Summary Hepatitis C virus (HCV) is remarkably efficient at evading host immunity to establish chronic infection. During chronic HCV infection, interleukin‐12 (IL‐12) produced by monocytes/macrophages (M/Mφ) is significantly suppressed. Programmed death‐1 (PD‐1), an inhibitory receptor on immune cells, plays a pivotal role in suppressing T‐cell responses during chronic viral infection. To determine whether PD‐1 regulates IL‐12 production by M/Mφ during chronic HCV infection, we examined the expressions of PD‐1, its ligand PDL‐1, and their relationship with IL‐12 production in M/Mφ from HCV‐infected, HCV‐resolved, and healthy subjects by flow cytometry. Toll‐like receptor (TLR) ‐mediated IL‐12 production by M/Mφ was selectively suppressed, while PD‐1/PDL‐1 expressions were up‐regulated, in HCV‐infected subjects compared with HCV‐resolved or healthy subjects. Up‐regulation of PD‐1 was inversely associated with the degree of IL‐12 inhibition in HCV infection. Interestingly, the reduced response of M/Mφ from HCV‐infected individuals to TLR ligands appeared not to be the result of a lack of the ability to sense pathogen, but to an impaired activation of intracellular janus kinase/signal transducer and activator of transfection (STAT) pathway as represented by inhibited STAT‐1 phosphorylation in M/Mφ from HCV‐infected individuals compared with HCV‐negative subjects. Successful HCV treatment with pegylated interferon/ribavirin or blocking PD‐1/PDL‐1 engagement ex vivo led to reduced PD‐1 expression and improved IL‐12 production as well as STAT‐1 activation in M/Mφ from HCV‐infected individuals. These results suggest that the PD‐1 inhibitory pathway may negatively regulate IL‐12 expression by limiting STAT‐1 phosphorylation in M/Mφ during chronic HCV infection.

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