Abstract
In pathogenic HIV and SIV infections of humans and rhesus macaques (RMs), preferential depletion of CD4⁺ Th17 cells correlates with mucosal immune dysfunction and disease progression. Interleukin (IL)-21 promotes differentiation of Th17 cells, long-term maintenance of functional CD8⁺ T cells, and differentiation of memory B cells and antibody-secreting plasma cells. We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections. To test this hypothesis, we infected 12 RMs with SIV(mac239) and at day 14 post-infection treated six of them with rhesus rIL-21-IgFc. IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation. Compared to untreated animals, IL-21-treated RMs showed (i) higher expression of perforin and granzyme B in total and SIV-specific CD8⁺ T cells and (ii) higher levels of intestinal Th17 cells. Remarkably, increased levels of Th17 cells were associated with reduced levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation in the chronic infection. In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells. Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bacterial Translocation / drug effects*
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Differentiation / drug effects
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Down-Regulation / drug effects
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Female
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Granzymes / biosynthesis
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Granzymes / genetics
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Granzymes / metabolism
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Immunity, Mucosal / drug effects*
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Immunoglobulin Fc Fragments / adverse effects
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / therapeutic use*
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Interleukins / adverse effects
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Interleukins / genetics
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Interleukins / therapeutic use*
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Intestinal Mucosa / drug effects*
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Intestinal Mucosa / immunology
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Intestinal Mucosa / pathology
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Intestinal Mucosa / virology
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Macaca mulatta
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Perforin / biosynthesis
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Perforin / genetics
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Perforin / metabolism
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Random Allocation
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Recombinant Fusion Proteins / adverse effects
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / therapeutic use
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Simian Acquired Immunodeficiency Syndrome / drug therapy*
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Simian Acquired Immunodeficiency Syndrome / immunology
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Simian Acquired Immunodeficiency Syndrome / metabolism
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Simian Acquired Immunodeficiency Syndrome / virology
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Simian Immunodeficiency Virus / drug effects*
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Simian Immunodeficiency Virus / isolation & purification
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Simian Immunodeficiency Virus / physiology
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Th17 Cells / drug effects*
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Th17 Cells / immunology
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Th17 Cells / pathology
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Th17 Cells / virology
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Up-Regulation / drug effects
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Viral Load / drug effects
Substances
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Immunoglobulin Fc Fragments
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Interleukins
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Recombinant Fusion Proteins
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Perforin
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Granzymes
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interleukin-21