Simian immunodeficiency virus-producing cells in follicles are partially suppressed by CD8⁺ cells in vivo

Human immunodeficiency virus (HIV)- and simian immunodeficiency virus (SIV)-specific CD8⁺ T cells are typically largely excluded from lymphoid B cell follicles, where HIV- and SIV-producing cells are most highly concentrated, indicating that B cell follicles are somewhat of an immunoprivileged site. To gain insights into virus-specific follicular CD8⁺ T cells, we determined the location and phenotype of follicular SIV-specific CD8⁺ T cells in situ, the local relationship of these cells to Foxp3⁺ cells, and the effects of CD8 depletion on levels of follicular SIV-producing cells in chronically SIV-infected rhesus macaques. We found that follicular SIV-specific CD8⁺ T cells were able to migrate throughout follicular areas, including germinal centers. Many expressed PD-1, indicating that they may have been exhausted. A small subset was in direct contact with and likely inhibited by Foxp3⁺ cells, and a few were themselves Foxp3⁺. In addition, subsets of follicular SIV-specific CD8⁺ T cells expressed low to medium levels of perforin, and subsets were activated and proliferating. Importantly, after CD8 depletion, the number of SIVproducing cells increased in B cell follicles and extrafollicular areas, suggesting that follicular and extrafollicular CD8⁺ T cells have a suppressive effect on SIV replication. Taken together, these results suggest that during chronic SIV infection, despite high levels of exhaustion and likely inhibition by Foxp3⁺ cells, a subset of follicular SIV-specific CD8⁺ T cells are functional and suppress viral replication in vivo. These findings support HIV cure strategies that augment functional follicular virus-specific CD8⁺ T cells to enhance viral control.