Inhibiting silencing information regulator 1 is conducive to the suppression of hepatitis B virus replication by...

Hepatitis B is a severe viral infectious disease, and there is no effective enough way to cure it completely at present. In this study, we first probed into the effect of sirtuin 1 inhibitor III (EX527) on hepatitis B virus (HBV) replication following inhibition of silencing information regulator 1 (SIRT1) and whether EX527 can enhance the efficacy of entecavir (ETV) in anti-HBV therapy. The synergistic interaction of EX527 (10 μM) with ETV (25 μg/mL) was performed in the HBV steady-state replicating cell line HepG2.2.15. The expression profiles of HBV DNA, total RNA, pregenomic RNA, hepatitis B surface antigen, hepatitis B e antigen, HBV X antigen, hepatitis B core antigen, tumor necrosis factor-α, interleukin-6, and nuclear factor-κB were examined by real-time quantitative polymerase chain reaction, ELISA, immunofluorescence, and Western blot. The results show that silenced SIRT1 expression significantly inhibited the replication of HBV. The combination of SIRT1 inhibitor and ETV further reduced HBV DNA levels (24 hours: P = .0012; 95% combination index (CI), 0.1563-0.3164; 48 hours: P = .0025; 95% CI, 0.1990-0.4746; 72 hours: P = .0009; 95% CI, 0.2011-0.3867), total RNA (24 hours: P < .0001; 95% CI, 0.3183-0.4506; 48 hours: P = .0011; 95% CI, 0.2500-0.4964; 72 hours: P = .0011; 95% CI, 0.2978-0.5937) and pregenomic RNA (24 hours: P < .0001; 95% CI, 0.2624-0.3194; 48 hours: P = .0001; 95% CI, 0.3158-0.4554; 72 hours: P = .0022; 95% CI, 0.2586-0.5975) levels compared to ETV monotherapy. Significant reduction in hepatitis B surface antigen (24 hours: P = .0002; 95% CI, 113.3526-173.7049; 48 hours: P < .0001; 95% CI, 128.9962-160.8836; 72 hours: P < .0001; 95% CI, 129.0970-164.7718), hepatitis B e antigen (24 hours: P = .0094; 95% CI, 1.2650-4.9331; 48 hours: P = .0215; 95% CI, 0.7548-5.4610; 72 hours: P = .0003, 95% CI, 4.5457-7.4308), HBV X antigen (24 hours: P = .0009; 95% CI, 0.2263-0.4302; 48 hours: P < .0001; 95% CI, 0.3094-0.3866; 72 hours: P = .0019; 95% CI, 0.2393-0.5325) and hepatitis B core antigen (24 hours: P = .0010; 95% CI, 0.3161-0.6200; 48 hours: P = .0022; 95% CI, 0.2847-0.6571; 72 hours: P = .0012; 95% CI, 0.2571-0.5188) levels were observed in the SIRT1 inhibitor and ETV combination groups. Cotreatment with EX527 and ETV had a more conspicuous effect on the inflammatory factors: tumor necrosis factor-α (mRNA: P < .0001; 95% CI, 0.2207-0.2961; protein: P = .0226; 95% CI, 5.3050-40.7000), interleukin-6 (mRNA: P < .0001; 95% CI, 0.2413-0.3220; protein: P = .0134; 95% CI, 0.5065-1.6998), and nuclear factor-κB (P = .0057; 95% CI, 0.1808-0.4268). These in vitro results indicated that the combination of SIRT1 inhibitor EX527 and ETV can effectively inhibit the replication of HBV. SIGNIFICANCE STATEMENT: This study has important theoretical and practical significance. It explores the factors influencing the replication of the hepatitis B virus from a new perspective and provides new ideas for follow-up research.