Replication Of Hepatitis Research Articles

STAT activation in regulatory CD4+ T cells of patients with primary sclerosing cholangitis.

Regulatory CD4+ T cells (Tregs) are pivotal for inhibition of autoimmunity. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology where contribution of Tregs is still unclear. Activation of the JAK-STAT pathway critically modifies functions of Tregs. In PSC, we studied activation of STAT proteins and Treg functions in response to cytokines. In 51 patients with PSC, 10 disease controls (chronic replicative hepatitis C), and 36 healthy controls we analyzed frequencies of Foxp3+CD25+CD127lowCD4+ Tregs, their expression of ectonucleotidase CD39, and cytokine-induced phosphorylation of STAT1, 3, 5, and 6 using phospho-flow cytometry. In parallel, we measured cytokines IFN-gamma, interleukin (IL)-6, IL-2, and IL-4 in serum via bead-based immunoassays. In patients with PSC, ex vivo frequencies of peripheral Tregs and their expression of CD39 were significantly reduced (p < .05 each). Furthermore, serum levels of IFN-gamma, IL-6, IL-2, and IL-4 were markedly higher in PSC (p < .05 each). Unlike activation of STAT1, STAT5, and STAT6, IL-6 induced increased phosphorylation of STAT3 in Tregs of PSC-patients (p = .0434). Finally, STAT3 activation in Tregs correlated with leukocyte counts. In PSC, we observed enhanced STAT3 responsiveness of CD4+ Tregs together with reduced CD39 expression probably reflecting inflammatory activity of the disease.

Furanocoumarins promote proteasomal degradation of viral HBx protein and down-regulate cccDNA transcription and replication of hepatitis B virus

Nucleot(s)ide analogues, the current antiviral treatments against chronic hepatitis B (CHB) infection, are non-curative due to their inability to eliminate covalently closed circular DNA (cccDNA) from the infected hepatocytes. Preclinical studies have shown that coumarin derivatives can effectively reduce the HBV DNA replication. We evaluated the antiviral efficacy of thirty new coumarin derivatives in cell culture models for studying HBV. Furanocoumarins Fc-20 and Fc-31 suppressed the levels of pre-genomic RNA as well as cccDNA, and reduced the secretion of virions, HBsAg and HBeAg. The antiviral efficacies of Fc-20 and Fc31 improved further when used in combination with the hepatitis B antiviral drug Entecavir. There was a marked reduction in the intracellular HBx level in the presence of these furanocoumarins due to proteasomal degradation resulting in the down-regulation of HBx-dependent viral genes. Importantly, both Fc-20 and Fc-31 were non-cytotoxic to cells even at high concentrations. Further, our molecular docking studies confirmed a moderate to high affinity interaction between furanocoumarins and viral HBx via residues Ala3, Arg26 and Lys140. These data suggest that furanocoumarins could be developed as a new therapeutic for CHB infection.

Prospective comparison of liver stiffness measurement methods in surveillance biopsies after liver transplantation.

Liver stiffness measurements (LSMs) have proven useful for non-invasive detection of fibrosis. Previous studies of LSMs after transplantation were performed in cohorts dominated by hepatitis C reinfections and indication biopsies for the evaluation of graft dysfunction. However, the diagnostic fidelity of LSMs for fibrosis is biased by inflammation e.g., during replicative hepatitis C or rejection. The current study aimed for a head-to-head comparison of two different LSMs, acoustic radiation force impulse (ARFI) and transient elastography (TE), and a determination of cut-off values for the detection of advanced fibrosis (any LAF score component ≥2) in grafts undergoing surveillance biopsies (svLbx) without recurrent hepatitis C. 103 svLbx were paired with valid LSMs at time of biopsy. AUROC analyses showed significant positive correlation with fibrosis for both methods (TE: AUROC = 0.819 (p < 0.001; 95%CI: 0.717-0.921); ARFI: AUROC = 0.771 (p = 0.001; 95%CI: 0.652-0.890). Patients were randomly assigned to training and validation cohorts for both LSM methods. Cut-off values were determined at 1.29 m/s (ARFI) and at 7.5 kPa (TE) in training cohorts. Sensitivity and specificity in training and validation cohorts were: TE: SEN 0.818 and 0.5; SPE 0.742 and 0.885; ARFI: SEN 0.818 and 1.0; SPE 0.75 and 0.586. LSMs were not associated with BANFF criteria for relevant graft injury. LSM is a good non-invasive tool to screen for advanced graft fibrosis but not for relevant graft injury in patients with (near) normal liver enzymes. Fibrosis cut-off values identified and validated in svLbx were lower than in previous cohorts using indication biopsies.

