Forsythoside B activates Siglec-14 to inhibit HIV-1 replication via the JAK1/STAT1 pathway.

Abstract

The HIV/AIDS epidemic poses a severe global health challenge. While antiretroviral therapy is crucial, it has limitations, including high costs and resistance, and requires long-term use. Consequently, novel antiviral agents with unique structures and innovative mechanisms are needed for better management of HIV/AIDS. We previously discovered that Siglec-14 inhibits HIV-1 replication. In this study, we employed homology modeling and AlphaFold 2 to predict the structure of Siglec-14, followed by molecular dynamics simulations to explore its conformational landscape. The MM/GBSA method was used to calculate the binding free energy of selected small molecules. Among them, Forsythoside B (FTS·B) exhibited the highest binding free energy and enhanced Siglec-14's conformational stability. SPR analysis further confirmed a strong binding affinity between FTS·B and Siglec-14. In vitro experiments demonstrated that FTS·B upregulates Siglec-14 expression and suppresses HIV-1 replication in macrophages. Mechanistically, FTS·B suppresses pro-inflammatory cytokines, increases the expression of interferon-stimulated genes and chemokines, and activates the JAK1/STAT1 pathway in Siglec-14 knockdown macrophages. Our results confirm that FTS·B, as an agonist of Siglec-14, effectively inhibits HIV-1 replication by upregulating Siglec-14 expression and modulating the JAK1/STAT1 signaling pathway, highlighting the potential clinical application value of FTS·B in HIV treatment.