Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents

TLDR

Hepatitis C virus spreads between hepatocytes by both classical entry and direct cell‑cell transfer, with the latter enabling persistence by evading neutralizing antibodies, yet its role in antiviral resistance remains unclear. The study aimed to characterize the phenotype of DAA‑resistant HCV strains in advanced cell‑cell transmission and spread models. Researchers employed state‑of‑the‑art in‑vitro systems to assess cell‑cell transmission and viral spread of resistant HCV. In genotype 2 HCV, cell‑cell transmission is the primary route of spread for DAA‑resistant strains, sustaining persistence and impeding eradication, but blocking this route with host‑targeting entry inhibitors alone or combined with DAAs inhibits dissemination, prevents resistance emergence, and achieves rapid viral clearance in cell culture.

Abstract

Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs.