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SIV-producing cells in follicles are partially suppressed by CD8+ cells in vivo.

SIV-producing cells in follicles are partially suppressed by CD8+ cells in vivo.
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Li S, Folkvord JM, Rakasz EG, Abdelaal HM, Wagstaff RK, Kovacs KJ, Kim HO, Sawahata R, MaWhinney S, Masopust D, Connick E, Skinner PJ,


Li S, Folkvord JM, Rakasz EG, Abdelaal HM, Wagstaff RK, Kovacs KJ, Kim HO, Sawahata R, MaWhinney S, Masopust D, Connick E, Skinner PJ, (click to view)

Li S, Folkvord JM, Rakasz EG, Abdelaal HM, Wagstaff RK, Kovacs KJ, Kim HO, Sawahata R, MaWhinney S, Masopust D, Connick E, Skinner PJ,

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Journal of virology 2016 Oct 5() pii

Abstract

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 immune privileged 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 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 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, 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 immune privileged 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 cells function, we characterized follicular virus-specific CD8(+) T cells in situ, in 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, are likely exhausted, and 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 frequencies of functional follicular virus-specific CD8(+) T cells.

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