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Identification of Antiviral Host Factors by Functional Gene Expression Analysis using HBV Infection Assay Systems

ABSTRACT: The in vitro HBV infection assay system was established in primary human hepatocytes (PXB cells) infected with HBV derived from the plasmid containing 1.3-mer HBV genome. Comprehensive and functional studies were performed by small interfering RNA knockdown and vector transfection experiments of the related genes and analyzed using microarray to reveal the host factors related to HBV regulation. Knockdown of STAT1 increased viral products in HBV-transfected HepG2 cells, but unexpectedly decreased in HBV-infected PXB cells. In RNA microarray analysis, STAT1 knockdown induced changes in intracellular molecules related to metabolism and protein synthesis in PXB cells, but not in HepG2 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253496 | GEO | 2025/01/16

REPOSITORIES: GEO

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Project description:The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8+ cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S194-202) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C141-151) from the capsid protein were validated by our discovery platform, but both were detected at a very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P606-616) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.

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Identification of Antiviral Host Factors by Functional Gene Expression Analysis using HBV Infection Assay Systems

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