Inhibition of Viral Replication Downregulates CD4⁺CD25^highRegulatory T Cells and Programmed Death-Ligand 1 in Chronic Hepatitis B

Abstract

Chronic hepatitis B is characterized by an impaired immune response to hepatitis B virus (HBV). Telbivudine treatment has significantly improved the clinical outcome of chronic HBV infection. However, the underlying mechanism behind the antiviral response of patients treated with nucleoside analogs remains unclear. To gather more evidence about the mechanism responsible for the weak immune response, in this study we analyzed the effects on HBV viral load of treatment with the nucleoside analogue telbivudine and the percentage of Tregs, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, and related cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum of 28 patients with chronic hepatitis B were collected at baseline, and 3 mo and 6 mo after therapy was begun. In parallel with the decline in viral load and serum ALT normalization, we found a decline in circulating CD4(+)CD25(high) Tregs, PD-L1 on CD4(+) T cells, and IL-9 production. The expression of PD-1 on CD4(+) T cells and the production of IFN-γ did not increase during therapy. Our findings suggest that the antiviral effect of the nucleoside analogs may be attributable not only to their direct effect on virus suppression, but also to their immunoregulatory capabilities.

Liver FOXP3 and PD1/PDL1 Expression is Down-Regulated in Chronic HBV Hepatitis on Maintained Remission Related to the Degree of Inflammation

“…Accordingly, our findings did not support an antiviral Teffs function restoration in long-term maintained remission of chronic HBV infection, since no significant differences of the expression of CD4 , IL2 , and IFNG were observed. Interestingly, the abovementioned findings, considering Teffs function at remission, are in line with the findings of Nan et al suggesting that the impaired immune responses of CHB patients are not fully restored by therapy, since no significant differences in the expression of IFN-gamma were found (23). On the other hand, the expressions of PD1 and PDL1 were significantly associated with the intensity of histological liver inflammation.…”

High Viral Burden Restricts Short-Lived Effector Cell Number at Late Times Postinfection through Increased Natural Regulatory T Cell Expansion

“…VV (17), HIV (40,41), HSV (18,19,40), HCV (40,42). Viral load appears to be an important regulator of Treg number as, for example, antiviral treatment during acute hepatitis B infection resulted in decreased nTreg that correlated with decreased virus load (43,44). This is potentially through increased production of IL-2, which promotes nTreg expansion and suppressive function (33).…”

Regulatory T Cells in HIV Infection: Can Immunotherapy Regulate the Regulator?

“…Recently, it has been shown in chronic Hepatitis B (HBV) that inhibition of viral replication by anti-HBV drugs is associated with diminished Treg expression [92]. However, the impact of ART on Treg frequency in HIV-infected patients remains controversial.…”