Impaired natural killer cell migration in HIV-infected individuals is caused by TIGIT-mediated inhibition of HIF-1α-dependent glycolysis

Natural killer (NK) cells serve as the first line of defense in the immune system and play a crucial role in fighting against HIV infection. The effective function of NK cells is closely related to their migratory capacity. However, the status of NK cell migration in HIV-infected individuals and the underlying regulatory mechanisms remain unknown. Here, we found that NK cell migration was significantly impaired in HIV-infected individuals, with even lower levels in immune non-responders (INRs) compared with immune responders (IRs), and was positively correlated with CD4⁺ T cell counts. Further investigation suggested that the reduced NK cell migration in HIV infection was caused by impaired glycolysis. Mechanistically, NK cell migration was regulated by the HIF-1α pathway. The inhibitory receptor TIGIT suppressed HIF-1α expression by inhibiting PI3K/AKT/mTORC1 and ERK signaling pathways, consequently weakening glycolysis in NK cells of HIV-infected individuals and ultimately leading to downregulation of migration. Collectively, we uncovered a mechanism of reduced NK cell migration during HIV infection and provided new insights for potential immunotherapeutic strategies. Schematic of the mechanism of regulating NK cell migration in HC and HIV-infected individuals: Under normal physiological conditions, NK cells express sufficient levels of the glucose transporter GLUT-1 to support glycolysis, enabling normal glucose uptake. Meanwhile, activation of PI3K/AKT/mTORC1 or ERK signaling pathways induces HIF-1α expression, which subsequently promotes intracellular glycolysis and maintains regular NK cell migration. During HIV infection, the expression of GLUT-1 on NK cells is down-regulated, resulting in impaired glucose uptake. Additionally, High TIGIT expression suppresses HIF-1α expression by inhibiting the PI3K/AKT/ mTORC1 or ERK signaling pathway, thereby impairing glycolysis and ultimately reducing NK cell migration.