HCV-Specific T Cells Remain Functionally Impaired Despite HCV Clearance

Hepatitis C virus (HCV)-specific T cells remain functionally impaired despite HCV clearance, which may explain why HCV cure does not lead to protective immunity and that reinfections can occur, according to study results published in the Journal of Hepatology.¹

Chronic HCV is characterized by functional impairment of virus-specific CD8+ T cells.^2,3 While interferon (IFN)-free direct-acting antiviral (DAA) therapies result in rapid clearance of HCV from patients who were infected, as well as a sustained virologic response (SVR), reverberation of HCV clearance on virus-specific CD8+ T cells remains unclear.¹ Thus, researchers investigated whether HCV clearance by DAAs could restore the functionality of exhausted HCV-specific CD8+ T cell responses in 40 patients who were chronically infected with HCV and had received IFN-free DAA therapy. They found that surface expression of multiple co-regulatory receptors of exhausted HCV-specific CD8+ T cells remained unaltered after clearance of HCV. In addition, cytokine production by HCV-specific CD8+ T cells remained impaired following HCV clearance and the proliferative capacity of HCV multimer-specific CD8+ T cells was not restored in the majority of patients.

The researchers also found that enhanced in vitro proliferative expansion of HCV-specific CD8+ T cell during HCV clearance was more likely in women, patients with low liver stiffness, and low alanine aminotransferase levels. In addition, HCV-specific CD8+ T cells that did not proliferate following HCV clearance could preferentially reinvigorate their proliferative capacity upon in vitro immune-check-point inhibition. However, altered mitochondrial dysfunction exhibited by exhausted HCV-specific CD8+ T cells could not be normalized after HCV clearance.

“Our data implies that exhausted HCV-specific CD8+ T cells during chronic hepatitis C still remain functionally and metabolically impaired at multiple levels following HCV clearance in most patients,” concluded the investigators.¹ They added that, “Our results might have implications in case of re-infection with HCV and for HCV vaccine development.”

References

1. Aregay A, Sekyere SO, Deterding K, et al. Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses [published online July 8, 2019]. J Hepatol. doi:10.1016/j.jhep.2019.06.025

2. Heim MH, Thimme R. Innate and adaptive immune responses in HCV infections. J Hepatol. 2014;61:S14-S25.

 3. Rehermann B, Thimme R. Insights from antiviral therapy into immune responses to hepatitis B and C virus infection. Gastroenterology. 2019;156:369-383.