Peptide YY inhibits transcription and replication of hepatitis B virus by suppressing promoter/enhancer activity.

Hepatitis B virus (HBV) infection is a noteworthy cause of liver diseases, especially cirrhosis and hepatocellular carcinomas. However, the interaction between the host and HBV has not been fully elucidated. Peptide YY (PYY) is a 36-amino-acid gastrointestinal hormone that is mainly involved in the regulation of the human digestive system. This study found that PYY expression was reduced in HBV-expressing hepatocytes and HBV patients. Overexpression of PYY could significantly inhibit HBV RNA, DNA levels, and the secretion of HBsAg. In addition, PYY inhibits HBV RNA dependent on transcription through reducing the activities of CP/Enh I/II, SP1 and SP2. Meanwhile, PYY blocks HBV replication independent on core, polymerase protein and ε structure of pregenomic RNA. These results suggest that PYY can impair HBV replication by suppressing viral promoters/enhancers in hepatocytes. Our data shed light on a novel role for PYY as anti-HBV restriction factor.

Study on the role of histone epigenetic modification in replication of hepatitis B virus

Hepatitis B virus (HBV) infection is a global health problem and lacks effective therapies in clinic. This study attempted to investigate the role of histone deacetylase 3 (HDAC3) in HBV replication. Cells were treated with 1.3 folds of HBV genome. The expression patterns of HDAC3, miR-29a-3p, and nuclear factor of activated T-cells 5 (NFAT5) in cells were determined by real-time quantitative polymerase chain reaction and Western blot analysis. HBV replication was assessed by measurements of HBV DNA, HBV RNA, hepatitis B surface antigen, and hepatitis B E antigen. After chromatin immunoprecipitation and RNA pull-down assays to testify gene interactions, rescue experiments and animal experiments were performed to assess the role of miR-29a-3p/NFAT5 in HBV replication and the role of HDAC3 in vivo. HDAC3 level was decreased by pHBV1.3 plasmid in a concentration-dependent manner. HDAC3 overexpression can inhibit HBV replication, which was neutralized by miR-29a-3p overexpression or NFAT5 downregulation. Mechanically, HDAC3 overexpression reduced the enrichment of histone 3 lysine 9 acetylation on the miR-29a-3p promoter to inhibit miR-29a-3p expression and then promote NFAT5 transcription. In vivo, HDAC3 restrained HBV replication through the miR-29a-3p/NFAT5 axis. Overall, HDAC3 downregulation was associated with HBV replication and HDAC3 overexpression inhibited HBV replication through H3K9ac/miR-29a-3p/NFAT5.

A RNase P Ribozyme Inhibits Gene Expression and Replication of Hepatitis B Virus in Cultured Cells.

