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At least 19 recordsLinked to original sources
PubMed2026

EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis.

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide, responsible for approximately 20 million infections annually. Despite the availability of a vaccine in China, no direct-acting antivirals are approved, and host factors required for HEV replication remain poorly defined. Here, using a genome-wide CRISPR/Cas9 knockout screen in a replicon system, we identified Eukaryotic Translation Initiation Factor 4H (EIF4H) and Y-Box Binding Protein 1 (YBX1) as essential host factors for HEV replication and pathogenesis. Knockout of either factor markedly impaired replication of HEV genotypes 1, 3, and 4, as well as HEV infection and production in hepatocellular carcinoma cells and human induced pluripotent stem cell-derived hepatocyte-like cells, while leaving SARS-CoV-2, hepatitis B virus, hepatitis C virus, and Zika virus unaffected, underscoring their HEV-specific roles. Mechanistically, EIF4H interacts with ORF1 via its methyltransferase-Y-papain-like protease region, and EIF4H deficiency alters the composition of the ORF1-associated replication complex. By contrast, YBX1 is dispensable for ORF1 translation and RNA binding but is specifically required for ORF1 proteolytic processing, a prerequisite for assembling a functional replication machinery. EIF4H knockout rats and liver-specific YBX1 knockout rats were largely resistant to rat HEV-C1 infection, showing profound reductions in viral shedding, suppressed hepatic and intestinal viral loads, and protection from liver pathology. Together, our findings establish EIF4H and YBX1 as essential host factors for HEV infection and pathogenesis and reveal potential targets for antiviral intervention.

Virus Replication↗
PubMed2026

Host-interferon-stimulated gene response to virus-host recombinant variants of hepatitis E virus and enhanced viral replication.

The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. HEV infection can become chronic in immunocompromised individuals, in whom virus-host recombinant variants (VHRVs) can be detected. These variants often harbor host-derived insertions in the polyproline-rich region (PPR), and most display enhanced replication in vitro. However, the mechanisms underlying this replicative advantage remain unclear. It is likely that genes of the infected cells are differentially expressed according to the replicative capacity of the strain. The host factors involved in the improvement of the replicative capacity of these VHRVs are yet to be identified.In this study, we analyzed the host transcriptional response to seven VHRVs in HepG2/C3A cells using bulk RNA sequencing at 48 h and 168 h post-infection. Five VHRVs (RNF19A, ZNF787, KIF1B, RPS17, EEF1A1) previously associated with a high replication rate induced more significant, distinct transcriptomic changes than low-replicative variants (RNA18, RPL6), particularly at 168 h. A shared set of 25 genes, especially interferon-stimulated genes (ISGs), was upregulated in cells infected with high-replicating variants. Interestingly, ISG induction was limited at 48 h despite high viral RNA concentrations, suggesting a delayed antiviral response. At 168 h, high ISG expression coincided with high viral loads, indicating that VHRVs may evade or exploit immune defenses. Our findings reveal candidate ISGs such as IFIT1 and ISG15 that may influence HEV persistence and immune escape. These results offer new insights into the interplay between VHRV replication and host immunity.IMPORTANCEHepatitis E virus (HEV) is a major cause of acute hepatitis and can cause chronic infections in immunocompromised individuals. Virus-host recombinant variants (VHRVs) having integrated host-derived insertions often replicate more effectively, yet the host determinants of this phenotype remain unclear. With RNA sequencing of HepG2/C3A-infected cells, we observed that high-replicating VHRVs induce a delayed but strong expression of interferon-stimulated genes (ISGs), including IFIT1 and ISG15, despite high viral loads. These results suggest that VHRVs may transiently modulate or evade aspects of host antiviral defenses. Our study revealed host transcriptional patterns associated with enhanced viral replication, providing insight into potential mechanisms that enhance HEV replication and highlighting candidate pathways that could influence the interplay between viral replication and immune responses, all requiring further investigation.

Humans↗
PubMed1978

Purification and partial characterization of hepatitis e antigen (HBeAg).

Purification of hepatitis e antigen (HBeAg) from 200 ml of chimpanzee plasma was accomplished by a combination of ion-exchange chromatography on diethylaminoethyl-cellulose followed by gel filtration. High-resolution sodium dodecyl sulfate-polyacrylamide gel electrophoresis of purified HBeAg demonstrated two major polypeptides with estimated molecular weights of 22,000 and 55,000. HBeAg labeled with 125I showed a high affinity for protein A-conjugated Sepharose CL-4B. The precipitation reaction between HBeAg and anti-HBe was inhibited by preincubating the purified antigen with rabbit anti-human immunoglobulin G (IgG). These data show that HBeAg is associated with a serum fraction with the biophysical and antigenic properties of an immunoblobulin of the IgG class. Sedimentation coefficient analysis of purified HbeAg resulted in an S20w value of 11.6 and a molecular weight value of 324,000. These findings, supported by gel filitration and polyacrylamide gradient gel electrophoresis, revealed that HBeAg has properties analogous to those of a dimer of IgG.

