glycoprotein-e2--hepatitis-c-virus has been researched along with Disease-Models--Animal* in 13 studies
1 trial(s) available for glycoprotein-e2--hepatitis-c-virus and Disease-Models--Animal
12 other study(ies) available for glycoprotein-e2--hepatitis-c-virus and Disease-Models--Animal
| Article | Year |
|---|---|
Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model.
Infection with hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, there is no approved therapeutic targeting this potentially druggable biomarker.. The anti-HCV activity of a fusion protein consisting of Avaren lectin and the fragment crystallizable (Fc) region of a human immunoglobulin G1 antibody, Avaren-Fc (AvFc) was evaluated through the use of in vitro neutralization assays as well as an in vivo challenge in a chimeric human liver (PXB) mouse model. Drug toxicity was assessed by histopathology, serum alanine aminotransferase, and mouse body weights.. AvFc was capable of neutralizing cell culture-derived HCV in a genotype-independent manner, with 50% inhibitory concentration values in the low nanomolar range. Systemic administration of AvFc in a histidine-based buffer was well tolerated; after 11 doses every other day at 25 mg/kg there were no significant changes in body or liver weights or in blood human albumin or serum alanine aminotransferase activity. Gross necropsy and liver pathology confirmed the lack of toxicity. This regimen successfully prevented genotype 1a HCV infection in all animals, although an AvFc mutant lacking HMG binding activity failed.. These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection, and AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients. Topics: Animals; Antiviral Agents; Disease Models, Animal; Female; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Humans; Immunoconjugates; Lectins; Liver; Male; Mice; Polysaccharides; Recombinant Fusion Proteins; Transplantation Chimera; Viral Envelope Proteins | 2021 |
The core domain of hepatitis C virus glycoprotein E2 generates potent cross-neutralizing antibodies in guinea pigs.
A vaccine that prevents hepatitis C virus (HCV) infection is urgently needed to support an emerging global elimination program. However, vaccine development has been confounded because of HCV's high degree of antigenic variability and the preferential induction of type-specific immune responses with limited potency against heterologous viral strains and genotypes. We showed previously that deletion of the three variable regions from the E2 receptor-binding domain (Δ123) increases the ability of human broadly neutralizing antibodies (bNAbs) to inhibit E2-CD81 receptor interactions, suggesting improved bNAb epitope exposure. In this study, the immunogenicity of Δ123 was examined. We show that high-molecular-weight forms of Δ123 elicit distinct antibody specificities with potent and broad neutralizing activity against all seven HCV genotypes. Antibody competition studies revealed that immune sera raised to high-molecular-weight Δ123 was poly specific, given that it inhibited the binding of human bNAbs directed to three major neutralization epitopes on E2. By contrast, the immune sera raised to monomeric Δ123 predominantly blocked the binding of a non-neutralizing antibody to Δ123, while having reduced ability to block bNAb binding to E2, and neutralization was largely toward the homologous genotype. This increased ability of oligomeric Δ123 to generate bNAbs correlates with occlusion of the non-neutralizing face of E2 in this glycoprotein form.. The results from this study reveal new information on the antigenic and immunogenic potential of E2-based immunogens and provide a pathway for the development of a simple, recombinant protein-based prophylactic vaccine for HCV with potential for universal protection. (Hepatology 2017;65:1117-1131). Topics: Animals; Antibodies, Neutralizing; Antibody Specificity; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epitopes; Genotype; Guinea Pigs; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Random Allocation; Statistics, Nonparametric; Viral Envelope Proteins; Viral Hepatitis Vaccines | 2017 |
Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model.