Hepatitis B virus (HBV), an international public health concern, is a leading viral cause of liver disease, such as hepatocellular carcinoma. Sequence-specific ribozymes derived from ribonuclease P (RNase P) catalytic RNA are being explored for gene targeting applications. In this study, we engineered an active RNase P ribozyme, M1-S-A, targeting the overlapping region of HBV S mRNA, pre-S/L mRNA, and pregenomic RNA (pgRNA), all deemed essential for viral infection. Ribozyme M1-S-A cleaved the S mRNA sequence efficiently in vitro. We studied the effect of RNase P ribozyme on HBV gene expression and replication using the human hepatocyte HepG2.2.15 culture model that harbors an HBV genome and supports HBV replication. In these cultured cells, the expression of M1-S-A resulted in a reduction of more than 80% in both HBV RNA and protein levels and an inhibition of about 300-fold in the capsid-associated HBV DNA levels when compared to the cells that did not express any ribozymes. In control experiments, cells expressing an inactive control ribozyme displayed little impact on HBV RNA and protein levels, and on capsid-associated viral DNA levels. Our study signifies that RNase P ribozyme can suppress HBV gene expression and replication, implying the promise of RNase P ribozymes for anti-HBV therapy.

Correction to: High dose of bile acid enables the cellular entry and replication of hepatitis C virus in vitro

Correction to: High dose of bile acid enables the cellular entry and replication of hepatitis C virus in vitro

High dose of bile acid enables the cellular entry and replication of hepatitis C virus in vitro

High dose of bile acid enables the cellular entry and replication of hepatitis C virus in vitro

Senescence and oxidative stress toxicities induced by lamivudine and tenofovir in Drosophila melanogaster

Lamivudine and tenofovir disoproxil fumarate act against the replication of hepatitis B and human immunodeficiency viruses via inhibition of the reverse transcriptase enzyme activity, thereby preventing the synthesis of viral DNA. Chronic administration of these drugs has been associated with toxicities, including senescence, oxidative stress and premature death. A study of these toxicities in Drosophila melanogaster, which share 75% genomic similarity with humans could help to develop a pharmacologic intervention. Susceptibility of D.melanogaster for lamivudine and tenofovir-induced toxicities were investigated. First, flies (≤3 days old) were fed with drugs-supplemented diet at varying concentrations (1mg to 300mg/10-gram diet) or distilled water for seven days to determine LD50. Secondly, five groups of 60 flies were fed with four concentrations of test drugs: 2.9mg, 5.82mg, 11.64mg and 23.28mg each per 10-gram diet for 28 days survival and lifespan assays. Then 5-day treatment plan was utilized to determine drugs toxicities on climbing ability and some biomarkers of oxidative stress. Finally, molecular docking was carried out using the Auto-dock vina mode to predict the biological interactions between the test drugs and D.melanogaster acetylcholinesterase (AChE) or glutathione-S-transferase (GST). The LD50 of lamivudine or tenofovir was 47.07 or 43.95mg/10g diet, respectively. Each drug significantly (P<0.05) reduced the survival rate, longevity and climbing performance of the flies dose-dependently. These drugs also altered levels of biochemical parameters: AChE, GST, superoxide dismutase (SOD), catalase (CAT), total thiol (T-SH), and malondialdehyde (MDA) of the flies significantly (P<0.05). In silico molecular analysis showed that the test drugs interacted with significantly (P<0.05) higher binding affinities at the same catalytic sites of D.melanogaster GST and AChE compared with substrates (glutathione or acetylcholine). The significant lamivudine and tenofovir-induced toxicities observed as increased mortality, climbing deficits and compromised antioxidant defence in D.melanogaster demands further research for possible pharmacological intervention.

Effects of new bone marrow mesenchymal stem cell (BMSC)-liposome nanoparticles on DNA methylation status of hepatitis B-related liver cancer

