Significance Simian immunodeficiency virus (SIV)-specific follicular CD8 T cells represent a unique subset of antiviral CD8 T cells that rapidly expand during pathogenic SIV infection, localize within B-cell follicles, and contribute to control of chronic SIV replication. The potential for these cells to infiltrate sites of ongoing viral replication and viral persistence and the ability to induce these cells by vaccination provide a tremendous opportunity to develop and optimize therapeutic strategies to target and reduce the HIV reservoirs in lymphoid tissues.