T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling.

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• The programmed death-1 (PD-1) and programmed death ligand-1 (PDL-1) pathway mediates T cell exhaustion, contributing to persistent viral infections.
• Chronic hepatitis C virus (HCV) infection is associated with impaired T lymphocyte function, but the role of PD-1/PDL-1 in this context is unclear.

Purpose of the Study:

• To investigate the role of the PD-1/PDL-1 pathway in T cell dysfunction during chronic HCV infection.
• To determine if HCV core protein influences PD-1/PDL-1 expression and T cell function.

Main Methods:

• Quantification of PD-1 expression on T cells from chronically HCV-infected patients and healthy donors.
• Exposure of healthy donor T cells to HCV core protein and assessment of PD-1/PDL-1 upregulation.
• Investigation of the mechanism of PD-1 upregulation by HCV core, including the role of gC1qR.
• Evaluation of T cell function (activation, proliferation, apoptosis) restoration by blocking PD-1/PDL-1.

Main Results:

• T cells from chronically HCV-infected patients exhibited significantly higher PD-1 expression compared to healthy donors.
• HCV core protein upregulated PD-1 and PDL-1 on healthy T cells, with PD-1 upregulation mediated by HCV core interaction with gC1qR.
• Blocking PD-1/PDL-1 engagement restored dysregulated T cell functions, including activation, proliferation, and apoptosis, impaired by HCV core.

Conclusions:

• HCV core protein upregulates the PD-1/PDL-1 pathway, a negative T cell signaling pathway implicated in viral persistence.
• This upregulation of PD-1/PDL-1 represents a novel mechanism by which HCV may evade host immune responses.
• Targeting the PD-1/PDL-1 pathway could be a potential therapeutic strategy for managing persistent HCV infection.