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

Nat Med. 2017 Mar;23(3):327-336. doi: 10.1038/nm.4275. Epub 2017 Feb 6.


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.

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Antioxidants / pharmacology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cytokines / immunology
  • Down-Regulation
  • Female
  • Hepatitis B / immunology
  • Hepatitis B, Chronic / genetics
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / metabolism
  • Humans
  • Male
  • Membrane Potential, Mitochondrial
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Polymerase Chain Reaction
  • Reactive Oxygen Species / metabolism*
  • Superoxides / metabolism
  • Transcriptome
  • Young Adult


  • Antioxidants
  • Cytokines
  • Reactive Oxygen Species
  • Superoxides