Lipoprotein components are crucial factors for hepatitis C virus (HCV) assembly and entry. As hepatoma cells producing cell culture-derived HCV (HCVcc) particles are impaired in some aspects of lipoprotein metabolism, it is of upmost interest to biochemically and functionally characterize the in vivo produced viral particles, particularly regarding how lipoprotein components modulate HCV entry by lipid transfer receptors such as scavenger receptor BI (SR-BI). Sera from HCVcc-infected liver humanized FRG mice were separated by density gradients. Viral subpopulations, termed HCVfrg particles, were characterized for their physical properties, apolipoprotein association, and infectivity. We demonstrate that, in contrast to the widely spread distribution of apolipoproteins across the different HCVcc subpopulations, the most infectious HCVfrg particles are highly enriched in apoE, suggesting that such apolipoprotein enrichment plays a role for entry of in vivo derived infectious particles likely via usage of apolipoprotein receptors. Consistent with this salient feature, we further reveal previously undefined functionalities of SR-BI in promoting entry of in vivo produced HCV. First, unlike HCVcc, SR-BI is a particularly limiting factor for entry of HCVfrg subpopulations of very low density. Second, HCVfrg entry involves SR-BI lipid transfer activity but not its capacity to bind to the viral glycoprotein E2. In conclusion, we demonstrate that composition and biophysical properties of the different subpopulations of in vivo produced HCVfrg particles modulate their levels of infectivity and receptor usage, hereby featuring divergences with in vitro produced HCVcc particles and highlighting the powerfulness of this in vivo model for the functional study of the interplay between HCV and liver components. Topics: Animals; Apolipoproteins E; Cell Line; Disease Models, Animal; Hepacivirus; Hepatitis C; Humans; Liver; Mice; Mice, Knockout; Scavenger Receptors, Class B; Viral Envelope Proteins; Virus Internalization | 2015 |
Antiviral lectins from red and blue-green algae show potent in vitro and in vivo activity against hepatitis C virus.
Hepatitis C virus (HCV) infection is a significant public health problem with over 170,000,000 chronic carriers and infection rates increasing worldwide. Chronic HCV infection is one of the leading causes of hepatocellular carcinoma which was estimated to result in ∼10,000 deaths in the United States in the year 2011. Current treatment options for HCV infection are limited to PEG-ylated interferon alpha (IFN-α), the nucleoside ribavirin and the recently approved HCV protease inhibitors telaprevir and boceprevir. Although showing significantly improved efficacy over the previous therapies, treatment with protease inhibitors has been shown to result in the rapid emergence of drug-resistant virus. Here we report the activity of two proteins, originally isolated from natural product extracts, which demonstrate low or sub-nanomolar in vitro activity against both genotype I and genotype II HCV. These proteins inhibit viral infectivity, binding to the HCV envelope glycoproteins E1 and E2 and block viral entry into human hepatocytes. In addition, we demonstrate that the most potent of these agents, the protein griffithsin, is readily bioavailable after subcutaneous injection and shows significant in vivo efficacy in reducing HCV viral titers in a mouse model system with engrafted human hepatocytes. These results indicate that HCV viral entry inhibitors can be an effective component of anti-HCV therapy and that these proteins should be studied further for their therapeutic potential. Topics: Animals; Antiviral Agents; Cell Line; Chlorophyta; Disease Models, Animal; Genotype; Hepacivirus; Hepatitis C; Humans; Mice; Models, Molecular; Plant Lectins; Protein Binding; Protein Conformation; Rhodophyta; Viral Envelope Proteins; Viral Load; Virus Internalization; Virus Replication | 2013 |
Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees.
Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log(10) reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation. Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Cell Line; Disease Models, Animal; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Hepatitis C, Chronic; Humans; Liver Transplantation; Mutation; Neutralization Tests; Pan troglodytes; RNA, Viral; Tetraspanin 28; Viral Envelope Proteins; Viral Load | 2012 |
Tupaia CD81, SR-BI, claudin-1, and occludin support hepatitis C virus infection.
