Signalling adaptor TRAF1 modulation, as a therapeutic target, to restore HCV-specific cytotoxic T cell response reactivity during chronic infection

Abstract

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.