Primary liver cancer is the most common tumor in China, with high morbidity and mortality. Nanotechnology has made continuous progress in recent years. In this study, new liposome nanoparticles were used to assemble the bone marrow mesenchymal stem cell (BMSC)-liposome nano-drug delivery system, to explore molecular mechanism of this technology in anti-HBV-related liver cancer. In this study, human hepatitis Brelated liver cancer cells were exposed to the novel BMSC-liposome nano-drug delivery system, and specific methylation analysis PCR (MSP) was used to detect cell apoptosis. Flow cytometry analysis was used to test cell cycle. Proliferation of human hepatitis B-related liver cancer cell line HepG2 was analyzed by MTT, while DNA methyltransferase (DNMT)/hepatitis B virus X protein (HBx) methylation status was detected by real time PCR. The new liposomal nanoparticle BMSC nano-drug delivery system increased the rate of cell apoptosis, inhibited the proliferation of HepG2, and blocked the cells in the G2/M phase. In addition, the new liposomal nanoparticle BMSC nano-drug delivery system reduced the content of hepatitis B virus X protein (HBx) in the HepG2 cells, and regulated virus replication by controlling the expression of methyltransferase (DNMT). DNA methylation level is one of the criteria for evaluating virus replication. The results from this study suggest that low-level methylation can contribute to the occurrence and development of tumors, and regional CpG island hypermethylation can increase DNase, to effectively promote the development of viral related diseases. HBx can effectively promote the progress of liver cancer through the expression of DNMT. In this study, a novel BMSC-liposome drug delivery system effectively controlled the replication of hepatitis B virus and increased the apoptosis of liver cancer cells. This process is closely related to inhibition of DNA methylase and promotion of HBx methylation.

Effects of miR-185-5p on replication of hepatitis C virus.

This article was designed to explore the effects and mechanisms of miR-185-5p on the replication of hepatitis C virus (HCV). Quantitative reverse transcription PCR (qRT-PCR) was performed for detecting the abundance of miR-185-5p and HCV RNA in HCV-infected primary hepatocytes and Huh7.5 cells. Dual-luciferase reporter gene assay was used for exploring the interaction between miR-185-5p and GALNT8. Western blot analyzed protein expression of GALNT8, NS3, and NS5A. miR-185-5p was remarkably downregulated in HCV-infected primary hepatocytes and Huh7.5 cells. miR-185-5p upregulation inhibited HCV RNA expression, while its inhibition promoted HCV replication. miR-185-5p induced accumulation of NS3 and NS5A in the cells. Dual-luciferase reporter gene assay verified the targeted relationship between miR-185-5p and GALNT8. In addition, the effects of overexpressing or knocking down miR-185-5p on HCV replication could be correspondingly eliminated by the overexpression or knockdown of GALNT8. miR-185-5p may target GALNT8 in JFH1-infected Huh7.5 cells and then inhibit HCV replication. miR-185-5p may be a potential target for treating HCV.

Cyclophilins and Their Roles in Hepatitis C Virus and Flavivirus Infections: Perspectives for Novel Antiviral Approaches.

Cyclophilins are cellular peptidyl-prolyl isomerases that play an important role in viral infections, with demonstrated roles in the replication of hepatitis C virus (HCV) and other viruses in the Flaviviridae family, such as dengue virus (DENV) and yellow fever virus (YFV). Here, we discuss the roles of cyclophilins in HCV infection and provide a comprehensive overview of the mechanisms underlying the requirement for cyclophilins during HCV replication. Notably, cyclophilin inhibitor therapy has been demonstrated to be effective in reducing HCV replication in chronically infected patients. While the roles of cyclophilins are relatively well-understood for HCV infection, cyclophilins are more recently emerging as host factors for flavivirus infection as well, providing potential new therapeutic avenues for these viral infections which currently lack antiviral therapies. However, further studies are required to elucidate the roles of cyclophilins in flavivirus replication. Here, we review the current knowledge of the role of cyclophilins in HCV infection to provide a conceptual framework to understand how cyclophilins may contribute to other viral infections, such as DENV and YFV. Improved understanding of the roles of cyclophilins in viral infection may open perspectives for the development of cyclophilin inhibitors as effective antiviral therapeutics for HCV and related viruses.

