T Cell Dysfunction by Hepatitis C Virus Core Protein Involves PD-1/PDL-1 Signaling

Abstract

Reports have shown that a negative T cell costimulatory pathway mediated by PD-1 (programmed death-1) and PDL-1 (programmed death ligand-1) is associated with T cell exhaustion and persistent viral infection. Persistent hepatitis C virus (HCV) infection in humans is also characterized by impaired T lymphocyte function, but the role of the PD-1 and PDL-1 pathway in HCV infection is unknown. Here we report that T cells isolated from chronically HCV-infected patients express significantly higher levels of PD-1 when compared with healthy donors. In addition, PD-1 and PDL-1 expression is upregulated on healthy donor T cells exposed to HCV core, a nucleocapsid protein that is immunosuppressive; upregulation of PD-1 is mediated through interaction of HCV core with the complement receptor, gC1qR. Importantly, T cell functions that are dysregulated by HCV core, including T cell activation, proliferation, and apoptosis, can be restored by blocking PD-1 and PDL-1 engagement. Our results indicate that HCV core can upregulate a key negative T cell signaling pathway associated with viral persistence and highly expressed on the T cells of persistently infected individuals. This upregulation of the PD-1 and PDL-1 pathway in humans represents a novel and perhaps common mechanism by which a virus usurps host machinery to facilitate persistence.

Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

“…For example, the HCV core protein induces PD-1 expression in T cells and monocytes (45,79). Lipopolysaccharide (LPS) and HIV-1 virions can induce PD-L1 expression in neutrophils (80).…”

Viral Modulation of T-Cell Receptor Signaling

“…Recombinant C protein also has a number of inhibitory effects on TcR signaling, including impaired activation of the signaling molecules Lck, ZAP-70, Akt, ERK, and MEK, upregulation of T-cell expression of the negative regulator PD-1, and cell cycle arrest. These effects have been reported to be dependent upon the interaction of C protein with the complement receptor gC1qR (72,(166)(167)(168)(169), which may facilitate the entry of C protein into T cells (31). In support of the importance of C protein in vivo, transgenic mice with C protein expression targeted to T cells by the CD2 promoter showed markedly depressed IL-2 and gamma interferon production after anti-CD3 stimulation of splenocytes (141).…”

Hemoglobin Subunit Beta Interacts with the Capsid Protein and Antagonizes the Growth of Classical Swine Fever Virus

“…It has been shown that interaction of the HCV C protein with cellular molecules impairs the host's immune response through mechanisms that result in the suppression of interleukin-12 synthesis in human macrophages (37), T cell dysfunction (38), and inhibition of T-lymphocyte activation and proliferation (25,39,40). In Friend leukemia cells treated with IFN, the induction and production of leukemia viruses are inhibited while induction of HB is slightly increased (33).…”