REVIEW PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection T. Watanabe, 1,2 A. Bertoletti 1,3,4 and T. A. Tanoto 1,3 1 Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore, Singapore; 2 Division of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan; 3 Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; and 4 Program Emerging Viral Diseases Unit, Duke-NUS Graduate Medical School, Singapore, Singapore Received March 2010; accepted for publication March 2010 SUMMARY. Dysfunctional virus-specific T cells are a hall- mark of many chronic viral infections. Recent studies have implicated the inhibitory PD-1/PD-L1 pathway with the functional impairment of T cells. In this respect, we will review the latest research on PD-1/PD-L1 pathway and T- cell exhaustion in the context of human chronic hepatitis B and C virus infections. We will also discuss the therapeutic potential of PD-1 blockade and how it may be enhanced through the modulation of other co-stimulatory/inhibitory pathways. Keywords: HBV, HCV, PD-1, PD-L1, T cell. INTRODUCTION The hepatitis B (HBV) and C (HCV) viruses are both non- cytopathic and hepatotrophic viruses capable of causing self- limited and chronic infections of the liver. Over 500 million chronic infections worldwide are attributed to these viruses, and while the majority of those chronically infected carriers remain largely asymptomatic, some do develop secondary liver complications which may progress to hepatocellular carcinoma (HCC) [1,2]. A large body of evidence has dem- onstrated the importance of T-cell immunity in the control of both viruses [3–19]. Virus-specific T cells in patients with persistent HBV or HCV infections are usually present in minute frequencies and are often functionally incapacitated. In contrast, patients with classical self-limiting HBV and HCV infections almost always have detectable virus-specific T cells in the periphery, with an intact proliferative, cyto- toxic and cytokine secretion capacity. This association, al- though not conclusive for the cause of chronicity, is a strong support for the need of a functionally intact T-cell response in the control of HBV and HCV. The cause of the above-mentioned T-cell dysfunction is at present debatable with several hypotheses proposed to account for the observed clinical and in vitro phenomenons. Prolonged exposure to high concentration of viral antigens [4], increased apoptosis of virus-specific T cells through Bcl-2 signalling [20], defective signalling through CD3f [21], immunoregulatory cells and cytokines [22–25] are just some of the plausible mechanisms. Recently, increasing number of studies has suggested the importance of inhibitory receptor pathways in T-cell exhaustion. Particularly, an extraordi- nary amount of effort has been focused to decipher the role of the PD-1/PD-L1 pathway. The PD-1 receptor is a member of the B7:CD28 family which is mainly expressed on the surface of activated T and B cells, while its ligands PD-L1 and PD-L2 are found in a wide variety of cell types, including hepatocytes [26] (Table 1). Ligation of PD-1 causes the recruitment of SHP-2 phosphatase, which in turn inhibits PI3K activity and downstream activation of Akt, resulting in the dampening of T-cell receptor (TCR) signalling and the eventual inhibition of T-cell activation [27–29]. The involvement of PD-1/PD-L1 pathway in chronic viral infection–associated T-cell exhaustion was first demonstrated in a murine lymphocytic choriomeningitis virus (LCMV) model [30]. Infection of mice with the clone 13 strain of LCMV, which results in viral persistence, led to the functional exhaustion of LCMV- specific CD8 T cells and the continuous elevated expression of PD-1. Functional recovery of the exhausted T cells was also shown to be possible with PD-1/PD-L1 blockade, restoring proliferation, cytokine secretion, cytotoxic capability and decreasing viral load. Abbreviations: DC, dendritic cells; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LCMV, lymphocytic choriomeningitis virus; SIV, Simian immunodeficiency virus; TCR, T-cell receptor. Correspondence: Antonio Bertoletti, Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, S(117609) Singapore, Singapore. E-mail: antonio_bertoletti@sics.a-star.edu.sg Journal of Viral Hepatitis, 2010, 17, 453–458 doi:10.1111/j.1365-2893.2010.01313.x Ó 2010 Blackwell Publishing Ltd