Signalling adaptor TRAF1 modulation, as a therapeutic target, to restore HCV-specific cytotoxic T cell response reactivity during chronic infection
Hepatitis C virus (HCV) worldwide infects around 170 million people. Two thirds of primo-infections develop a chronic disease that could lead to cirrhosis and hepatocellular carcinoma. This infection can be cured with direct acting anti-virals (DAA) but there are still difficult to treat cases relap...
| Autores: | , |
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| Tipo de recurso: | conjunto de datos |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Consorcio Madroño |
| Repositorio: | e-cienciaDatos, Repositorio de Datos del Consorcio Madroño |
| OAI Identifier: | doi:10.21950/P2RKZB |
| Acceso en línea: | https://doi.org/10.21950/P2RKZB |
| Access Level: | acceso abierto |
| Palabra clave: | Medicine, Health and Life Sciences Infectious Diseases Hepatology Viral Hepatitis CD8 T cell response Exhaustion Co-stimulation Immunotherapy Hepatitis C 4-1BB TRAF1 CD127 PD-1 Mcl-1 |
| Sumario: | Hepatitis C virus (HCV) worldwide infects around 170 million people. Two thirds of primo-infections develop a chronic disease that could lead to cirrhosis and hepatocellular carcinoma. This infection can be cured with direct acting anti-virals (DAA) but there are still difficult to treat cases relapsing after treatment, in which immunotherapy could play a role in curation. A successful immune response against HCV depends on virus-specific CD8+ T cells. During chronic infection, these cells are functionally impaired. The degree of this immune impairment could rely on the grade of co-stimulation failure over time of infection. The analysis of this dataset shows that: (1) Patients with short-mid lasting HCV infection had mild exhausted T cells, featured by loss of the key signal transducer (TRAF1) of the positive checkpoint 4-1BB/4-1BBL. (2) The functionality of these cells can be restored by IL-7-induced TRAF1 up-regulation, while in long-lasting infection to block the negative-costimulatory pathway PD-1/PD-L1 was also necessary. (3) Nevertheless, this last strategy was only useful in slow-fibrosers, suggesting an extreme T cell exhaustion or deletion in rapid fibrosers. In sum, our work supports novel ways of restoring specific CD8+ T cell response during chronic HCV infection, shedding light on the importance of TRAF1 signalling, which could be a promising target for immunotherapy in non-responders to DAA. |
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