GCN5 Acetyltransferase Inhibits PGC1α-induced Hepatitis B Virus Biosynthesis

Hepatitis B virus （HBV） biosynthesis is primarily restricted to hepatocytes due to the governing of liver-enriched nuclear receptors （NRs） on viral RNA synthesis. The liver-enriched NR hepatocyte nuclear factor 4α （HNF4α, the key regulator of genes implicated in hepatic glucose metabolism, is also a primary determinant of HBV pregenomic RNA synthesis and HBV replication. Peroxisome proliferator-activated receptor-r coactivator la （PGCla） coactivates and further enhances the effect of HNF4α on HBV biosynthesis. Here, we showed that the acetyltransferase General Control Non-repressed Protein 5 （GCN5） acetylated PGC 1 α, leading to alteration of PGC 1 α from a transcriptionally active state into an inactive state. As a result, the coactivation activity of PGCla on HBV transcription and replication was suppressed. Apparently, an acetylation site mutant of PGC 1 α （PGC 1 αR13） still had coactivation activity as GCN5 could not suppress the coactivation activity of the mutant. Moreover, a catalytically inactive acetyltransferase mutant GCN5m, due to the loss of acetylation activity, failed to inhibit the coactivation function of PGClα in HBV biosynthesis. Our results demonstrate that GCN5, through its acetyltransferase activity, inhibits PGCla-induced enhancement of HBV transcription and replication both in vitro and in vivo.

Inhibition of hepatitis B virus replication by quercetin in human hepatoma cell lines

Hepatitis B virus(HBV) infection is one of the most serious and prevalent viral diseases in the world. Although several anti-HBV drugs have been used clinically, their side and adverse effects limit treatment efficacy. Therefore, it is necessary to identify novel potential anti-HBV agents. The flavonol quercetin has shown activity against some retroviruses, but its effect on HBV remains unclear. In the present study, quercetin was incubated with Hep G2.2.15 cells, as well as Hu H-7 cells transfected with an HBV plasmid. Quercetin was shown to significantly reduce Hepatitis B surface antigen(HBs Ag) and Hepatitis B e antigen(HBe Ag), secretion and HBV genomic DNA levels in both cell lines. In addition, co-incubation with lamivudine(3TC), entecavir(ETV), or adefovir(Ade) further enhanced the quercetin-induced inhibition of HBV replication. This inhibition was partially associated with decreased heat shock proteins and HBV transcription levels. The results indicate that quercetin inhibited HBV antigen secretion and genome replication in human hepatoma cell lines, which suggests that quercetin may be a potentially effective anti-HBV agent.

Exploring the therapeutic potential of precision T-Cell Receptors (TCRs) in targeting KRAS G12D cancer through in vitro development

Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.

Recent advances in the study of hepatitis B virus covalently closed circular DNA

Chronic hepatitis B infection is caused by hepatitis B virus(HBV) and a total cure is yet to be achieved. The viral covalently closed circular DNA(ccc DNA) is the key to establish a persistent infection within hepatocytes. Current antiviral strategies have no effect on the pre-existing ccc DNA reservoir. Therefore, the study of the molecular mechanism of ccc DNA formation is becoming a major focus of HBV research. This review summarizes the current advances in ccc DNA molecular biology and the latest studies on the elimination or inactivation of ccc DNA, including three major areas:(1) epigenetic regulation of ccc DNA by HBV X protein,(2) immune-mediated degradation,and(3) genome-editing nucleases. All these aspects provide clues on how to finally attain a cure for chronic hepatitis B infection.