Use of sofosbuvir-based regimens in the treatment of adolescents and children with chronic hepatitis C

Sofosbuvir has ushered in a new era of hepatitis C treatment with its strong inhibition on the replication of hepatitis C virus, favorable safety profile and less interactions with other drugs. Sofosbuvir-based regimens have been included as the first-line therapies for the treatment of adults with chronic hepatitis C (CHC) in international guidelines. Available clinical trial data show that sofosbuvir with ribavirin and ledipasvir/sofosbuvir are highly efficacious and safe in CHC patients aged 3-17 years old; therefore, they can meet the unmet medical needs of adolescents and children with CHC in China. Furthermore, the pan-genotypic sofosbuvir/velpatasvir is being investigated in adolescents and children with CHC, which is expected to make the treatment in such patients more convenient upon approval.

Preparation and functional evaluation of monoclonal antibodies targeting Hepatitis B Virus Polymerase

ABSTRACT HBV pol plays a critical role in the replication of hepatitis B virus (HBV). Previous studies conducted on HBV pol have produced limited evidence on HBV pol expression due to the lack of effective detection methods. The present study used the HBV pol (159–406 aa) protein as a target to screen for specific monoclonal antibodies that recognize HBV pol and subsequently evaluate their diagnostic and therapeutic value. Four antibodies (P3, P5, P12, P20) against HBV pol were obtained. Among them, the P20 antibody indicated optimal binding with HBV pol as demonstrated by Western blotting (WB) in a cell model transfected with the HBV genome. We also expressed P5 and P12 antibodies in mouse liver cells by transfection and the results indicated significant antiviral effects caused by these two antibodies especially P12. In summary, the present study established an antibody which was denoted P20. This antibody can be used to detect HBV pol expression by four HBV genomes via WB analysis. In addition, the antibody denoted P12 could exert antiviral effects via intracellular expression, which may provide a promising approach for the treatment of chronic hepatitis B.

Evaluation for the Genetic Association between Store-Operated Calcium Influx Pathway (STIM1 and ORAI1) and Human Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Infection.

Simple SummaryIn this study, we systematically evaluated the genetic susceptibility between the store-operated calcium (SOC) influx pathway (stromal interaction molecule 1 (STIM1) and ORAI1) and human hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) infection. In total, 3631 patients with CHB were recruited, forty polymorphisms of STIM1 and ORAI1 were comprehensively analyzed. Three single-nucleotide polymorphisms (SNPs) of STIM1 (rs6578418, rs11030472, and rs7116520) and one SNP of ORAI1 (rs6486795) showed a trend of being significantly associated with HCC. In particular, our functional studies (images from total internal reflection fluorescence microscopy and transwell migration assay) revealed that calcium (Ca2+) signaling is essential for the migration of HCC. Based on such a comprehensively screening in 3631 patients with chronic hepatitis, our results indicate the important role of store-operated calcium pathways in HCC.Hepatocellular carcinoma (HCC) often develops from chronic hepatitis B (CHB) through replication of hepatitis B virus (HBV) infection. Calcium (Ca2+) signaling plays an essential role in HBV replication. Store-operated calcium (SOC) channels are a major pathway of Ca2+ entry into non-excitable cells such as immune cells and cancer cells. The basic components of SOC signaling include the STIM1 and ORAI1 genes. However, the roles of STIM1 and ORAI1 in HBV-mediated HCC are still unclear. Thus, long-term follow-up of HBV cohort was carried out in this study. This study recruited 3631 patients with chronic hepatitis (345 patients with HCC, 3286 patients without HCC) in a Taiwanese population. Genetic variants of the STIM1 and ORAI1 genes were detected using an Axiom CHB1 genome-wide array. Clinical associations of 40 polymorphisms were analyzed. Three of the STIM1 single-nucleotide polymorphisms (SNPs) (rs6578418, rs7116520, and rs11030472) and one SNP of ORAI1 (rs6486795) showed a trend of being associated with HCC disease (p < 0.05). However, after correction for multiple testing, none of the SNPs reached a significant level (q > 0.05); in contrast, neither STIM1 nor ORAI1 showed a significant association with HCC progression in CHB patients. Functional studies by both total internal reflection fluorescence images and transwell migration assay indicated the critical roles of SOC-mediated signaling in HCC migration. In conclusion, we reported a weak correlation between STIM1/ORAI1 polymorphisms and the risk of HCC progression in CHB patients.

