Background & aims: HDV superinfection of chronically HBV-infected patients is the most aggressive form of chronic viral hepatitis, with an accelerated progression towards fibrosis/cirrhosis and increased risk of liver failure, hepatocellular carcinoma, and death. While HDV infection is not susceptible to available direct anti-HBV drugs, suboptimal responses are obtained with interferon-α-based therapies, and the number of investigational drugs remains limited. We therefore analyzed the effect of several innate immune stimulators on HDV replication in infected hepatocytes.
Methods: We used in vitro models of HDV and HBV infection based on primary human hepatocytes (PHHs) and the non-transformed HepaRG cell line that are relevant to explore new innate immune therapies.
Results: We describe here, for the first time, anti-HDV effects of Pam3CSK4 and BS1, agonists of Toll-like receptor (TLR)-1/2, and the lymphotoxin-β receptor (LTβR), respectively. Both types of agonists induced dose-dependent reductions of total intracellular HDV genome and antigenome RNA and of HDV protein levels, without toxicity in cells monoinfected with HDV or co/superinfected with HBV. Moreover, both molecules negatively affected HDV progeny release and strongly decreased their specific infectivity. The latter effect is particularly important since HDV is thought to persist in humans through constant propagation.
Conclusions: Immune-modulators inducing NF-κB pathways in hepatocytes can inhibit HDV replication and should be further evaluated as a possible therapeutic approach in chronically HBV/HDV-infected patients.
Lay summary: Hepatitis delta virus causes the most severe form of viral hepatitis. Despite positive recent developments, effective treatments remain a major clinical need. Herein, we show that immune-modulators that trigger the NF-κB pathways could be effective for the treatment of hepatitis delta infections.
Keywords: HDV-AG(s), HDV anti-genome(s); HDV-G(s), HDV genome(s); Hepatitis B virus; Hepatitis D virus; IFN, interferon; IL-, interleukin-; L-HDAg, large HDV antigen; LTβR, lymphotoxin-β receptor; NF-κB; NTCP, Na+-taurocholate cotransporting polypeptide; PHH, primary human hepatocyte; Peg-IFN-α, pegylated interferon-α; RNP, ribonucleoprotein; S-HDAg, small HDV antigen; TLR, Toll-like receptor; TNF, tumor necrosis factor; antiviral activity; dHepaRG, differentiated HepaRG cells; hepatocytes; lymphotoxin beta receptor; rh, recombinant human; toll-like receptor; vge, viral genome equivalent.
© 2021 The Author(s).