Juan Ramón Larrubia

Bim-mediated apoptosis and PD-1/PD-L1 pathway impair reactivity of PD1+/CD127− HCV-specific CD8+ cells targeting the virus in chronic hepatitis C virus infection

PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8(+) cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8(+) cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1(-)/CD127(+) cells from RI cases was preserved, while it was impaired on PD-1(+)/CD127(-) cells from PI patients. PD1(+)/CD127(+) population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8(+) cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8(+) cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8(+) cells targeting the virus are PD-1(+)/CD127(-)/Bim(+) and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity.

Adaptive immune response during hepatitis C virus infection.

Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

Safety and efficacy of triple therapy with peginterferon, ribavirin and boceprevir within an early access programme in Spanish patients with hepatitis C genotype 1 with severe fibrosis: SVRw12 analysis

The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection.

Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate naïve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.

Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients

Chronic hepatitis B (CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue (NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus (HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen (HBsAg), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBsAg loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBsAg seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure a close follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host’s immune system. Viral parameters that have been described as good predictors of response in HBeAg(+) cases, have proven useless in HBeAg(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.

P1158 EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM

P1158 EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM S. Bruno, S. Bollani, J.M. Pascasio, A.L. Zignego, V. Di Marco, C. Magni, M. Rizzetto, A. Ciancio, A. Alberti, S. Piovesan, A. Mangia, J. De la Revilla, J.R. Larrubia, F. Gea, S. Babudieri, R. Perez-Alvarez, C. Colletta, R. Barcena, X. Forns, M. Romero-Gomez, M. Koch, M. Massari, M. Caremani, J. Crespo, J.M. Navarro, J. Arenas, M.B. Delgado, M. Pirisi, M. Zuin, A. Licata, F. Mazzotta, A. Colombo, M. Russello, I. Fermandez, T. Santantonio, C.M. Fernandez-Rodriguez, F. Farina, B. Ruiz Antoran, P. Maisonneuve, A. Craxì, J.L. Calleja, Italian and Spanish (IAS)-BOC Study Group. AO Fatebenefratelli e Oftalmico, Milano, Italy; Hospital Universitario Virgen del Rocio, Sevilla, Spain; Università degli Studi di Firenze, Firenze, Università degli Studi di Palermo, Palermo, AO L Sacco, Milano, Università di Torino, Torino, Università di Padova, Padova, IRCCS Casa del Sollievo e della Sofferenza, San Giovanni Rotondo, Italy; Hospital Universitario Puerta de Hierro, Madrid, Hospital Universitario de Guadalajara, Guadalajara, Hospital U. La Paz, Madrid, Spain; Università degli Studi di Sassari, Sassari, Italy; Hospital Universitario Central de Asturias, Oviedo, Spain; COQ Ospedale Madonna del Popolo, Omegna, Italy; Hospital Universitario Ramon y Cajal, Madrid, Hospital Clinic, Barcelona, Hospital Universitario de Valme, Sevilla, Spain; AO S Filippo Neri, Roma, IRCCS – ASMN Reggio Emilia, Reggio Emilia, AO di Arezzo, Arezzo, Italy; Hospital Universitario Marques de Valdecilla., Santander, Hospital Costa del Sol, Marbella, Hospital Donostia, Donostia, Hospital Universitario A Coruña, La Coruna, Spain; Università degli Studi di Novara, Novara, Università degli Studi di Milano, Milano, Azienda Ospedaliera di Siena, Siena, AO S Anna, Como, ARNAS Garibaldi, Catania, Italy; Hospital Universitario 12 de Octubre, Madrid, Spain; Università di Foggia, Foggia, Italy; Hospital U. Fundacion Alcorcon, Alcorcon, Spain; Ospedale Cà Foncello, Treviso, Epidemiology and Biostatistics, Istituto Europeo di Oncologia, Milano, Italy E-mail: savino.bruno@fbf.milano.it