Issues in selecting HCV-infected candidates for anti-viral treatment.
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ABSTRACT:
SUBMITTER: Lok AS
PROVIDER: S-EPMC6499256 | biostudies-literature | 2012 Apr
REPOSITORIES: biostudies-literature
Publications
Issues in selecting HCV-infected candidates for anti-viral treatment.
Clinical liver disease 20120426 2
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Project description:Long waiting times for kidney transplant (KT) and the high risk of mortality on dialysis have prompted investigation into strategies to utilize hepatitis C virus (HCV)-infected organs to decrease discard rates of potentially viable kidneys. Due the opioid epidemic, the number of HCV-infected donors has increased significantly. With the development of direct-acting antiviral therapies for HCV infection, now more than 95% of patients who received treatment are cured. Experimental trials have used direct-acting antiviral therapy to treat HCV infection in HCV-uninfected transplant recipients of kidneys from HCV-viremic donors. To date, HCV has been eradicated in all cases. Though these strategies will potentially increase the donor pool of available kidneys, shorten waitlist times, and ultimately decrease mortality in patients waiting for KT, identifying the ideal candidates and educating them about a protocol to utilize direct-acting antiviral therapy to cure HCV after it is transmitted is essential. We present our approach to patient selection and education for a clinical trial in transplantation of HCV viremic kidneys into uninfected recipients.
| S-EPMC6733639 | biostudies-literature
Project description:ObjectiveIncreasing evidence suggests that miRNAs have a profound impact on host defense to Hepatitis C virus (HCV) infection and clinical outcome of standard HCV therapy. In this study, we investigated modulation of miRNA expression in Huh7.5 hepatoma cells by HCV infection and in vitro interferon-αtreatment.MethodsMiRNA expression profiling was determined using Human miRNA TaqMan® Arrays followed by rigorous pairwise statistical analysis. MiRNA inhibitors assessed the functional effects of miRNAs on HCV replication. Computational analysis predicted anti-correlated mRNA targets and their involvement in host cellular pathways. Quantitative RTPCR confirmed the expression of predicted miRNA-mRNA correlated pairs in HCV-infected Huh7.5 cells with and without interferon-α.ResultsSeven miRNAs (miR-30b, miR-30c, miR-130a, miR-192, miR-301, miR-324-5p, and miR-565) were down-regulated in HCV-infected Huh7.5 cells (p<0.05) and subsequently up-regulated following interferon-α treatment (p<0.01). The miR-30(a-d) cluster and miR-130a/301 and their putative mRNA targets were predicted to be associated with cellular pathways that involve Hepatitis C virus entry, propagation and host response to viral infection.ConclusionsHCV differentially modulates miRNAs to facilitate entry and early establishment of infection in vitro. Interferon-α appears to neutralize the effect of HCV replication on miRNA regulation thus providing a potential mechanism of action in eradicating HCV from hepatocytes.
| S-EPMC3572124 | biostudies-literature
Project description:BackgroundThe dynamic of HIV-viral load (VL) remains poorly investigated in HIV/HCV patients under direct acting antivirals (DAAs).MethodsWe retrospectively evaluated HIV-VL at baseline (BL) during and up to 24 weeks post-DAAs in a cohort of 305 HIV-1/HCV patients, on ART and with no HIV virological failure (VF) in the 6 months before treatment with DAAs; during the period of observation VF was defined as confirmed VL≥50 copies/mL; virological blips (VB, transient, not confirmed, VL ≥50 copies/mL). Stepwise Cox regression models were fitted to estimate adjusted hazard ratios (aHR) of VF.ResultsFifteen VF occurred in 13 patients over 187 person-years of follow-up (PYFU): incidence rate (IR) of 8.0 per 100-PYFU (95% CI = 4.0-12.1); 29 VBs were detected in 26 patients over 184 PYFU: IR = 15.8 per 100-PYFU (95% CI = 10.0-21.5). The most prominent factor associated with VF was the presence of BL HIV residual viremia (RV = HIV-RNA detectable but not precisely quantifiable) [aHR = 12.26 (95% CI = 3.74-40.17), P<0.0001]. Other factors were ≥1 VBs in the 6 months before DAAs [aHR = 6.95 (95% CI = 1.77-27.37) P = 0.006] number of ART regimens failed before DAAs initiation [aHR (per more regimen) = 1.22 (95% CI = 1.04-1.42), P = 0.012] and age [aHR (per year older) = 1.16 (95% CI = 1.04-1.29), P = 0.010].ConclusionsOur findings underline the importance for close monitoring HIV-VL in selected patients. Whether this phenomenon is triggered by the rapid clearance of HCV remains to be established.
