Still, HIS-HUHEP mice should offer a useful tool to further study intrahepatic NK-cell responses during different phases of HBV infection where NK cells may modulate anti-viral responses. A broad and robust T-cell response is essential for viral clearance, yet in the context of CHB patients, excess stimulation by viral antigens induces hypo-responsive PD-1+ T cells. 8,11,30We found that PD-1+ T cells were similarly enriched in the livers of HBV-infected HIS-HUHEP mice. Infected hepatocytes and antigen-presenting cells constituted a source of PD-L1 expression that may create an immunosuppressive environment and promote PD-1 mediated T-cell exhaustion. Interestingly, in low-dose inoculated and ETV-treated mice, the frequency of PD-1+ memory CD4+ T cells correlated with viral loads.
HIS-HUHEP mice provide a valuable model for investigating intrahepatic NK-cell responses across various stages of HBV infection, where NK cells may influence antiviral activity. While a strong T-cell response is critical for viral clearance, chronic HBV infection often leads to the overstimulation of T cells by viral antigens, resulting in the accumulation of hypo-responsive PD-1+ T cells. In HBV-infected HIS-HUHEP mice, we observed a similar enrichment of PD-1+ T cells in the liver, with infected hepatocytes and antigen-presenting cells expressing PD-L1, potentially fostering an immunosuppressive environment that drives T-cell exhaustion. Notably, in mice treated with low-dose inoculation and ETV, the frequency of PD-1+ memory CD4+ T cells showed a correlation with viral load levels.
HIS-HUHEP mice can serve as a valuable resource for investigating intrahepatic NK-cell responses throughout various stages of HBV infection, where NK cells may influence antiviral responses. A strong and effective T-cell response is crucial for the clearance of the virus; however, in patients with chronic hepatitis B (CHB), excessive stimulation from viral antigens leads to a prevalence of hypo-responsive PD-1+ T cells. In our studies, we identified a similar increase of PD-1+ T cells in the livers of HBV-infected HIS-HUHEP mice. Infected hepatocytes and antigen-presenting cells were found to express PD-L1, contributing to an immunosuppressive environment that could lead to PD-1 mediated T-cell exhaustion. Notably, in mice that received low-dose inoculation and were treated with ETV, the presence of PD-1+ memory CD4+ T cells showed a correlation with viral loads.
HIS-HUHEP mice can be used as a tool to study intrahepatic NK-cell responses during different stages of HBV infection, during which NK cells can modulate antiviral responses. A robust and efficient T-cell response is essential for virus clearance, but in CHB patients, over-stimulated PD-1+ T cells are found due to over-stimulation by viral antigens. In our experiments, we also found a similar proliferation of PD-1+ T cells in the livers of HBV-infected HIS-HUHEP mice. PD-L1 was expressed by infected hepatocytes and antigen-presenting cells, which provided an immunosuppressive milieu that may induce PD-1 mediated T-cell exhaustion. Interestingly, in low-dose inoculated mice treated with ETV, the number of PD-1+ memory CD4+ T cells was associated with viral loads.
HIS-HUHEP mice can be a useful model for studying intrahepatic NK-cell responses during different phases of HBV infection, where NK cells may play a role in antiviral responses. A robust and potent T-cell response is essential for viral clearance; however, in CHB patients, overstimulation by viral antigens results in a high frequency of hypo-responsive PD-1+ T cells. We also observed a comparable expansion of PD-1+ T cells in the livers of HBV-infected HIS-HUHEP mice in our experiments. Infected hepatocytes and antigen-presenting cells were observed to express PD-L1, which may create an immunosuppressive milieu that could result in PD-1-mediated T-cell exhaustion. Interestingly, in mice inoculated with low dose and treated with ETV, the number of PD-1+ memory CD4+ T cells was correlated with viral loads.