Hepatitis C virus (HCV)-related research has been hampered by the lack of appropriate small-animal models. It has been reported that tree shrews, or tupaias (Tupaia belangeri), can be infected with serum-derived HCV. However, these reports do not firmly establish the tupaia as a reliable model of HCV infection. Human CD81, scavenger receptor class B type I (SR-BI), claudin 1 (CLDN1), and occludin (OCLN) are considered essential receptors or coreceptors for HCV cell entry. In the present study, the roles of these tupaia orthologs in HCV infection were assessed. Both CD81 and SR-BI of tupaia were found to be able to bind with HCV envelope protein 2 (E2). In comparison with human CD81, tupaia CD81 exhibited stronger binding activity with E2 and increased HCV pseudoparticle (HCVpp) cell entry 2-fold. The 293T cells transfected with tupaia CLDN1 became susceptible to HCVpp infection. Moreover, simultaneous transfection of the four tupaia factors into mouse NIH 3T3 cells made the cells susceptible to HCVpp infection. HCVpp of diverse genotypes were able to infect primary tupaia hepatocytes (PTHs), and this infection could be blocked by either anti-CD81 or anti-SR-BI. PTHs could be infected by cell culture-produced HCV (HCVcc) and did produce infectious progeny virus in culture supernatant. These findings indicate that PTHs possess all of the essential factors required for HCV entry and support the complete HCV infection cycle. This highlights both the mechanisms of susceptibility of tupaia to HCV infection and the possibility of using tupaia as a promising small-animal model in HCV study. Topics: Animals; Antigens, CD; CD36 Antigens; Cell Line; Claudin-1; Disease Models, Animal; Hepacivirus; Humans; Membrane Proteins; Mice; Molecular Sequence Data; Occludin; Protein Binding; Sequence Analysis, DNA; Tetraspanin 28; Tupaia; Viral Envelope Proteins; Virus Internalization | 2011 |
Hepatitis C virus and disrupted interferon signaling promote lymphoproliferation via type II CD95 and interleukins.
The molecular mechanisms of lymphoproliferation associated with the disruption of interferon (IFN) signaling and chronic hepatitis C virus (HCV) infection are poorly understood. Lymphomas are extrahepatic manifestations of HCV infection; we sought to clarify the molecular mechanisms of these processes.. We established interferon regulatory factor-1-null (irf-1(-/-)) mice with inducible and persistent expression of HCV structural proteins (irf-1/CN2 mice). All the mice (n = 900) were observed for at least 600 days after Cre/loxP switching. Histologic analyses, as well as analyses of lymphoproliferation, sensitivity to Fas-induced apoptosis, colony formation, and cytokine production, were performed. Proteins associated with these processes were also assessed.. Irf-1/CN2 mice had extremely high incidences of lymphomas and lymphoproliferative disorders and displayed increased mortality. Disruption of irf-1 reduced the sensitivity to Fas-induced apoptosis and decreased the levels of caspases-3/7 and caspase-9 messenger RNA species and enzymatic activities. Furthermore, the irf-1/CN2 mice showed decreased activation of caspases-3/7 and caspase-9 and increased levels of interleukin (IL)-2, IL-10, and Bcl-2, as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes. IL-2 and IL-10 were induced by the HCV core protein in splenocytes.. Disruption of IFN signaling resulted in development of lymphoma, indicating that differential signaling occurs in lymphocytes compared with liver. This mouse model, in which HCV expression and disruption of IFN signaling synergize to promote lymphoproliferation, will be an important tool for the development of therapeutic agents that target the lymphoproliferative pathway. Topics: Age Factors; Animals; Apoptosis; B-Lymphocytes; Caspases; Cell Proliferation; Disease Models, Animal; fas Receptor; Female; Hepacivirus; Hepatitis C, Chronic; Interferon Regulatory Factor-1; Interleukin-10; Interleukin-12; Interleukin-2; Interleukins; Lymphoma; Lymphoproliferative Disorders; Male; Mice; Mice, Knockout; Mice, Transgenic; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Spleen; T-Lymphocytes; Time Factors; Viral Core Proteins; Viral Envelope Proteins; Viral Nonstructural Proteins; Viral Proteins | 2009 |
Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis.
