title: Maintenance of intestinal Th17 cells and reduced microbial translocation in SIV-infected rhesus macaques treated with interleukin (IL)-21.
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.
authors.affiliation: University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Suresh
authors.initials: S
authors.lastname: Pallikkuth
authors.forename: Luca
authors.initials: L
authors.lastname: Micci
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Ende
authors.forename: Robin I
authors.initials: RI
authors.lastname: Iriele
authors.forename: Barbara
authors.initials: B
authors.lastname: Cervasi
authors.forename: Benton
authors.initials: B
authors.lastname: Lawson
authors.forename: Colleen S
authors.initials: CS
authors.lastname: McGary
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Rogers
authors.forename: James G
authors.initials: JG
authors.lastname: Else
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: Kirk
authors.initials: K
authors.lastname: Easley
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Savita
authors.initials: S
authors.lastname: Pahwa
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018928:Immunity, Mucosal / Q000187:drug effects*; D007141:Immunoglobulin Fc Fragments / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D007378:Interleukins / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D054353:Perforin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000821:virology; D015854:Up-Regulation / Q000187:drug effects; D019562:Viral Load / Q000187:drug effects; D000098546:Interleukin-21
chemical_list: D007141:Immunoglobulin Fc Fragments; D007378:Interleukins; D011993:Recombinant Fusion Proteins; D054353:Perforin; D053804:Granzymes; D000098546:Interleukin-21