Schistosomiasis has been associated with increased HIV acquisition. Yegorov et al. explored the impact of S. mansoni treatment on HIV susceptibility and discovered that schistosomiasis therapy reduced ex vivo HIV viral entry into both mucosal and systemic CD4+ T cells. Transcriptomic analysis identified up-regulation of global interferon IFN-I pathways and antiviral genes post-Sm treatment, which help explain reduced HIV infectivity. These findings could help guide HIV prevention programs in regions with high endemic disease burden.