Curcumin inhibits HIV-1 by modulating FOXP3 and suppressing CCR5 via PI3K/AKT and JAK/STAT pathways.

Despite advances in antiretroviral therapy, HIV-1 persistence and immune dysregulation remain unresolved challenges. Here, we demonstrate that curcumin, a low-toxicity natural compound, can inhibit HIV-1 through simultaneous inhibition of the PI3K/AKT and JAK/STAT pathways, leading to downregulation of the viral co-receptor CCR5 and the immune checkpoint transcription factor FOXP3. Using CHIP and EMSA experiments, we found that curcumin disrupts the binding of FOXP3 to the CCR5 promoter, thereby reducing viral entry. Network pharmacology and molecular docking identified STAT3 and AKT1 as key targets. Most importantly, we found that crosstalk between the PI3K/AKT and JAK/STAT pathways is a pharmacological axis for HIV-1 treatment through high-throughput sequencing technology, mass spectrometry and CO-IP experiments. Our findings provide a mechanistic basis for the repurposing of curcumin as an adjuvant to HAART, with implications for therapies targeting viral reservoirs.