Work

Sustained suppression of HBV replication by a long-acting lipophilic TFV phosphonate prodrug is not potentiated by macrophages or increased activation of anti-viral interferon-stimulated genes (ISGs) 2187

Year: 2025

Type: article

Abstract: Description Chronic hepatitis B treatment requires daily oral therapy with Tenofovir (TFV) prodrugs. Treatment cessation leads to HBV reactivation, underscoring the significance of adherence to therapy. We developed a long-acting amino acid-free hydrophobic and lipophilic crystalline phosphonate TFV prodrug nanosuspension, NM5TFV, and aimed to investigate how NM5TFV suppresses HBV replication. In vivo experiments were performed on HBV transgenic mice administered a single i.m. injection of NM5TFV at 200 and 400 mg/kg TFV equivalents. HBV viral load in blood was tested weekly until the HBV DNA rebound occurred. NM5TFV caused >2.5 log 10 reduction in HBV DNA after a single injection, with a rebound at 12 weeks. HepAD38 cells co-cultured or not with monocyte-derived macrophages (MDM) were treated with NM5TFV for 48h to measure HBV DNA and cccDNA (qPCR), ISGs, and inflammasome (IFS) mRNAs (RT-PCR). Exposure of HepAD38 cells to NM5TFV reduced HBV DNA and cccDNA levels 2-fold. Co-culture of HBV+ cells with MDM did not potentiate NM5TFV’s suppression of HBV replication, suggesting that M5TFV prodrug is efficiently activated in HepAD38 cells independent of MDM active drug transfer. NM5TFV does not affect ISG and IFS gene activation in HepAD38 cells and mouse liver tissue. We conclude that NM5TFV exhibited significant anti-viral activity by directly suppressing HBV DNA and cccDNA in infected hepatocytes, with no ISG/IFS activation or MDM’s help. Funding Sources NIH R01AI163042 Topic Categories Viral Immunology (VIR)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.137