In chronic HBV infection, exhausted HBV-specific CD8 T cells express misregulated mitochondrion and proteasome functions. To better characterize the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion we analyzed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to target simultaneously both mitochondrial and proteostasis functions were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in chronic HBV patients.Lysosome-mediated degradation pathways were analyzed by flow cytometry in virus-specific CD8 T cells from chronic HBV patients, in comparison to patients able to resolve spontaneously HBV infection and healthy subjects. Mitochondrial function, intracellular proteostasis and cytokine production were evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol and oleuropein and their metabolites, either alone or in combination with other bioactive compounds.HBV-specific CD8 T cells of chronic patients showed impaired autophagic flux. A significant improvement of mitochondrial, proteostasis and antiviral CD8 functions was elicited by resveratrol and oleuropein. Cytokine production was also enhanced by synthetic metabolites which correspond to those generated by resveratrol and oleuropein metabolism in vivo, suggesting that these polyphenols may display their effect also after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalizing effect of mt-antioxidants and of PD-1/PD-L1 blockade.Targeting simultaneously multiple altered intracellular pathways with the combination of mitochondria-antioxidants and natural polyphenols may represent a promising strategy in the perspective of novel immune reconstitution therapies to treat chronic HBV infection.