКОЙ ЭПИЛЕПСИЕЙ НА ФОНЕ ХРОНИЧЕСКОГО ГЕРПЕСВИРУСНОГО ЭНЦЕФАЛИТА

The aim of our research was search of possible ways to optimize the diagnostic care for patients with symptomatic focal epilepsy with chronic parainfectious encephalitis associated with viruses of the family Herpes viridae. Materials and Methods. The study included 180 patients (107 women and 73 men) aged 18 to 50 years. Diagnostic methods include analysis of objective and subjective neurological symptoms, video-EEG monitoring, multimodal evoked potentials, brain MRI, laboratory methods (hemogram, immunogram, antibody titers of IgG and IgM to antigens of viruses HSV-1, HSV-2, CMV, VZV, HHV-6 and EBV, antibody avidity). Results. Relapsing course labial / facial herpes with subacute course was recorded in 93.1% of patients without epilepsy versus 95.7% patients with epilepsy (φ=0,764, p>0.05). Patients had a combined lesion of the central and peripheral nervous system involvement in the pathological process of II and VIII of the pairs (usually), V and VII pairs of cranial nerves (rarely), and the presence of chronic diseases of the paranasal sinuses in the form of chronic hyperplastic sinusitis. Patients with epilepsy, the total concentration of the major classes of immunoglobulins was smaller compared with uncomplicated encephalitis (IgA – 1,12 g/l vs. 1,5 g/l; IgG – 10,3 g/l vs. 13.8 g/l). This indicates a highly probable functional deficiency of B-lymphocytes and is manifested in the reduction antiteloproduktsii that promotes slow accumulation of specific antibodies, chronic process, an increase in viral load and associated complications. Reduced visual afferentation was 65.5% cases of encephalitis without epilepsy vs. 62.4% encephalitis with epilepsy. Reduced hearing afferentation observed less frequently (24.1% vs. 26.9%, respectively). Changes in cognitive evoked potentials identified in 28.7% cases of encephalitis without epilepsy vs. 53.8% encephalitis with epilepsy. Conclusions. Possible ways to optimize the diagnostic care for patients with symptomatic epilepsy parainfectious include a multidisciplinary approach (neurologist, neuroscientist, epileptologist, immunologist, otolaryngologist, ophthalmologist, psychotherapist), immune status, serum antibodies to herpesviruses, video-EEG monitoring, multimodal evoked potentials, neuropsychological testing, brain MRI with contrast, MR spectroscopy mediobasal (limbic) parts of brain.

Complications of Varicella – Report of Case with Hemorrhagic-Necrotic Rash and Cerebellar Ataxia

Varicella is usually self-limiting but occasionally severe infectious disease (with 2 to 6% of cases resulting in complications). The aim was to report a case with hemorrhagic-necrotic rash, discrete cerebellar ataxia and immune suppression. A two-year-and-seven-month-old boy with fever, tonsillitis and rose-colored-spots rash was treated with Amoxiclav and antihistamines followed by improvement. Eight days after treatment, fever, vesiculous rash (consequently hemorrhagicnecrotic) and enlarged lymph nodes appeared. On admission, the child was in severe condition, with generalized polymorph rash (vesicles with bloody content on necrotic surface, few crusts), generalized enlarged and painful lymph nodes, increased breath and heart rates, hepatosplenomegaly, depressed patellar and Achilles reflexes, positive Babinski sign; without signs of meningeal irritation. Ataxia had observed and Romberg was positive. Laboratory investigations revealed anemia, thrombocytopenia and normal humoral immunity. Lymphopenia (12.28%), decreased total Т-lymphocytes, normal CD4+/ CD8+ T-lymphocytes ratio at normal CD4+ and decreased CD8+ Т cells, increased В-lymphocytes were found by flow-cytometry. Serological investigations (ELISA) revealed significant titers of specific IgM antibodies against three different herpesviruses (HSV-1, HSV-2 and Varicella zoster virus). Complex etiologic and supportive treatment was administered. The child had improved after sixth day and was discharged on eleventh day . Hemorrhagic-necrotic form of varicella is rare. It occurs mainly in immunocompromised patients, but immunocompetent individuals also could be affected. This requires the use of broad diagnostic panel for precise etiological diagnosis, which will facilitate the proper treatment and favorable outcome.

Evaluation of 2 multiplex real-time PCR assays for the detection of HSV-1/2 and Varicella zoster virus directly from clinical samples

We compared the performance of 2 multiplex assays (Focus Simplexa and Quidel Lyra) to individual real-time PCR for the detection of herpes simplex virus-1 (HSV-1), HSV-2, and Varicella zoster virus (VZV) from clinical specimens. Results were compared to a consensus standard, defined as the result obtained by at least 2 of the 3 molecular methods. The sensitivity of the Quidel assay ranged from 92.0% for HSV-1 to 97.7% for HSV-2, while the specificity for all targets was 100%. The Focus assay demonstrated 100% sensitivity for all targets, and the percent specificity ranged from 96.8% for HSV-1 to 100% for HSV-2 and VZV.