We developed hepatitis C virus (HCV) core-E1-E2 and HCV core transgenic mice on a common genetic background to assess the contribution of HCV structural proteins to hepatocarcinogenesis. Eight-week-old core-E1-E2, core, and nontransgenic mice inbred on the FVBxC57Bl/6 background were treated with diethylnitrosamine (DEN) and sacrificed at 32 weeks old. Proliferation and apoptosis were assessed by immunohistochemistry. The effect of viral proteins on apoptosis was evaluated in HepG2 cells in which apoptosis was induced by anti-Fas antibody. HCCs were identified at 32 weeks in the majority of DEN-treated mice from all three groups. The mean size of HCCs was significantly larger in core-E1-E2 transgenic (4.63 +/- 1.48 mm), compared with core transgenic (0.78 +/- 0.26 mm, P = .01), and nontransgenic (1.0 +/- 0.19 mm, P = .002) mice. While there were no differences in proliferation, the apoptotic index in core-E1-E2 transgenic HCCs was significantly lower than those found in core and non-transgenic HCCs. Core-E1-E2 transfected HepG2 cells demonstrated a significantly lower apoptotic index (0.35 +/- 0.11) compared with that of core transfected cells (0.74 +/- 0.07, P = .0103). Analysis of a Fas-induced apoptosis model in HCV transgenic mice confirmed that core-E1-E2 transgenic liver underwent significantly less apoptosis than transgenic tissue expressing core only. In conclusion, HCV core-E1-E2 transgenic mice develop significantly larger tumors than transgenic mice expressing core alone or nontransgenic mice. The accelerated tumor phenotype is attributable to suppression of apoptosis rather than enhanced proliferation. These data implicate HCV E1 and/or E2 in conjunction with core as antiapoptotic, tumor accelerator proteins. Topics: Animals; Apoptosis; Cell Proliferation; Diethylnitrosamine; Disease Models, Animal; fas Receptor; Hepacivirus; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Viral Envelope Proteins | 2005 |
Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. The purpose of this study was to determine how the HCV structural proteins affect the dynamic structural and functional properties of hepatocytes and measure the extra-hepatic manifestations induced by these viral proteins. A transgenic mouse model was established by expressing core, E1 and E2 proteins downstream of a CMV promoter. HCV RNA was detected using RT-PCR in transgenic mouse model tissues, such as liver, kidney, spleen and heart. Expression of the transgene was analysed by real-time PCR to quantify viral RNA in different tissues at different ages. Immunofluorescence analysis revealed the expression of core, E1 and E2 proteins predominantly in hepatocytes. Lower levels of protein expression were detected in spleen and kidneys. HCV RNA and viral protein expression increased in the liver with age. Histological analysis of liver cells demonstrated steatosis in transgenic mice older than 3 months, which was more progressed with age. Electron microscopy analysis revealed alterations in nuclei, mitochondria and endoplasmic reticulum. HCV structural proteins induce a severe hepatopathy in the transgenic mouse model. These mice became more prone to liver and lymphoid tumour development and hepatocellular carcinoma. In this model, the extra-hepatic effects of HCV, which included swelling of renal tubular cells, were mild. It is likely that the HCV structural proteins mediate some of the histological alterations in hepatocytes by interfering with lipid transport and liver metabolism. Topics: Age Factors; Animals; Carcinoma, Hepatocellular; Cell Nucleus; Disease Models, Animal; Endoplasmic Reticulum; Fatty Liver; Female; Hematologic Neoplasms; Hepatitis C; Hepatocytes; Kidney; Liver; Liver Neoplasms; Male; Mice; Mice, Transgenic; Mitochondria; Viral Core Proteins; Viral Envelope Proteins | 2005 |
Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees.
