Precision-cut liver slices as a model for the evaluation of host-targeting agents against hepatitis B and delta viruses

Abstract Developing new therapeutic strategies against hepatitis B virus (HBV) and hepatitis delta virus (HDV) is essential to cure these infections. Yet evaluation of host-targeting agents (HTAs) with in vitro and in vivo models remains challenging. Therefore, we assessed precision-cut liver slices (PCLS) as an HBV/HDV co-infection model to study virus-host interactions and HTAs. Our ex vivo PCLS infection protocol allows to establish HBV and HDV infection within the liver’s three-dimensional architecture. Treatment with two well-characterized HTAs produced distinct antiviral effects consistent with each mechanism: Bulevirtide blocked entry; Lonafarnib induced intracellular hepatitis delta antigen accumulation. The TLR8 agonist Selgantolimod showed anti-HBV activity not previously seen in cultured hepatocytes, indicating crosstalk between immune and infected cells within PCLS. These results provide the first characterization of PCLS as an ex vivo model of HBV/HDV co-infection and antiviral testing. Thus, PCLS could expedite pre-clinical HTA characterization against viral liver diseases while reducing animal experimentation. Competing Interest Statement FZ and BT received grants from Aligos, Assembly Bio, AusperBio, Beam Therapeutics, Blue Jay and ImCheck; FZ had consulting activities with Aligos, Assembly, Blue Jay and GSK. SPF is an employee of Gilead Sc. All the other authors declare no competing interests.