期刊
JOURNAL OF INFECTIOUS DISEASES
卷 209, 期 3, 页码 441-451出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jit469
关键词
HIV-1; gp120; IL-6; Myeloid Derived Suppressor Cells
资金
- National Institute of Neurological Disorders and Stroke [R01 NS084912]
- International Maternal Perinatal Adolescent AIDS Clinical Trials Network (through the National Institute of Allergy and Infectious Diseases) [U01 AI068632]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-DK-9-001/HHSN267200800001C]
Background. Factors responsible for myeloid-derived suppressor cell (MDSC) expansion and T-cell dysfunction during human immunodeficiency virus type 1 (HIV) infection are unknown. This study investigated the role of MDSCs during HIV infection. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured with gp120 and infectious or inactivated HIV, with or without anti-interleukin 6 (IL-6) antibody. CD33(+), CD4(+), and CD8(+) cells were isolated from PBMCs and cocultured in the presence or absence of inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and arginase 1 inhibitors. CD11b(+)CD33(+)CD14(+)HLA-DR-/lo MDSCs, phosphorylated STAT3 (pSTAT3), and CD4(+)CD25(+)FoxP3(+) cells were evaluated by flow cytometry. IL-6, interferon gamma (IFN-gamma), interleukin 10 (IL-10), and gp120 levels were quantified by an enzyme-linked immunosorbent assay. Results. MDSCs expanded when PBMCs were exposed to infectious or inactivated HIV. Exposure to gp120 led to MDSC expansion, with increases in IL-6 levels and pSTAT3 expression. Anti-IL-6 abrogated MDSC expansion and pSTAT3 expression. gp120-expanded CD33(+) MDSCs inhibited IFN-gamma release from autologous T cells, which was restored upon ROS and iNOS inhibition. gp120-expanded CD33(+) MDSCs increased IL-10 and CD4(+)CD25(+)FoxP3(+) regulatory T-cell levels in CD4(+) T-cell cocultures. Finally, high frequencies of MDSCs were present in HIV-infected persons, compared with healthy controls. Conclusions. These findings demonstrate that HIV gp120 induces IL-6 and MDSC expansion, which contributes to immune suppression by modulating cytokine and cellular responses.
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