Human herpes simplex virus: life cycle and development of inhibitors.

WHO reports that 90% of human population is infected by different types of herpesviruses, which develop latency or cause oral and genital herpes, conjunctivitis, eczema herpeticum, and other diseases. Herpesvirus almost always accompanies HIV-infection and complicates AIDS treatment. Herpes simplex virus type 1 is one of the most wide spread viruses from the Herpesviridae family. HSV virion, genome structure, replication mechanisms, antiherpes drug development strategies, including design of prodrugs, and mutations causing ACV-resistance in clinical HSV isolates are discussed in this review.

ET-17 * TRANSIENT FASTING ENHANCES REPLICATION AND THERAPEUTIC ACTIVITY OF ONCOLYTIC HSV IN GLIOBLASTOMA THERAPY

BACKGROUND AND OBJECTIVE: Short term fasting has been shown to enhance efficacy of chemotherapy by sensitizing tumor cells and protecting normal cells in a variety of cancer models including glioblastoma (GBM). Malignant cells, unlike normal cells, respond to fasting by promoting oncogenic signaling and protein synthesis, which could in turn sensitize them to anti-cancer agents, broadening therapeutic window. We hypothesize that fasting increases replication of oncolytic herpes simplex virus (oHSV) and its oncolytic activity in glioblastoma. MATERIALS AND METHODS: Patient-derived GBM cell lines, MGG8F and MGG29F, were subjected to transient fasting by switching culture medium [DMEM (4.5 g/L of glucose) supplemented with 10% fetal calf serum (FCS)] to DMEM with low glucose (0.5 g/L) and 1% FCS. oHSV G47Δ [ϒ34.5(-), ICP6 (-), LacZ (+), α47 (-)], currently tested in a phase I/II trial for recurrent GBM, and its derivative G47Δ-US11fluc, expressing firefly luciferase driven by the late US11 promoter, were used to investigate the impacts of short term fasting on late HSV gene expression, virus yields and tumor cell killing. RESULTS: 24-hour fasting followed by 24-hour recovery with regular medium increased luciferase expression after G47Δ-US11fluc infection of MGG8F and MGG29F cells. Transient fasting mediated 2-3-fold increase in G47Δ yields in both GBM cells, but not in normal human astrocytes. Although transient fasting alone did not alter cell growth, it significantly enhanced G47Δ killing of GBM cells in vitro. In vivo, 48-hour food restriction doubled luciferase activity and caused no toxicity when G47Δ-US11fluc was intratumorally injected in orthotopic MGG8F xenografts. CONCLUSION: Transient fasting increased viral replication of G47Δ and strengthened its oncolytic activity in GBM cells. These results suggest that transient fasting may be effectively combined to enhance oncolytic HSV therapy of GBM.

The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling.

Viral DNA sensing within the cytosol of infected cells activates type I interferon (IFN) expression. MITA/STING plays an essential role in this pathway by acting as both a sensor for the second messenger cGAMP and as an adaptor for downstream signaling components. In an expression screen for proteins that can activate the IFNB1 promoter, we identified the ER-associated protein ZDHHC1 as a positive regulator of virus-triggered, MITA/STING-dependent immune signaling. Zdhhc1(-/-) cells failed to effectively produce IFNs and other cytokines in response to infection with DNA but not RNA viruses. Zdhhc1(-/-) mice infected with the neurotropic DNA virus HSV-1 exhibited lower cytokine levels and higher virus titers in the brain, resulting in higher lethality. ZDHHC1 constitutively associated with MITA/STING and mediates dimerization/aggregation of MITA/STING and recruitment of the downstream signaling components TBK1 and IRF3. These findings support a role for ZDHHC1 in mediating MITA/STING-dependent innate immune response against DNA viruses.

Clinico-immunohistochemical aspects of recovery of reproductive function of women with chronic endometritis

20 female patients aged 18-40 years old with a complicated anamnesis have been examined. Besides the regular clinical analysis the Pipel-byopsy was carried out with the immunohistochemical and histological investigation of the material. The expression level of estrogen and progesterone receptors has been determined. As well as the antigens of HSV, CMV and Epstein-Barr virus. In the case when chronic endometritis was diagnosed with the appearance of any of the viruses, the immunomodulating and antiviral therapy was administered. In the treatment of chronic endometritis associated with herpes simplex virus is advisable to administer an antiviral drug cour at least 3 months.