Search

• PD-1/PD-L1 signalling involves T-cell exhaustion in patients with chronic hepatitis B virus (HBV) infection. • Increased expression of PD-1 is considered to be associated with infectious diseases. • PD-1.9 and PD-1.9 are associated with HBV-associated liver disease outcomes. • Increased sPD-1 levels are associated with HBV-related liver inflammation and fibrosis. Programmed cell death-1 (PD-1) variants and circulating level of soluble PD-1 are associated with susceptibility to malignant and infectious disease. This study aimed to examine the association of PD-1.5 and PD-1.9 variants, and plasma sPD-1 level with hepatitis B virus (HBV) infection and disease progression. The study cohort consisted of adults infected with HBV (n =513) – stratified by clinical course, including chronic hepatitis B (CHB, n =173), liver cirrhosis (LC, n =134) and hepatocellular carcinoma (HCC, n =206) – and matched healthy controls (HC, n =196). The PD-1.5 (rs2227981 C/T) and PD-1.9 (rs2227982 C/T) genetic variants were genotyped by Sanger sequencing, and plasma sPD-1 levels were quantified by enzyme immunoassay. Plasma sPD-1 levels were significantly higher among patients infected with HBV. The highest plasma sPD-1 levels were observed in patients with CHB, followed by patients with LC and HCC. In addition, the plasma sPD-1 levels correlated positively with liver inflammation [aspartate transaminase (AST): rho=0.57, P <0.0001; alanine aminotransferase: rho=0.57, P <0.0001], and were positively correlated with liver fibrosis [AST to platelet ratio index score: rho=0.53, P <0.0001). The PD-1.9 TT genotype was less common in patients with CHB compared with patients with LC, HCC, and HCC+LC in both codominant and recessive models (P <0.01), and was found to be a risk factor for HCC predisposition {HCC vs non-HCC: odds ratio (OR) 2.0 [95% confidence interval (CI) 1.13–3.7], P adj =0.017}. The PD-1.5 CT genotype was associated with reduced risk of acquiring HCC [OR 0.6 (95% CI 0.4–0.9), P adj =0.031]. sPD-1 level was associated with liver inflammation and progression of liver fibrosis, and the PD-1.5 and PD-1.9 variants were associated with HBV infection and progression of liver disease. [ABSTRACT FROM AUTHOR]

Highlights • The NTCP S267F variant is associated with a lower risk of chronic HBV infection. • First study on NTCP S267F variant on concomitant HDV infection in Vietnamese population. • The NTCP S267F is correlated with a reduced risk on clinical progression of liver cirrhosis and liver cancer. Abstract Objectives To determine potential associations of the rs2296651 variant (c.800C > T, S267F) of NTCP with HBV and HBV plus concomitant HDV infection as well as with the progression of related liver diseases. Methods The S267F variant was genotyped by DNA sequencing in 620 HBV-infected patients and 214 healthy controls (HCs). Among the patients, 450 individuals were tested for HDV by a nested PCR assay. Logistic regression was applied to examine the association. Results The S267F variant was found more frequently among HCs (16%) compared to HBV-infected (6%) and HBV-HDV co-infected patients (3%) (HBV patients vs HC: OR = 0.32, P = 0.00002 and HDV patients vs. HC: OR = 0.17, P = 0.018). The frequency of S267F variant was inversely correlated with CHB, LC or HCC patients compared with HCs (OR = 0.31, P = 0.001; OR = 0.32, P = 0.013; OR = 0.34, P = 0.002, respectively). S267F variant was also associated with decreased risk of the development of advanced liver cirrhosis (LC) and hepatocellular carcinoma (HCC) (Child B and C vs. Child A, OR = 0.26, adjusted P = 0.016; BCLC B,C,D vs. BCLC A, OR = 0.038, P = 0.045, respectively). In addition, patients with the genotype CT had lower levels of AST, ALT, total and direct bilirubin as well as higher platelet counts, indicating an association with a more favorable clinical outcome. Conclusion The NTCP S267F variant of the SLC10A1 gene exhibits protective effects against HBV and HDV infection and is associated with a reduced risk of developing to advanced stages of LC and HCC. [ABSTRACT FROM AUTHOR]

• Activation of PD-1/PD-L1 signaling pathway is considered to cause HBV-specific CD8+T cell exhaustion in chronic HBV infection. • Increased expression of PD-L1 involves in various health conditions, including infectious diseases, chronic inflammations, cancers. • The missense variant PD-L1 rs2297136 is associated with HBV infection susceptibility and liver disease progression. • Plasma sPD-L1 correlated with liver inflammation and associated with clinical outcomes in HBV infected patients. Soluble molecules of programmed death ligand 1 (sPD-L1) are known to modulate T-cell depletion, an important mechanism of hepatitis B virus (HBV) persistence and liver disease progression. In addition, PD-L1 polymorphisms in the 3′-UTR can influence PD-L1 expression and have been associated with cancer risk, although not definitively. The purpose of this study was to investigate the association of PD-L1 polymorphisms and circulating levels of sPD-L1 in HBV infection and live disease progression. In this study, five hundred fifty-one HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 186), liver cirrhosis (LC, n = 142) and hepatocellular carcinoma (HCC, n = 223) and 240 healthy individuals (HC) were enrolled. PD-L1 polymorphisms (rs2297136 and rs4143815) were genotyped by in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of PD-L1 polymorphisms with HBV infection as well as with progression of related liver diseases. Plasma sPD-L1 levels were quantified by ELISA assays. The PD-L1 rs2297136 AA genotype was associated with HBV infection susceptibility (HBV vs. HC: OR = 1.6; 95%CI = 1.1–2.3; p = 0.0087) and disease progression (LC vs. CHB: OR = 1.8; 95%CI = 1.1–2.9; p = 0.018). Whereas, the rs2297136 GG genotype was a protective factor for HCC development. Plasma sPD-L1 levels were significantly high in HBV patients (p < 0.0001) and higher in the LC followed by CHB and HCC groups. High sPD-L1 levels correlated with increased liver enzymes and with advanced liver disease progression (Child-pugh C > B > A, p < 0.0001) and BCLC classification (BCLC D > C > B > A, p = 0.031). We could, for the first time, conclude that PD-L1 rs2297136 polymorphism and plasma sPD-L1 protein levels associate with HBV infection and HBV-related liver disease progression. [ABSTRACT FROM AUTHOR]