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

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

  • Cell Death Dis. 2025 Nov 7;16(1):805. doi: 10.1038/s41419-025-08039-4.
Xiaowen Yu 1,  Jie Zhou 1,  Jie Lei 1,  Hongchi Ge 1,  Zining Zhang 1,  Yajing Fu 1,  Xiaoxu Han 1,  Qinghai Hu 1,  Haibo Ding 1,  Wenqing Geng 1,  Hong Shang # 2,  Yongjun Jiang # 3
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, 110001, China.
  • 2 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, 110001, China. [email protected].
  • 3 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, 110001, China. [email protected].
  • # Contributed equally.
PMID: 41203617 DOI: 10.1038/s41419-025-08039-4
Abstract

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.

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