T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling.
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.
Yao
Zhi Q
ZQ
Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614, USA.
King
Ellis
E
Prayther
Deborah
D
Yin
Deling
D
Moorman
Jonathan
J
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D016174:Hepacivirus / Q000276:immunology* / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D011951:Receptors, Complement / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014758:Viral Core Proteins / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D011951:Receptors, Complement; D014758:Viral Core Proteins; C032402:complement 1q receptor; C069130:nucleocapsid protein, Hepatitis C virus