Importantly, we pinpointed a major protective mechanism of hsa-miR-31 against HIV infection, that is, hsa-miR-31 maintains the homeostasis of CD4+ T cells via directly targeting STAT1 to tune the IFN-γ-Stat1-T-bet axis, a positive feedback loop known for governing the activation of CD4+ T cells. This evidence concerns the gene CD4 and HIV infectious disease.