Chronic HBV infection impairs the glucose metabolism and effector function of NK cells via HBsAg/IL-15/mTOR axis.

Natural killer (NK) cell function is impaired in patients with chronic hepatitis B (CHB) infection; however, the underlying mechanisms are not fully understood. Here, we collected the blood samples from healthy donors (HDs) and patients with CHB, and then analyzed the characteristics of NK cells by RNA-seq analysis, flow cytometry, Seahorse assay. HBV-carrier mice were used to confirm the findings in vivo. We found that the dysfunction of NK cells in peripheral blood of patients with CHB was associated with the disturbance of glycolysis. Further investigation showed chronic HBV infection impaired the activation of mammalian target of rapamycin (mTOR) in NK cells, resulting in decreased expression of molecules involved in glycolysis, including HIF-1α and GLUT1. Mechanistically, we found that HBsAg suppressed IL-15-triggered mTOR activity by competitively binding to the IL-15 receptor β (IL-15Rβ, CD122) on NK cells, leading to the decreased expression of HIF-1α and its downstream genes. Significantly, HBsAg neutralizing antibody intravenous injection or mTOR agonist MHY1485 intraperitoneal injection restored the IL-15/mTOR signaling in NK cells of HBV-carrier mice, resulting in NK cell activation and HBV clearance. Further, transferring MHY1485-pretreated NK cells isolated from HBV-carrier mice displayed augmented anti-HBV effects in recipient HBV-carrier mice. These findings reveal a new mechanism by which chronic HBV infection induces NK cell dysfunction, and highlight the potential of mTOR activation and HBsAg clearance as therapeutic strategies for CHB treatment via recovering NK cell immune functions.