Hepatic gene expression before and during interferon and ribavirin combination therapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17183 | GEO | 2009/12/31
SECONDARY ACCESSION(S): PRJNA119677
REPOSITORIES: GEO
Similar Datasets
Project description:Patients who cleared HCV viremia early during therapy tended to show favorable outcomes, whereas patients who needed a longer period to clear HCV had poorer outcomes. We explored the mechanisms of treatment resistance by comparing hepatic gene expression before and during treatment We explored the mechanisms of treatment resistance by comparing hepatic gene expression before and during treatment. Liver biopsy was performed in 30 patients before and one week after starting combination therapy with IFN + Rib. Hepatocytes and liver-infiltrating lymphocytes (LILs) were obtained from 12 patients using laser capture micro dissection (LCM).
2009-12-30 | E-GEOD-17183 | biostudies-arrayexpress
Project description: Not available
| S-DIXA-D-1037 | biostudies-other
Project description:The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-alpha, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals.
2012-01-01 | GSE23031 | GEO
Project description:The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-alpha, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals. RNA from three samples were treated with Ribavirin and compared to three PBS treated samples
2012-01-01 | E-GEOD-23031 | biostudies-arrayexpress
Project description:In individuals highly exposed to hepatitis C virus (HCV), reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection. Broad neutralising antibodies (BnAbs) and Envelope 2 (E2)-specific memory B cell (MBCs) responses were examined longitudinally in 15 subjects with varied reinfection outcomes. BnAb responses were associated with MBC recall, but not with reinfection clearance. Strong evidence of antigen imprinting was found, and the B cell receptor repertoire showed a high level of clonality with ongoing somatic hypermutation of many clones over subsequent reinfection events. Single cell transcriptomic analyses showed that cleared reinfections featured an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection. MBC quality, but not necessarily breadth of nAb responses, is important for protection against antigenically diverse variants, which is encouraging for HCV vaccine development.
2024-06-13 | GSE269792 | GEO
Project description:Lack of immunocompetent animal models for hepatitis C virus (HCV) impedes vaccine development and studies of immune responses. Norway rat hepacivirus (NrHV) infection in rats shares HCV-defining characteristics, including hepatotropism, chronicity, immune responses, and aspects of pathology. To exploit genetic variants and research tools, we previously adapted NrHV to prolonged infection in laboratory mice. Through intrahepatic RNA inoculation of molecular clones of identified variants, we here characterized four mutations in the envelope proteins responsible for mouse adaptation, including one disrupting a glycosylation site. These mutations led to high titer viremia, similar to that observed in rats. In 4-week-old mice, infection was cleared after around 5 weeks compared to 2-3 weeks for non-adapted virus. In contrast, the mutations led to persistent but attenuated infection in rats, and they partially reverted accompanied by an increase in viremia. Attenuated infection in rat but not mouse hepatoma cells demonstrated that the characterized mutations were indeed mouse adaptive rather than generally enhancing fitness in both cell lines, and that species determinants and not immune interactions were responsible for attenuation in rats. Unlike persistent NrHV infection in rats, acute resolving infection in mice was not associated with development of neutralizing antibodies. Finally, infection of scavenger receptor B-I (SR-BI) knockout mice suggested that adaptation to mouse SR-BI was not a primary function of the identified mutations. Rather, the virus may have adapted to lower dependency on SR-BI, thereby potentially surpassing species-specific differences. In conclusion, we identified specific determinants of NrHV mouse adaptation, suggesting species-specific interactions during entry.
2023-02-27 | GSE225619 | GEO
Project description:Background: NK cells during chronic viral infection have been well studied over the last decade. We performed an unbiased next-generation RNA-sequencing approach to identify commonalities or differences of the effect of HIV, HCV and HBV viremia on NK cell transcriptomes. Methods: Using cell sorting, we obtained CD3-CD56+ NK cells from blood of 6 HIV, 11 HCV, and 32 HBV infected and untreated patients. Library preparation and sequencing were done using Illumina mRNA-Seq Sample Prep Kit and the HiSeq 2000, HiSeq2500 or NextSeq 500, and further analysis by an in-house analytic pipeline. Results: In NK cells from HIV, HCV and HBV patients, transcriptome analysis identified 272, 53, and 56 differentially expressed genes, respectively (fold change >1.5, q-value 0.2). Interferon stimulated genes were induced in NK cells from HIV/HCV patients, but not during HBV infection. HIV viremia downregulated ribosome assembly genes in NK cells. In HBV, viral load and ALT variation had little effect on genes related to NK effector function. Conclusion: We compare, for the first time, NK cell transcripts of viremic HIV, HCV and HBV patients. We clearly demonstrate distinctive NK cell gene signatures in 3 different populations, suggestive for a different degree of functional alterations of the NK cell compartment as compared to healthy individuals.
2019-01-26 | GSE125686 | GEO
Project description:T cell exhaustion is a well-defined process diminishing the efficacy of the CD8 response in persistent viremia. What is less understood is whether early differences in T cell regulation already predetermine the fate of the T cell response and infection outcome. Its dichotomous outcome that is unique among human viral infections makes hepatitis C virus infection uniquely suited to compare transcriptional regulation between HCV-specific CD8 T cells that do and do not achieve viral control. Using differential gene expression and gene set enrichment analyses we validate HCV-specifcic CD8 T cell transcriptional modules.
2017-01-18 | GSE93711 | GEO
Project description:In this study, we evaluated transcriptional responses in circulating leukocytes to assess for biomarkers of adverse outcomes in transplant patients after transplantation from a HCV-infected donor. We enrolled renal transplant recipients with and without HCV and performed RNA sequencing on serial samples. CMV DNAemia and allograft rejection outcomes were measured. Regularized logistic regression was utilized to develop gene expression classifiers predictive of clinical outcomes.
2023-02-08 | GSE213705 | GEO