Animals↗
PubMed2026

The Differential Effects of Immunosuppressants on Hepatitis E Virus Replication and the Triggered Inflammatory Responses in Macrophages.

Organ transplant recipients are at high risk of developing chronic infection when exposed to hepatitis E virus (HEV), which can rapidly progress to liver fibrosis and cirrhosis. Macrophages play a key role in the response to the infection and disease progression. However, the interactions amongst immunosuppressants, macrophages, the course of HEV infection and activation of inflammatory response remain unclear. In this study, we generated M0, M1 and M2 macrophages from the human THP-1 cell line. These macrophages were then infected with HEV and treated with different immunosuppressants. We visualised viral infection using laser confocal microscopy, and quantitatively analysed viral replication and inflammatory responses by bulk sequencing, RT-qPCR, ELISA and Western blotting. We found that the M1 inflammatory macrophages exhibited the highest, while M2 macrophages had the lowest levels of viral RNA. Genome-wide transcriptome analysis indicated that viral, inflammation and immunity-related pathways were predominantly upregulated by HEV infection. Dexamethasone exerted potent inhibitory effects on inflammatory response in macrophages. Mycophenolic acid (MPA) demonstrated inhibitory effects on viral replication, IL-1β and TNF-α expression, whereas mTOR inhibitors had the opposite effects, and tacrolimus showed no clear effect. In conclusion, immunosuppressants can differentially affect HEV replication and the subsequent inflammatory responses in macrophages.

Humans↗
PubMed2025

Genetic characterization of rat hepatitis E virus (Rocahepevirus ratti) in urban brown rats (Rattus norvegicus) in Helsinki, Finland.

We report complete and partial genome sequences of rat hepatitis E virus (RHEV, Rocahepevirus ratti), from archived brown rats captured in Helsinki, Finland. Phylogenetic analysis confirmed the presence of the pathogenic RHEV genotype C1 in the Helsinki region. Finnish strains clustered together with strains from South Korea and Spain. However, the polytomous topology of phylogenetic trees and the large genetic distances between spatially distinct strains suggest that RHEV has remained inadequately sampled on a global scale. Further surveillance of rocahepeviruses is needed to assess their threat to public health and to understand their diversity and evolutionary patterns.

Animals↗
PubMed1978

Radioimmunoassay for the detection of hepatitis e antigen (HBeAG) and antibody (anti-HBe).

A solid phase micro-immunoradiometric assay (micro-SPIRA) for the detection of hepatitis e antigen (HBeAg) and antibody has been developed. Chimpanzee anti-HBe/2 was developed by repeated immunizations with purified antigen containing HBeAg/1 and HBeAg/2. An anti-HBe/2 titer of 1:4 was determined by immunodiffusion (ID) analysis. Anti-HBe/1 was not detected. The anti-HBe IgG used in the assay was purified from plasma by a combination of DEAE-cellulose and affinity chromatography. The sensitivity of the micro-SPIRA for antigen and antibody was 193 ng/ml and 65 ng/ml, respectively. By comparing relative endpoint titers obtained by ID to micro-SPIRA, it was determined that micro-SPIRA for antigen and antibody is 320 and greater than 1300 times more sensitive, respectively, than ID. The specificity of the assay was ascertained by the examination of various non-B specimens. The application of the assay to a panel of 50 hepatitis B surface antigen (HBsAg)-positive specimens resulted in an increase in positivity of 18% for antigen and 22% for antibody.

Animals↗
PubMed1979

Demonstration of hepatitis B e antigen in hepatitis B core particles obtained from the nucleus of hepatocytes infected with hepatitis B virus.

Liver tissue infected with hepatitis B virus was homogenized and nuclei were separated by centrifugation. Hepatitis B core particles were obtained from the nucleus by the digestion with pronase followed by ultracentrifugation in a sucrose density gradient. Hepatitis B core particles were then treated with sodium dodecyl sulphate and 2 mercaptoethanol and tested for hepatitis B e antigen (HBeAg) by the haemagglutination method. The antigenicity of HBeAg was clearly demonstrated in hepatitis B core particles so treated, although untreated core particles did not reveal any detectable HBeAg activity. The localization of HBeAg in hepatitis B core particles was further supported by the results of a fluorescent antibody technique. When a frozen section of the liver infected with hepatitis B virus was stained with the specific rabbit antibody against HBeAg labelled with fluorescent isothiocyanate, only nuclei of hepatocytes were stained, in a similar distribution to hepatitis B core antigen visualized by fluorescent antibody against hepatitis B core antigen in a nearby section.

