HIV Type 1 gp120-Induced Expansion of Myeloid Derived Suppressor Cells Is Dependent on Interleukin 6 and Suppresses Immunity

• Published in: The Journal of infectious diseases Vol. 209; no. 3; pp. 441 - 451
• Main Authors: Garg, Ankita, Spector, Stephen A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2014
• Subjects: Antigens, CD - analysis; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Coculture Techniques; Female; Flow Cytometry; Forkhead Transcription Factors - analysis; Fundamental and applied biological sciences. Psychology; HIV Envelope Protein gp120 - immunology; HIV-1 - immunology; HIV/AIDS; HLA-DR Antigens - analysis; Human immunodeficiency virus 1; Humans; Immune Tolerance; Immunophenotyping; Infectious diseases; Interferon-gamma - secretion; Interleukin-6 - immunology; Leukocytes, Mononuclear - immunology; Major and Brief Reports; Male; Medical sciences; Microbiology; Miscellaneous; Virology; Young Adult; HIV-1; gp120; Myeloid Derived Suppressor Cells; IL-6; Virus; Infection; Interleukin 6; HIV-1 virus; Cytokine; Retroviridae; Human immunodeficiency virus; Lentivirus; Myeloid cell
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit469

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 gpl20 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 γ (IFN-γ), 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-γ 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.