2. Academic Validation
  3. Siglec14-TLR2 axis mediates anti-HIV-1 immunity in macrophages

Siglec14-TLR2 axis mediates anti-HIV-1 immunity in macrophages

  • Int Immunopharmacol. 2025 Sep 24:166:115595. doi: 10.1016/j.intimp.2025.115595.
Minjuan Shi 1,  Beibei Lu 1,  Wudi Wei 1,  Shanshan Chen 1,  Jie Liu 2,  Xi Hu 1,  Rongfeng Chen 2,  Zongxiang Yuan 1,  Jinming Su 2,  Xiu Chen 1,  Qiao Tang 2,  Yuting Wu 1,  Li Ye 3,  Hao Liang 4,  Junjun Jiang 5
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of AIDS Prevention and Treatment & School of Public Health, Guangxi Medical University, Nanning 530021, China.
  • 2 Guangxi Key Laboratory of AIDS Prevention and Treatment & School of Public Health, Guangxi Medical University, Nanning 530021, China; Joint Laboratory for Emerging Infectious Diseases in China (Guangxi)-ASEAN, Life Sciences Institute, Guangxi Medical University, Nanning 530021, China.
  • 3 Guangxi Key Laboratory of AIDS Prevention and Treatment & School of Public Health, Guangxi Medical University, Nanning 530021, China; Joint Laboratory for Emerging Infectious Diseases in China (Guangxi)-ASEAN, Life Sciences Institute, Guangxi Medical University, Nanning 530021, China. Electronic address: yeli@gxmu.edu.cn.
  • 4 Guangxi Key Laboratory of AIDS Prevention and Treatment & School of Public Health, Guangxi Medical University, Nanning 530021, China; Joint Laboratory for Emerging Infectious Diseases in China (Guangxi)-ASEAN, Life Sciences Institute, Guangxi Medical University, Nanning 530021, China. Electronic address: lianghao@gxmu.edu.cn.
  • 5 Guangxi Key Laboratory of AIDS Prevention and Treatment & School of Public Health, Guangxi Medical University, Nanning 530021, China; Joint Laboratory for Emerging Infectious Diseases in China (Guangxi)-ASEAN, Life Sciences Institute, Guangxi Medical University, Nanning 530021, China. Electronic address: jiangjunjun@gxmu.edu.cn.
PMID: 40997501 DOI: 10.1016/j.intimp.2025.115595
Abstract

HIV-exposed seronegative (HESN) individuals exhibit natural resistance to HIV-1 Infection, providing a unique model to identify host factors that confer protection against the virus. Building upon our previous transcriptomic studies identifying Siglec14 as a key correlate of HIV-1 resistance in HESN individuals, we investigated its functional role in HIV-1 pathogenesis. We found that HIV-1 Infection upregulates Siglec14 in macrophages, where it suppresses viral replication through potent Antiviral activity. Mechanistically, Siglec14 directly interacts with HIV-1 Nef protein and subsequently engages TLR2, triggering phosphorylation and activation of NF-κB p65 and IRF3. This dual signaling cascade initiates robust Antiviral responses via (1) NF-κB-mediated production of proinflammatory chemokines (CXCLs), and (2) IRF3-dependent induction of type I interferons (e.g., IFN-β) and interferon-stimulated genes (ISGs). Our results establish Siglec14 as a critical innate immune sensor that orchestrates Antiviral defenses through TLR2-mediated signaling, highlighting its potential as a therapeutic target for HIV immunotherapy and vaccine development.

Keywords

HIV-1; Macrophages; Siglec14; TLR2 signaling.

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