Cell Nucleus↗
PubMed1979

Radioimmunoassay in the detection of the hepatitis B e antigen/antibody system in asymptomatic carriers of hepatitis B surface antigen. Correlation with serum Dane particle associated DNA polymerase activity.

A radioimmunoassay for hepatitis e antigen (HBeAg) and antibody to e (anti-HBe) was developed and sera of 71 asymptomatic chronic carriers of hepatitis B surface antigen (HBsAg), in 44 of whom liver biopsy was obtained, were tested. In addition, testing for Dane particle associated DNA polymerase activity was performed in all sera. HBeAg was detected in 14 subjects (19.7%) and anti-HBe in 46 (64.8%). The highest proportion of HBeAg positivity (40%) was found among carriers with histological evidence of chronic hepatitis, whereas anti-HBe was present in 80% of carriers with normal liver histology, in 58% of carriers with non-specific reactive hepatitis and in 60% of carriers with chronic liver lesions. DNA polymerase activity was present in 92.8% of sera positive for HBeAg, in 13% of sera positive for anti-HBe, and in 9% of sera negative for both markers. Our results demonstrate that not all HBsAg carriers reactive to HBeAg show evidence of chronic hepatitis nor, conversely, that anti-HBe is invariably associated with the healthy carrier state of HBsAg. Finally, circulating Dane particles, as revealed by the presence of serum specific DNA polymerase activity, may also be present in anti-HBe positive sera other than those of some HBsAg carriers lacking both HBeAg and anti-HBe.

Carrier State↗
PubMed1977

Hepatitis B e antigen and infectivity of hepatitis B virus.

For confirmation of the difference in the infectivity of hepatitis B surface antigen (HBS Ag)-positive serum according to differences in the e antigen system, four chimpanzees were inoculated with serum positive for hepatitis B e antigen (HBe Ag), and three chimpanzees were inoculated with serum positive for antibody to HBe Ag (anti-HBe). Since the infectivity titrations are not yet completed, the end infectivity titer of each serum is not known. All four chimpanzees given injections of 10(-1), 10(-4), or 10(-8) dilutions of HBe Ag-positive serum developed hepatitis B virus infection, whereas the one chimpanzee injected with undiluted anti-HBe-positive serum became infected, and other chimpanzees injected with diluted anti-HBe-positive sera did not. As judged from the length of the incubation period before appearance of HBS Ag in blood, there seemed to be a remarkable difference in infectivity between the HBe Ag-positive serum and the anti-HBe-positive serum; the former serum was 10(8) times more infectious than the latter.

Animals↗
PubMed1977

Hepatitis B e antigen and antibody activity in hepatitis B virus infection.

Groups of institutionalized subjects, volunteer blood donors with serologic evidence of asymptomatic hepatitis B virus infection, and patients with acute type B viral hepatitis were studied for the presence of hepatitis B e antigen and antibody in a sequential manner over a period of two to three years. HBeAg was detected in 9.5% of institutionalized residents and volunteer blood donors and in 24% of patients with acute type B viral hepatitis. HBeAg positive subjects frequently had persistently elevated pyruvic glutamic transaminase levels in the serum. Anti HBe activity was observed in 26 to 32% of subjects positive for hepatitis B surface antigen. Long-term follow-up indicated that HBsAg positive subjects with anti HBe did not eventually become seronegative for HBsAg.

Adolescent↗
PubMed1978

Duality of hepatitis B e antigen in serum of persons infected with hepatitis B virus: evidence for the nonidentity of e antigen with immunoglobulins.

Hepatitis B e antigen (HBeAg) is detected in the serum of some persons infected with hepatitis B virus. Owing to a close correlation of HBeAg and hepatitis B virus in the serum, it has been used as a practical indicator of infectivity. Two entities of HBeAg activity physicochemically different from each other were demonstrated in the serum of persons infected with hepatitis B virus. One was associated with a molecule that precipitated in 1.33 M ammonium sulfate solution, was larger than IgG, and had an electrophoretic mobility in the beta- to gamma-globulin regions and an isoelectric point of approximately pH 5.7. In contrast, the other HBeAg activity was associated with a molecule that was soluble in 1.33 M ammonium sulfate solution, was smaller than IgG, and had an electrophoretic mobility in the alpha-globulin region and an isoelectric point at pH 4.8. In spite of their marked physicochemical differences, a line of antigenic identity was clearly observed for them when they were tested against antibody to HBeAg by a them when they were tested against antibody to HBeAg by a double immunodiffusion method. The HBeAg activity associated with the large molecule was completely removed by an affinity column of anti-IgG, whereas the activity of the small molecule was not. These results indicate that, in the serum, HBeAg exists as a molecule smaller than IgG and also in association with IgG.

