CD8 T cells play a critical role in controlling and eradicating virus-infected cells. Although many studies demonstrated the notable anti-viral effect of HIV-specific CD8 T cells during HIV infection, these cells fail to fully eliminate viral replication. The phenomenon that only a small population of HIV-specific CD8 T cells migrate into B cell follicles where HIV-producing cells are most highly concentrated during chronic infection is one major mechanism account for the failure of these cells to fully suppress HIV replication. It is not known whether this phenomenon also occurs during early infection. Moreover, whether follicular HIV-specific CD8 T cells are functional in suppressing viral replication is not fully understood. Simian immunodeficiency virus (SIV)-infected rhesus macaques are a good animal model for HIV research. In the present study, we determined the location, abundance and phenotype of follicular SIV-specific CD8 T cells in lymph nodes from SIV-infected rhesus macaques using in situ tetramer staining combined immunohistochemistry, confocal microscopy and quantitative image analysis. We found 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. Similar to chronic infection, low levels of SIV-specific CD8 T cells migrate into B cell follicles during early stages of infection and a subset of these cells likely possess cytolytic function and suppress viral replication. In addition, low levels of follicular SIV-specific CD8 T cells from GCs during early infection may set the stage for the establishment of persistent chronic infection. These findings provide important insights into HIV immunopathogenesis and support HIV cure strategies that augment functional follicular virus-specific CD8 T cells to enhance viral control. We also evaluated the effect of ALT-803, a novel human IL-15 superagonist and potent immunostimulatory molecule, on SIV-specific CD8 T cells in chronically SIV-infected rhesus macaques. We found that ALT-803 drives dramatic expansion of SIV-specific CD8 T cells in lymphoid tissues and, importantly, induces significant accumulation of SIV-specific CD8 T cells in B cell follicles, reducing the number of SIV-producing cells within B cell follicles. These data justify the further evaluation of ALT-803 for eradication of HIV-infected cells.
University of Minnesota Ph.D. dissertation. May 2018. Major: Comparative and Molecular Biosciences. Advisor: Pamela Skinner. 1 computer file (PDF); x, 159 pages.
Location, abundance and phenotype of follicular simian immunodeficiency virus-specific CD8 T lymphocytes.
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