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.
Bibliographical noteFunding Information:
We thank Vaiva Vezys for a thoughtful review of the manuscript, the NIH Nonhuman Primate Reagent Resource for CD8-depleting antibodies, the Immunology Services and Virology Services of the Wisconsin National Primate Research Center for providing CD4 count and plasma viral load data, and Heather Simmons of the Wisconsin National Primate Research Center for consultation and assistance in providing rhesus macaque tissue specimens. This work was supported by Public Health Service grants from the National Institutes of Health (grants R01AI096966, R01AI090732, and R56AI080418), by Wisconsin National Primate Research Center grant P51OD011106/P51RR000167, by the Wisconsin National Primate Research Center Pathology and Scientific Protocol Implementation Units, NIH Tetramer Core Facility (contract HHSN272201300006C), by the NIH Nonhuman Primate Reagent Resource (grant R24 RR016001), and by the National Institute of Allergy and Infectious Diseases (contract HHSN 2722000900037C). This work, including the efforts of Eva Rakasz, was funded by HHS | National Institutes of Health (NIH) (P51OD011106/P51RR000167). This work, including the efforts of Elizabeth Connick and Pamela J. Skinner, was funded byHHS| National Institutes of Health (NIH) (R01AI096966). This work, including the efforts of David Masopust, was funded by HHS | National Institutes of Health (NIH) (R01AI090732). This work, including the efforts of Elizabeth Connick and Pamela J. Skinner, was funded by HHS | National Institutes of Health (NIH) (R56AI080418).