INVITRO STUDY FOR THE OPTIMAL PRODUCTION OF HEPATITIS B VIRUS SUBVIRAL PARTICLES FOR MEDICAL PURPOSES

During replication of hepatitis B virus (HBV), HBV infected cells secrete infectious viral particles and large quantities of subviral particles which are assembled from surface protein without a viral genome. For the current study, the cell line of HepG2.2.15 genetically integrated with the HBV surface region was cultured as an expression system for in vitro production of hepatitis B virus subviral particles (HBVsvp) at different time for commercial purposes. Recorded Results showed that culturing and incubation of HepG2.2.15 cells over 7 days incubation period resulted in continuous secretion of HBsvp in the supernatant. ELISA's quantitative measurement of hepatitis B surface antigen reported that the highest titer of virus was day seven. Quantitative detection of HBsAg by ELISA indicated that the highest virus titer was at day seven. According to their size, subviral spherical particles recognized by a diameter of 22 nm. In conclusion, in vitro cultivation and incubation of HepG2.2.15 for secretion of HBsAg may be used in studying HBV replication thus, opening a new era for various studies from basic virology, in vitro diagnosis, to drug development against HBV genotypes.

Replication of Hepatitis E Virus (HEV) in Primary Human-Derived Monocytes and Macrophages In Vitro.

HEV is the most causative agent of acute viral hepatitis globally. HEV causes acute, chronic, and extrahepatic manifestations. Chronic HEV infection develops in immunocompromised patients such as organ transplant patients, HIV-infected patients, and leukemic patients. The source of chronic HEV infection is not known. Also, the source of extrahepatic manifestations associated with HEV infection is still unclear. Hepatotropic viruses such as HCV and HBV replicate in peripheral blood mononuclear cells (PBMCs) and these cells become a source of chronic reactivation of the infections in allograft organ transplant patients. Herein, we reported that PBMCs and bone marrow-derived macrophages (BMDMs), isolated from healthy donors (n = 3), are susceptible to HEV in vitro. Human monocytes (HMOs), human macrophages (HMACs), and human BMDMs were challenged with HEV-1 and HEV-3 viruses. HEV RNA was measured by qPCR, the marker of the intermediate replicative form (ds-RNA) was assessed by immunofluorescence, and HEV capsid protein was assessed by flow cytometry and ELISA. HEV infection was successfully established in primary HMOs, HMACs, and human BMDMs, but not in the corresponding cells of murine origin. Intermediate replicative form (ds RNA) was detected in HMOs and HMACs challenged with HEV. The HEV load was increased over time, and the HEV capsid protein was detected intracellularly in the HEV-infected cells and accumulated extracellularly over time, confirming that HEV completes the life cycle inside these cells. The HEV particles produced from the infected BMDMs were infectious to naive HMOs in vitro. The HEV viral load was comparable in HEV-1- and HEV-3-infected cells, but HEV-1 induced more inflammatory responses. In conclusion, HMOs, HMACs, and human BMDMs are permissive to HEV infection and these cells could be the source of chronic and recurrent infection, especially in immunocompromised patients. Replication of HEV in human BMDMs could be related to hematological disorders associated with extrahepatic manifestations.

Hepatitis B Virus RNA Profiles in Liver Biopsies by Digital Polymerase Chain Reaction.

