Lnc-AIFM2-1 promotes HBV immune escape by acting as a ceRNA for miR-330-3p to regulate CD244 expression

Abstract

Chronic hepatitis B (CHB) virus infection is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) immune escape is regulated by the exhaustion of virus-specific CD8+ T cells, which is associated with abnormal expression of negative regulatory molecule CD244. However, the underlying mechanisms are unclear. To investigate the important roles of non-coding RNAs play in CD244 regulating HBV immune escape, we performed microarray analysis to determine the differential expression profiles of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in patients with CHB and patients with spontaneous clearance of HBV. Competing endogenous RNA (ceRNA) was analyzed by bioinformatics methods and confirmed by the dual-luciferase reporter assay. Furthermore, gene silencing and overexpression experiments were used to further identify the roles of lncRNA and miRNA in HBV immune escape through CD244 regulation. The results showed that the expression of CD244 on the surface of CD8+ T cells was significantly increased in CHB patients and in the co-culture system of T cells and HBV-infected HepAD38 cells, which was accompanied by the reduction of miR-330-3p and the elevation of lnc-AIFM2-1. The down-regulated miR-330-3p induced the apoptosis of T cells by lifting the inhibition of CD244, which was reversed by miR-330-3p mimic or CD244-siRNA. Lnc-AIFM2-1 promotes the accumulation of CD244, which is mediated by decreased miR-330-3p, and then reduced the clearance ability of CD8+ T cells to HBV through regulated CD244 expression. And the injury in the ability of CD8+ T cells to clear HBV can be reversed by lnc-AIFM2-1-siRNA, miR-330-3p mimic, or CD244-siRNA. Collectively, our findings indicate that lnc-AIFM2-1 on CD244 by acting as a ceRNA of miR-330-3p contributes to HBV immune escape, which may provide novel insights into the roles of interaction networks among lncRNA, miRNA, and mRNA in HBV immune escape, highlighting potential applications of lnc-AIFM2-1 and CD244 for diagnosis and treatment in CHB.

Hsa-circRNA-0015004 promotes hepatocellular carcinoma development via miRNA-330-3p/RCC2 axis

“…MiR-330-3p has been acknowledged for its suppressive effects on various human tumors, including colorectal cancer, melanoma, and ovarian cancer (21)(22)(23). Notably, miR-330-3p downregulation ampli es HCC cell proliferation (24,25). In line with the previous studies, miR-330-3p expression was decreased in both HCC cell lines and tissues.…”

A Systematic Review of the Advances in the Study of T Lymphocyte Suppressor Receptors in HBV Infection: Potential Therapeutic Targets

“…These findings suggest that the expression of CD244 may play an independent role in the chronicity of HBV infection. It is now believed that the possible mechanism is that Lnc-AIFM2-1 acts as an endogenous competitive RNA (ceRNA) for miR-330-3p to regulate the expression of CD244 on CD8+ T cells and contributes to the immune escape of HBV [ 61 ]. Studies conducted at the epigenetic level have revealed that examining the gene regulation process in immune cells during HBV clearance can provide valuable insights into the expression of crucial genes that determine the function of immune cells.…”

NAC1 transcriptional activation of LDHA induces hepatitis B virus immune evasion leading to cirrhosis and hepatocellular carcinoma development

“…Jurkat cells were placed in the upper chamber of Transwell while LX-2 cells were placed in the lower chamber. This process was done to detect the impact of LX-2 cells on the apoptosis and proliferation of immune cells Jurkat [ 10 ].…”

“…HBV immune escape plays a pivotal role in the development of liver cirrhosis, impeding the ability of the immune system to eliminate the HBV virus, thus leading to persistent infection [ 10 ]. This not only heightens the risk of patients developing cirrhosis and liver cancer, but also complicates treatment [ 11 ].…”

“…This not only heightens the risk of patients developing cirrhosis and liver cancer, but also complicates treatment [ 11 ]. Furthermore, advancements in the research on HBV immune evasion enhance our comprehension of the interplay between the virus and the host immune system, yielding significant insights for the formulation of vaccines and antiviral therapies [ 10 ]. In conclusion, a comprehensive understanding of the repercussions of cirrhosis and liver cancer, along with the mechanisms behind HBV immune escape, is imperative for the prevention and management of these critical health conditions.…”