Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8⁺Cells<i>In Vivo</i>

Abstract

ABSTRACT 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. IMPORTANCE 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.