Chronic hepatitis C virus (HCV) infection of the liver with either genotype 1 or genotype 3 gives rise to distinct pathologies, and the two viral genotypes respond differently to antiviral therapy.

To understand these clinical differences, we compared gene transcription profiles in liver biopsies from patients infected with either gt1 or gt3, and uninfected controls.

Gt1‐infected biopsies displayed elevated levels of transcripts regulated by type I and type III interferons (IFN), including genes that predict response to IFN‐α therapy. In contrast, genes controlled by IFN‐γ were induced in gt3‐infected biopsies. Moreover, IFN‐γ levels were higher in gt3‐infected biopsies. Analysis of hepatocyte‐derived cell lines confirmed that the genes upregulated in gt3 infection were preferentially induced by IFN‐γ. The transcriptional profile of gt3 infection was unaffected by IFNL4 polymorphisms, providing a rationale for the reduced predictive power of IFNL genotyping in gt3‐infected patients.

The interactions between HCV genotypes 1 and 3 and hepatocytes are distinct. These unique interactions provide avenues to explore the biological mechanisms that drive viral genotype‐specific differences in disease progression and treatment response. A greater understanding of the distinct host–pathogen interactions of the different HCV genotypes is required to facilitate optimal management of HCV infection.