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 SIV-producing 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.

HIV- and SIV-specific CD8⁺ T cells are typically largely excluded from lymphoid B cell follicles, where virus-producing cells are most highly concentrated, suggesting that B cell follicles are somewhat of an immunoprivileged site where virus-specific CD8⁺ T cells are not able to clear all follicular HIV- and SIV-producing cells. To gain insights into follicular CD8⁺ T cell function, we characterized follicular virus-specific CD8⁺ T cells in situ by using an SIV-infected rhesus macaque model of HIV. We found that subsets of follicular SIV-specific CD8⁺ T cells are able to migrate throughout the follicle, are likely inhibited by Foxp3⁺ cells, and are likely exhausted but that, nonetheless, subsets are likely functional, as they express markers consistent with effector function and show signs of suppressing viral replication in vivo These findings support HIV cure strategies that increase the frequency of functional follicular virus-specific CD8⁺ T cells.