Replication of hepatitis B virus (HBV) originates from covalently closed circular DNA (cccDNA) and involves reverse transcription of pregenomic RNA (pgRNA), which is also called core RNA and encodes the capsid protein. The RNA coding for hepatitis B surface antigen (HBsAg) in the envelope of viral or subviral particles is produced from cccDNA or from HBV DNA integrated into the host genome. Because only cccDNA can generate the core and the 3′ redundancy regions of HBV RNA, we aimed to clarify to what extent such HBV integrations are expressed by quantifying the different HBV RNA species in liver tissue. Digital droplet polymerase chain reaction (ddPCR) was employed to quantify six HBV RNA targets in 76 liver biopsies from patients with chronic infection, comprising 14 who were hepatitis B e antigen (HBeAg) positive and 62 who were HBeAg negative. In patients who were HBeAg negative, HBV RNA from the S RNA region was >1.6 log10 units higher than in the core and 3′ redundancy regions (P < 0.0001), indicating that >90% of S RNA was integration derived. HBeAg‐negative samples showed 10 times lower levels of pgRNA (5′ core) compared with core RNA (3′ part of core; P < 0.0001), suggesting that a large proportion of core RNA might have a downstream shift of the transcription starting point. In multiple regression analysis, HBV DNA levels in serum were most strongly dependent on pgRNA. Conclusion: In patients who were HBeAg negative, integration‐derived S RNA seemed to predominate and a large proportion of the core RNA lacked the 5′ part. Because this part comprises the down‐regulator of transcription 1 sequences, which are necessary for virus production (plus strand translocation), the finding might help to explain the low level of HBV DNA in serum that frequently is observed in patients with chronic HBV infection who are HBeAg negative.

Very-long-chain fatty acid metabolic capacity of 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) promotes replication of hepatitis C virus and related flaviviruses

Flaviviridae infections represent a major global health burden. By deciphering mechanistic aspects of hepatitis C virus (HCV)-host interactions, one could discover common strategy for inhibiting the replication of related flaviviruses. By elucidating the HCV interactome, we identified the 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) as a human hub of the very-long-chain fatty acid (VLCFA) synthesis pathway and core interactor. Here we show that HSD17B12 knockdown (KD) impairs HCV replication and reduces virion production. Mechanistically, depletion of HSD17B12 induces alterations in VLCFA-containing lipid species and a drastic reduction of lipid droplets (LDs) that play a critical role in virus assembly. Oleic acid supplementation rescues viral RNA replication and production of infectious particles in HSD17B12 depleted cells, supporting a specific role of VLCFA in HCV life cycle. Furthermore, the small-molecule HSD17B12 inhibitor, INH-12, significantly reduces replication and infectious particle production of HCV as well as dengue virus and Zika virus revealing a conserved requirement across Flaviviridae virus family. Overall, the data provide a strong rationale for the advanced evaluation of HSD17B12 inhibition as a promising broad-spectrum antiviral strategy for the treatment of Flaviviridae infections.

Эффективность энтеросорбции в комплексной терапии вирусного гепатита А у детей

Objective. To evaluate therapeutic efficacy and safety of Enterosgel adsorbent and compare it with standard therapy in children with viral hepatitis Patients and methods. This open-label, prospective, randomized, controlled trial was conducted in the Regional Hospital for Infectious Diseases of Karaganda. We examined 98 children (mean age 10.56 ± 0.36 years) diagnosed with hepatitis A. The diagnosis was verified by identification of the marker reflecting active replication of hepatitis A virus (аnti-HAV IgM) using enzyme-linked immunosorbent assay. We evaluated the dynamics of clinical symptoms and liver function tests, including total bilirubin and its fractions, as well as levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The experimental group included 52 patients who received Enterosgel; the control group comprised 46 patients who received standard for hepatitis A therapy. Results. Enterosgel ensured more rapid resolution of clinical symptoms of acute hepatitis A and normalization of liver function tests compared to patients with the control group. This led to a shorter period of intoxication, vomiting, and jaundice, as well as to reduced ALT, and shorter in-hospital stay. Key words: hepatitis A, intoxication, jaundice, enterosorbent, Enterosgel