The relationship of viral persistence, the immune response to hepatitis C virus (HCV) envelope proteins, and envelope sequence variability was examined in chimpanzees. Antibody reactivity to the HCV envelope proteins E1 or E2 was detected by enzyme-linked immunosorbent assay (ELISA) in more than 90% of a human serum panel. Although the ELISAs appeared to be sensitive indicators of HCV infection in human serum panels, the results of a cross-sectional study revealed that a low percentage of HCV-inoculated chimpanzees had detectable antibody to E1 (22%) and E2 (15%). Viral clearance, which was recognized in 28 (61%) of the chimpanzees, was not associated with an antibody response to E1 or E2. On the contrary, antibody to E2 was observed only in viremic chimpanzees. A longitudinal study of animals that cleared the viral infection or became chronically infected confirmed the low level of antibody to E1, E2, and the HVR-1. In 10 chronically infected animals, the sequence variation in the E2 hypervariable region (HVR-1) was minimal and did not coincide with antibody to E2 or to the HVR-1. In addition, low nucleotide and amino acid sequence variation was observed in the E1 and E2 regions from two chronically infected chimpanzees. These results suggest that mechanisms in addition to the emergence of HVR-1 antibody escape variants are involved in maintaining viral persistence. The significance of antibodies to E1 and E2 in the chimpanzee animal model is discussed. Topics: Amino Acid Sequence; Animals; Cell Line; Cross-Sectional Studies; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Longitudinal Studies; Molecular Sequence Data; Pan troglodytes; Recombinant Fusion Proteins; Sequence Analysis, DNA; Viral Envelope Proteins; Viremia; Virus Latency | 1999 |
Sialadenitis histologically resembling Sjogren syndrome in mice transgenic for hepatitis C virus envelope genes.
Hepatitis C virus (HCV), a major causative agent of non-A, non-B chronic hepatitis, is also suggested to be associated with extrahepatic manifestations such as mixed cryoglobulinemia and glomerulonephritis. Two independent lines of transgenic mice carrying the HCV envelope genes have been shown previously to express the HCV envelope proteins in organs, including the liver and salivary glands, which results in no pathological changes in the liver. Further analysis of these animals now has revealed that they develop an exocrinopathy involving the salivary and lachrymal glands. This pathology resembles Sjogren syndrome, which also is suggested to have a possible association with chronic hepatitis C. These observations suggest that HCV might be involved in the pathogenesis of sialadenitis in humans and that this transgenic mouse system would be a good animal model for the study of HCV infection. Topics: Age Factors; Animals; Disease Models, Animal; Female; Genes, Viral; Hepacivirus; Hepatitis C; Lacrimal Apparatus; Liver; Male; Mice; Mice, Transgenic; Salivary Glands; Sialadenitis; Sjogren's Syndrome; Viral Envelope Proteins | 1997 |
Murine humoral immune response against recombinant structural proteins of hepatitis C virus distinct from those of patients.
We examined the humoral immune response to recombinant structural proteins of hepatitis C virus (HCV) such as C, E1 and E2 in immunized mice. Mice showed high induction of antibodies against these three structural proteins. Conformational and/or linear epitopes of these regions showed high responses in mice. Comparison with patients revealed higher anti-E1 and anti-E2 responses in mice and 15 immunoreactive peptides which are unique to mice, especially 11 peptides from the E2 region. The hydrophilic regions of these proteins were found to be the most immunogenic. Therefore, the murine immune system against recombinant E1 and E2 glycoproteins was distinct from those of patients in natural infection, and may be a target to find protective activity against HCV infection. Topics: Animals; Antibody Formation; Base Sequence; Cell Line; Disease Models, Animal; DNA, Viral; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Insecta; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Sequence Data; Recombinant Fusion Proteins; Viral Core Proteins; Viral Envelope Proteins; Viral Structural Proteins | 1996 |