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

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.