Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV infection: Effect of viremia levels and antiviral treatment☆
Introduction
The hepatitis C virus (HCV) establishes persistent infection and causes chronic liver injury in the majority of infected individuals. The adaptive immunity has a central role in the pathogenesis of this viral infection and understanding the behavior of the T cell response is crucial for the design of effective strategies to control HCV [1], [2], [3], [4], [5]. Different studies in the chronic as well as in the early acute phase of HCV infection have suggested that a functional impairment of the HCV-specific cell-mediated immune response plays an important role in HCV persistence [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. Moreover, recent studies have provided us with a better understanding of both the positive and negative signals regulating the antigen-specific T cell function and their importance with respect to the outcome of viral infections [18], [19], [20]. PD-1/PD-L1 molecules are part of one of these regulatory pathways that has first been reported to inhibit the virus-specific CD8 cell function in lymphocytic choriomeningitis virus infection [21], [22]. PD-1 is expressed on thymocytes and it is up-regulated on activated T and B cells [21], [22]. Its ligands are the PD-L1 and PD-L2 molecules; PD-L2 expression is limited to professional antigen-presenting cells (APCs), whereas PD-L1 has a much broader tissue distribution and it has recently been described to be induced in hepatocytes by viral infection and by interferon-alpha and -gamma [21], [22], [23]. PD-1 engagement blocks cellular entry into the cell cycle and the production of effector cytokines [21], [22]. Many recent findings indicate that this pathway plays a role also in the pathogenesis of human infections caused by HBV, HIV and HCV [24], [25], [26], [27], [28], [29], [30], [31], [32]. Previous studies performed both in acute and in chronic HCV infection indicated that PD-1 is highly expressed by HCV-specific CD8 cells and that blockade of the PD-1/PD-L1 pathway by anti-PDL-1 antibodies can improve the function of HCV-specific CD8 cells [7], [29].
In continuation of these studies, the present work was undertaken to better understand to what extent the antiviral function of CD4 and CD8 cells can be reconstituted by PD-1/PD-L1 blockade in situations of chronic exposure to high viral antigen concentrations and whether antiviral therapy in chronically evolving acute HCV infections can facilitate this immunological reconstitution. Our data suggest that increasing amounts of virus in patients with chronic evolution of HCV infection are associated with enhanced expression of PD-1 on virus-specific CD8 cells and a lower likelihood of functional T cell restoration by PD-1/PD-L1 blockade. A better recovery of the T cell function was observed at lower levels of viremia and under IFN-α/ribavirin therapy. Although limited to a small cohort of patients, this more efficient effect of anti-PD-L1 observed under antiviral therapy suggests a possible strategy to improve the efficacy of IFN/ribavirin treatment to be assessed in patients with a long-lasting condition of chronic HCV infection who require improved protocols of therapy to increase their sustained response rate.
Section snippets
Patients
A total of 14 patients were enrolled at the Unit of Infectious Diseases and Hepatology of the Azienda Ospedaliero-Universitaria and were studied from the acute phase of HCV infection to one–two years of follow-up. All patients were infected by HCV genotype 1. Six of them with persistent elevation of serum alanine aminotransferase (ALT) levels and persistently positive HCV–RNA were treated with IFN-α plus ribavirin 3 to 6 months after the onset of acute hepatitis. The diagnosis of acute
PD1 and PDL-1 expression is related to viremia levels and IFN-α treatment
PD-1 MFI was analyzed on virus-specific CD8 cells of 12 HLA-A2 positive patients using tetramers containing three different HLA-A2 restricted HCV epitopes (NS3 1073, NS3 1406, NS4 1992). By plotting PD-1 MFI values against the corresponding viremia levels derived from all time points tested in each patient, a linear correlation was found between PD-1 mean fluorescence intensity (MFI) and HCV–RNA (p < 0.001) (Fig. 1A). The decline of viremia, either spontaneous of induced by IFN-α therapy, was
Discussion
It is well known that HCV has a high propensity to persist. To accomplish this, the virus has developed several strategies to evade HCV-specific T cell responses [3], [4]. These include the direct inhibitory effect of viral proteins on T cell responses and the emergence of escape mutations [33], [34], [35]. Moreover, viral proteins can interfere with viral recognition by the innate immune system, thereby making innate responses poorly efficient in the early containment of infection [36].
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The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.