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Gene expression profiling in human primary hepatocytes and human induced pluripotent stem cell-derived hepatocytes before and after IL-1β Treatment

ABSTRACT: The shared transmission routes of hepatitis B virus (HBV) and hepatitis C virus (HCV) result in coinfections that accelerate and exacerbate liver disease. The clinical burden is further exacerbated in the era of direct-acting antivirals (DAAs) against HCV, where reports of HBV reactivation post-DAA treatment in coinfected patients have emerged. Beyond an HCV-induced canonical interferon (IFN) response, the mechanisms through which HCV suppresses HBV remain poorly understood. Here, we employ a multicellular liver culture system, co-culturing human-induced pluripotent stem cells (hiPSCs)-derived hepatocytes, hepatic stellate cells and macrophages, that supports productive HCV and HBV infection and replicates clinical coinfection dynamics. We demonstrate that IL1β from macrophages activated by HCV modulates host factors involved in HBV infection independent of IFN signaling. By combining bioinformatic predictions with reporter assay validation, we identified the transcriptional mediators of these changes. Hepatocytes downregulate expression of HBV receptor SLC10A1 due to induction of a truncated C/EBPβ isoform, which negatively regulates the full-length variant’s activity. Simultaneously, IL1β induces the expression of ISG20, a known anti-HBV factor, through USF1 phosphorylation. Finally, we show that a modified treatment protocol combining DAA with an HBV entry inhibitor effectively prevents HBV reactivation. Our findings position this liver culture platform as a tool not only for detailed mechanistic dissection of the complex multicellular responses in HBV-HCV coinfection, but also for nominating and testing future therapeutic avenues for coinfected patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254235 | GEO | 2025/09/22

REPOSITORIES: GEO

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Project description:Chronic immune activation is a hallmark of human immunodeficiency virus (HIV) infection and the best prognostic indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) restores normal immune response and effectively prolongs life. In HIV-infected individuals who are coinfected with hepatitis C virus (HCV) the immune system is activated despite effective HIV antiretroviral therapy controlling viral load. Here we examined CD14+ monocyte gene expression by high-density microarray analysis and T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV, monoinfected HIV and HIV/HCV coinfected subjects with undetected HIV viral load. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological (NP) performance, which was summarized as global deficit scores (GDS). Gene expression analysis of CD14+ monocytes from coinfected subjects revealed an elevated type 1 interferon (IFN) response profile unique to coinfection. For both CD4 and CD8 T cells, coinfection triggered significantly increased expression of activation markers CD38 and HLA-DR. In the coinfected group, mild cognitive impairment was associated with a type 1 IFN monocyte response but not plasma lipopolysaccharide. These observations raise the possibility that cognitive impairment evident in the HIV/HCV population is associated with the IFN response detected in coinfected individuals. Monocytes isolated from healthy controls (n=17), HCV monoinfected (n=19) and HIV/HCV coinfected (n=17) were analyzed for gene expression using high-density microarrays. Whole blood was collected in Vacutainer CPT tubes (BD Biosciences) and PBMCs were enriched by centrifugation. Typically, three million CD14+ monocytes were isolated from 30 ml of whole blood using an anti-CD14 monoclonal antibody immunomagnetic - ferrous bead conjugate according to the manufacturer’s instructions (Miltenyi Biotech). Monocyte purity exceeded 97% with <1% T or B cell contamination as determined by flow cytometry. Monocyte RNA was isolated using a Qiagen RNeasy Micro Kit with an RNA integrity value exceeding 9. Complementary DNA was synthesized and labeled with biotin (iExpress iAmplify kit, Applied Microarrays) and hybridized to Codelink Whole Human Genome Bioarrays (55K probes, Applied Microarrays). Slides were scanned (Axon GenePix 4000B, Molecular Devices), analyzed (CodeLink Expression Software Kit v4.1) and microarray data were normalized with loess normalization using R and Bioconductor package. Determination of differential gene expression and multiple testing correction / false discovery rate adjustments were performed using GeneSpring GX 7.3 software package (Agilent). Microarray data was analyzed using a variety of custom data analytic techniques for gene expression profile identification as described previously. Correlations were determined by Spearman rank correlation coefficient.

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Gene expression profiling in human primary hepatocytes and human induced pluripotent stem cell-derived hepatocytes before and after IL-1β Treatment

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