Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Oct 18, 2015; 7(23): 2449-2458
Published online Oct 18, 2015. doi: 10.4254/wjh.v7.i23.2449
Programmed death-1/programmed death-L1 signaling pathway and its blockade in hepatitis C virus immunotherapy
Mohamed L Salem, Ahmed El-Badawy
Mohamed L Salem, Center of Excellence in Cancer Research, Tanta University, Tanta 31527, Egypt
Mohamed L Salem, Immunology and Biotechnology Division, Zoology Department, Faculty of Science, Tanta 31527, Egypt
Ahmed El-Badawy, Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, 6th of October City, Giza 12588, Egypt
Author contributions: Salem ML and El-Badawy A contributed equally to this work.
Supported by Science and Technology Development Fund (STDF; grants No. 1469 and No. 5245); and Tanta University Fund, Egypt to Mohamed L Salem, the Principal investigator of these projects.
Conflict-of-interest statement: We declare that authors have no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Mohamed L Salem, PhD, Professor, Center of Excellence in Cancer Research, Tanta University, Tanta 31527, Egypt. cecr@unv.tanta.edu.eg
Telephone: +20-12-74272624
Received: April 11, 2015
Peer-review started: April 15, 2015
First decision: June 2, 2015
Revised: June 29, 2015
Accepted: September 2, 2015
Article in press: September 7, 2015
Published online: October 18, 2015
Processing time: 190 Days and 19.1 Hours
Abstract

Chronic hepatitis C virus (HCV) infection is a public health issue that often progresses to life-threatening complications, including liver cirrhosis, fibrosis, and hepatocellular carcinoma. Impaired immune responses to HCV are key features of chronic HCV infection. Therefore, intervention strategies usually involve enhancing the immune responses against HCV. Cytotoxic CD8+ T lymphocytes (CTLs) play a critical role in the control of HCV infection. However, their cytolytic function can be impaired by the expression of co-inhibitory molecules. Programmed death-1 (PD-1) receptor and its ligand PD-L1 function in a T cell co-inhibitory pathway, which either blocks the function of CTLs or the differentiation of CD8+ T cells. During chronic HCV infection, the immune inhibitory receptor PD-1 is upregulated on dysfunctional HCV-specific CD8+ T cells. As such, blockade of the PD-1/PD-L1 pathway in these CD8+ T cells might restore their functional capabilities. Indeed, clinical trials using therapies to block this pathway have shown promise in the fostering of anti-HCV immunity. Understanding how chronic HCV infection induces upregulation of PD-1 on HCV specific T cells and how the PD-1/PD-L1 interaction develops HCV specific T cell dysfunction will accelerate the development of an efficacious prophylactic and therapeutic vaccination against chronic HCV infections, which will significantly improve HCV treatments and patient survival. In this review, we discuss the relationship between PD-1 expression and clinical responses and the potential use of PD-1 blockade for anti-HCV therapy.

Keywords: Hepatitis C virus; Programmed death-1; Hepatitis C virus immunotherapy; Exhausted T cells; Hepatitis C virus immune escape

Core tip: The programmed death-1 (PD-1)/PD-L1 pathway is an attractive target for anti-hepatitis C virus (HCV) immunotherapy because it restores the functional capacities of HCV-specific T cells. This is an extremely promising development in anti-HCV vaccines research since restoration of exhausted anti-HCV T cells is a major challenge when developing either prophylactic or therapeutic vaccines. This review will discuss the correlation between PD-1 expression and the clinical outcome in HCV patients and how this information can be potentially applied to block PD-1/PD-L1 pathway for HCV immunotherapy.