Electrophoresis, Disc↗
PubMed1979

A partial characterization of hepatitis B e antigen.

Partially purified hepatitis B e antigen (HBeAG) was prepared by ultracentrifugation, ammonium sulfate precipitation, and molecular sieve chromatography of sera obtained from asymptomatic carriers of hepatitis B surface antigen. The antigenic specificity of the HBeAG preparations was investigated further with affinity chromatography. The results indicated that HBeAG is distinct and separable from DNA polymerase activity. Columns coupled with either goat IgG prepared from antiserum to human IgG or antibody to HBeAg bound all detectable HBeAg and bound 31% and 100% of the IgG, respectively, from a partially purified HBeAg preparation. Rate zonal sucrose sedimentation and molecular sieve and ion-exchange chromatography indicated a variability in molecular weight and charge; this finding suggested a heterogenous population of immunoreactivities containing HBeAg. Our preliminary results suggest the existence of an HBeAg-IgG complex.

Carrier State↗
PubMed1979

Active E rosette-forming cells in the peripheral blood of patients with chronic active hepatitis.

E rosette-forming cells (E-RFC) and active E-RFC were studied in the peripheral blood in patients with chronic active hepatitis (CAH), chronic persistent hepatitis (CPH), and in control subjects. A significant reduction in active E-RFC (a subpopulation of T lymphocytes considered actively involved in cell-mediated immune reactions) was found in patients with untreated CAH, both HBSAg positive or negative. In contrast, patients with immunosuppressive-treated CAH showed an increased relative number of active E-RFC. A significant increase in active E-RFC was demonstrable in other immunosuppressive-treated chronic inflammatory disorders. In CPH active E-RFC were not different from normal controls. The number of E-RFC showed a relative and absolute decrease in both CPH and untreated CAH. These studies demonstrate an increase in active E-RFC in immunosuppressive-treated CAH and suggest that prednisone and azathioprine may have a differential effect on T lymphocyte subpopulations.

Adolescent↗
PubMed1977

Hepatitis B "e" antigen: an apparent association with lactate dehydrogenase isozyme-5.

Serums containing the "e" antigen of hepatitis B virus were subjected to electrophoresis in polyacrylamide gel. An extra band appeared in the lactate dehydrogenase isozyme pattern, but this band was undetectable in serums containing antibodies to the e antigenic determinant. Prior separation of the lactate dehydrogenase isozyme-5 fraction by chromatography of serum on minicolumns of diethylaminoethyl-Sephadex-A50 improved electrophoretic identification of the extra band. Neutralization with antibodies to the e antigen as well as by antibodies to the homologous d or y component of the hepatitis B surface antigen removed the extra band; antibodies to the lactate dehydrogenase isozyme-5 removed both the normal and the extra enzymatic band of isozyme-5. This feature of the e antigen provides an assay system for laboratory diagnosis of potential clinical usefulness and suggests its possible role in pathogenesis of hepatocellular injury.

Antibody Specificity↗
PubMed1979

Hepatitis B e antigen, DNA polymerase activity, and infection of household contacts with hepatitis B virus.

To determine if the presence of hepatitis B e antigen (HBeAg) and elevated DNA polymerase activity in the serum of chronic HBeAg carriers indicate increased contagiousness in a household setting, the household contacts of 74 carriers were prospectively evaluated for serologic evidence of hepatitis B infection. Thirty of the HBsAg carriers had HBeAg and 44 had anti-HBe. Twenty-eight HBeAg-positive carriers regularly demonstrated elevated DNA polymerase when serially drawn serum samples were analyzed. None of the anti-HBE-positive carriers demonstrated elevation of DNA polymerase activity. Both household contacts of HBeAg-positive and anti-HBe-positive carriers demonstrated serologic evidence of hepatitis B infection (HBsAg, anti-HBs, and anti-HBc). However, infection was significantly more frequent among spouses and sexual partners of carriers who had either HBeAg (P less than 0.001) or elevated DNA polymerase activity (P less than 0.001). Thus, the data indicate that a particular subpopulation of spouses and sexual partners of hepatitis B carriers are at significantly greater risk for acquiring infection.

Adult↗