| S-EPMC8812874 | biostudies-literature
Project description:Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from 4-50 infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.
| S-EPMC4230741 | biostudies-literature
Project description:Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are missed by previous studies, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated and harbored genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide wealthy resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.
2023-10-30 | GSE246452 | GEO
Project description:BackgroundCo-infection with HIV and HCV is very common. It is estimated that over 5 million people are co-infected with HIV and HCV worldwide. Accumulated evidence shows that each virus alters the course of infection of the other one. CD8+ T cells play a crucial role in the eradication of viruses and infected target cells. To the best of our knowledge, no one has investigated the gene expression profiles in HIV/HCV-co-infected individuals.MethodologyGenome-wide transcriptomes of CD8+ T cells from HIV/HCV-co-infected or mono-infected treatment-naïve individuals were analyzed by microarray assays. Pairwise comparisons were performed and differentially expressed genes were identified followed by quantitative real-time PCR (qRT-PCR) validation. Directed Acyclic Graphs (DAG) from Web-based Gene SeT AnaLysis Toolkit (WebGestalt) and DAVID bioinformatics resources 6.7 (the Database for Annotation, Visualization, and Integrated Discovery) were used to discover the Gene Ontology (GO) categories with significantly enriched gene numbers. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were also obtained by using WebGestalt software.Results and conclusionsA total of 110, 24 and 72 transcript IDs were shown to be differentially expressed (> 2-fold and p<0.05) in comparisons between HCV- and HIV-mono-infected groups, HIV/HCV-co-infected and HIV-mono-infected groups, and HIV/HCV-co-infected and HCV-mono-infected groups, respectively. In qRT-PCR assay, most of the genes showed similar expressing profiles with the observation in microarray assays. Further analysis revealed that genes involved in cell proliferation, differentiation, transcriptional regulation and cytokine responses were significantly altered. These data offer new insights into HIV/HCV co-infections, and may help to identify new markers for the management and treatment of HIV/HCV co-infections.
| S-EPMC3441577 | biostudies-literature
Project description:Hepatitis C virus (HCV) poses a global threat to public health. HCV envelop protein E2 is the major component on the virus envelope, which plays an important role in virus entry and morphogenesis. Here, for the first time, we affinity purified E2 complex formed in HCV-infected human hepatoma cells and conducted comparative mass spectrometric analyses. 85 cellular proteins and three viral proteins were successfully identified in three independent trials, among which alphafetoprotein (AFP), UDP-glucose: glycoprotein glucosyltransferase 1 (UGT1) and HCV NS4B were further validated as novel E2 binding partners. Subsequent functional characterization demonstrated that gene silencing of UGT1 in human hepatoma cell line Huh7.5.1 markedly decreased the production of infectious HCV, indicating a regulatory role of UGT1 in viral lifecycle. Domain mapping experiments showed that HCV E2-NS4B interaction requires the transmembrane domains of the two proteins. Altogether, our proteomics study has uncovered key viral and cellular factors that interact with E2 and provided new insights into our understanding of HCV infection.
