Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B

P Fisicaro, V Barili, B Montanini, G Acerbi, M Ferracin… - Nature medicine, 2017 - nature.com
P Fisicaro, V Barili, B Montanini, G Acerbi, M Ferracin, F Guerrieri, D Salerno, C Boni…
Nature medicine, 2017nature.com
Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B
infection, and this condition can be corrected only partially through the modulation of
inhibitory pathways, which suggests that a more complex molecular interplay underlies T
cell exhaustion. To gain broader insight into this process and identify additional targets for
the restoration of T cell function, we compared the transcriptome profiles of HBV-specific
CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T …
Abstract
Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.
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