Several studies have shown that the expression of SOCS1 and SOCS3 genes negatively regulate the response of HCV infection to interferon therapy and interferon-free regimens.
During hepatitis C virus (HCV) infection, HCV proteins interfere with interferon (IFN) signaling pathways and upregulate transcription of suppressor of cytokine signaling 1 and 3 genes (SOCS1 and SOCS3), which results in impaired immune response.
These findings suggest that Tim-3 plays a crucial role in negative regulation of innate immune responses, through crosstalk with PD-1 and SOCS-1 and limiting STAT-1 phosphorylation, and may be a novel target for immunotherapy to HCV infection.
Although CsA had little effect on IFN-α signaling pathway in uninfected hepatocytes, CsA treatment of HCV-infected hepatocytes specifically upregulated the expression of IFN regulatory factor-1 and inhibited the expression of suppressor of cytokine signaling-1 and protein inhibitor of activated signal transducers and activators of transcription-x, the primary negative regulators of IFN signaling pathway.
These data demonstrate that PD-1 and SOCS-1 are linked in dysregulating T-cell signaling during HCV infection, and their cross-talk may coordinately inhibit T-cell signaling pathways that lead to T-cell exhaustion during chronic viral infection.
SOCS-1 methylation was positively associated with patient age (P=0.002) and HCV infection status (P=0.004), and was inversely associated with HBV infection (P=0.0002).
Recently, we have shown that SOCS-1/3 overexpression in hepatic cells abrogates signaling of type I interferons (IFN) which may contribute to the frequently observed IFN resistance of hepatitis C virus (HCV).