In plants and invertebrate animals, RNA silencing is a form of nucleic acid-based adaptive immunity. By contrast, jawed vertebrates have evolved complex protein-based adaptive immunity. Although short interfering RNAs (siRNAs) have been used as artificial tools to silence viral infection in human cells, it remains unknown whether mammalian viruses naturally elicit such immunity in vertebral cells. Here, we report the evidence that HIV-1 encodes viral siRNA precursors in its genome and that natural HIV-1 infection provokes nucleic acid-based immunity in human cells. To combat this cellular defense, HIV-1 has evolved in its Tat protein a suppressor of RNA silencing (SRS) function. Tat abrogates the cell's RNA-silencing defense by subverting the ability of Dicer to process precursor double-stranded RNAs into siRNAs.