Restoring NAD+ with NMN Rescues Immune Cell Function Against Hepatitis B

New Study: Restoring NAD+ with NMN Rescues Immune Cell Function Against Hepatitis B



Highlight: In chronic HBV infection elevated ROS production is associated to high DNA damage in HBV-specific CD8 T cells

- Response to DNA damage is dysfunctional
- Up-regulation of CD38 and persistent activation of Poly-ADP-Ribose Polymerases (PARPs) contribute to NAD consumption
- NAD depletion maintains and amplifies cellular dysfunctions in exhausted HBV-specific T Cells
-NAD replenishment can restore the T cell function

Chronic Hepatitis B (CHB) is a persistent viral infection that affects millions of people worldwide. The infection can cause severe liver damage, liver cancer, and ultimately death. One of the hallmarks of CHB infection is the exhaustion of virus-specific CD8 T cells, which are essential for the clearance of the virus. Elevated levels of reactive oxygen species (ROS) derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The researcher demonstrated how the use of nicotinamide mononucleotide (NMN) and nicotinamide adenine dinucleotide (NAD) can potentially restore the function of exhausted CD8 T cells in CHB system.

The Mechanism of CD8 T cell Exhaustion in CHB

Studies have shown that CD8 T cell exhaustion in CHB patients is associated with defective DNA repair processes, including NAD-dependent parylation. NAD depletion is indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, mitochondrial, and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function. This suggests that multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion, which is similar to the process of cell senescence.

The Role of CD38 in CD8 T Cell Exhaustion

CD38 has been recognized as the major NAD consumer and its overexpression has been associated with high NAD consumption and subsequent depletion, and with altered mitochondrial function. In aged mice, CD38 overexpression was associated with low mitochondrial membrane potential and increased dependence on glycolysis, metabolic features common to HBV-specific CD8 T cells in CHB. CD38 overexpression may be causally involved in NAD shortage in exhausted HBV-specific CD8 T cells.

The Role of NAD in CD8 T cell Function

NAD is an essential coenzyme that plays a crucial role in the maintenance of energy homeostasis, DNA repair, and redox signaling. The restoration of intracellular NAD levels can improve mitochondrial and proteostasis functions and thus restore the function of exhausted CD8 T cells in CHB. In addition, NAD supplementation can also restore DNA repair mechanisms and improve HBV-specific antiviral CD8 T cell function.

CD8 T cell exhaustion is a major obstacle in the clearance of chronic viral infections, including CHB. The use of NAD precursor NMN and NAD supplementation has shown promising results in the restoration of the function of exhausted CD8 T cells in CHB patients. CD38 overexpression and subsequent NAD depletion are major factors contributing to CD8 T cell exhaustion in CHB patients.

Therefore, the correction of these deregulated intracellular functions by NAD supplementation represents a promising potential therapeutic strategy for chronic HBV infection. Further studies are needed to explore the full potential of NMN and NAD as a treatment for CHB.

 

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