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Project description:The human immunodeficiency virus (HIV) epidemic in Russia, driven by injection drug use, has seen a steady rise in the past two decades. Hepatitis C virus (HCV) infection is highly prevalent in people who inject drugs (PWID). The study aimed to describe the current frequency of HCV testing and treatment among HIV-infected PWID in St. Petersburg, Russia. This study examined baseline data from the "Linking Infectious and Narcology Care" (LINC) and "Russia Alcohol Research Collaboration on HIV/AIDS" (Russia ARCH) studies. Participants included in this analysis were HIV-infected with a history of injection drug use. Descriptive statistics were performed to assess frequency of HCV testing and treatment. Participants (n=349 [LINC], 207 [Russia ARCH]) had a mean age of 33.8 years (IQR: 31-37) in LINC and 33.0 (IQR: 30-36) in Russia ARCH; 26.6% (LINC) and 29.0% (Russia ARCH) were female; 100% were Caucasian. Nearly all participants had been tested for HCV (98.9% in LINC, 97.1% in Russia ARCH). Almost all reported being diagnosed HCV positive (98.9% in LINC, 97.1% in Russia ARCH). Only 2.3% of LINC and 5.0% of Russia ARCH participants reported ever receiving HCV treatment. Among these cohorts of HIV-infected PWID in St. Petersburg, Russia, as of 2015 nearly all reported being tested for HCV and testing positive, while only 3.3% received any HCV treatment. In this new era of effective HCV pharmacotherapy, an enormous chasm in the HCV treatment cascade in Russia exists providing substantial opportunities for curing HCV in HIV-infected Russians with a history of injection drug use.
| S-EPMC5313079 | biostudies-literature
Project description:We developed a strategy to treat hepatitis C virus (HCV) infection by replacing five endogenous microRNA (miRNA) sequences of a natural miRNA cluster (miR-17-92) with sequences that are complementary to the HCV genome. This miRNA cluster (HCV-miR-Cluster 5) is delivered to cells using adeno-associated virus (AAV) vectors and the miRNAs are expressed in the liver, the site of HCV replication and assembly. AAV-HCV-miR-Cluster 5 inhibited bona fide HCV replication in vitro by up to 95% within 2 days, and the spread of HCV to uninfected cells was prevented by continuous expression of the anti-HCV miRNAs. Furthermore, the number of cells harboring HCV RNA replicons decreased dramatically by sustained expression of the anti-HCV miRNAs, suggesting that the vector is capable of curing cells of HCV. Delivery of AAV-HCV-miR-Cluster 5 to mice resulted in efficient transfer of the miRNA gene cluster and expression of all five miRNAs in liver tissue, at levels up to 1,300 copies/cell. These levels achieved up to 98% gene silencing of cognate HCV sequences, and no liver toxicity was observed, supporting the safety of this approach. Therefore, AAV-HCV-miR-Cluster 5 represents a different paradigm for the treatment of HCV infection.
| S-EPMC3589168 | biostudies-literature
Project description:ObjectiveThe primary objective of this study was to estimate the incidence of treatment failure (TF) to protease inhibitor monotherapies (PI/r-MT) with lopinavir/ritonavir (LPV/r) or darunavir/ritonavir (DRV/r).DesignA multicenter cohort of HIV-infected patients with viral load (VL) ≤50 copies/mL, who underwent a switch from any triple combination therapy to PI/r-MT with either LPV/r or DRV/r.MethodsVL was assessed in each center according to local procedures. Residual viremia was defined by any HIV-RNA value detectable below 50 copies/mL by a Real-Time PCR method. Standard survival analysis was used to estimate the rate of TF (defined by virological failure or interruption of monotherapy or reintroduction of combination therapy). A multivariable Cox regression analysis with automatic stepwise procedures was used to identify factors independently associated with TF among nadir and baseline CD4+ counts, residual viremia, time spent with <50 HIV-RNA copies/mL before switch, history of virological failure, HCV co-infection, being on a PI/r and hemoglobin concentrations at baseline.ResultsSix hundred ninety patients fulfilled the inclusion criteria and were included in this analysis. Their median follow-up was 20 (10-37) months. By month 36, TF occurred in 176 (30.2%; 95% CI:25.9-34.5) patients. Only CD4+ nadir counts (adjusted hazard ratio [aHR] = 2.03 [95% CI: 1.35, 3.07] for counts ≤100 vs. >100 cells/μL) and residual viremia (aHR = 1.48 [95% CI: 1.01-2.17] vs. undetectable VL) were independently associated to TF.ConclusionsResidual viremia and nadir CD4+ counts <100 cells/μL should be regarded as the main factors to be taken into account before considering switching to a PI/r-MT.
| S-EPMC5305227 | biostudies-literature