STING agonists activate latently infected cells and enhance SIV-specific responses ex vivo in naturally SIV controlled cynomolgus macaques

• Published in: Scientific reports Vol. 9; no. 1; p. 5917
• Main Authors: Yamamoto, Takuya, Kanuma, Tomohiro, Takahama, Shokichi, Okamura, Tomotaka, Moriishi, Eiko, Ishii, Ken J., Terahara, Kazutaka, Yasutomi, Yasuhiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.04.2019; Nature Publishing Group
• Subjects: 38/22; 38/77; 38/90; 631/250/254; 631/250/255/1901; 692/699/255/1901; 96/31; Agonists; Animals; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytotoxicity; Deoxyribonucleic acid; Dinucleoside Phosphates - pharmacology; DNA; Gag protein; HIV; Human immunodeficiency virus; Humanities and Social Sciences; Imidazoles - pharmacology; Immune response (cell-mediated); Latent infection; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Ligands; Lymphocytes; Lymphocytes T; Macaca fascicularis; Male; Membrane Proteins - agonists; multidisciplinary; Natural killer cells; Nucleotides, Cyclic - pharmacology; Pattern recognition; Pattern recognition receptors; Peripheral blood mononuclear cells; Science; Science (multidisciplinary); Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - drug effects; Simian Immunodeficiency Virus - immunology; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; TLR7 protein; Toll-like receptors; Toll-Like Receptors - agonists; Viral Load; Viremia; Virus Activation - drug effects; Virus Activation - immunology; Virus Latency - drug effects; Virus Latency - immunology; α-Interferon; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42253-3

To achieve a functional cure for HIV, treatment regimens that eradicate latently HIV-infected cells must be established. For this, many groups have attempted to reactivate latently-infected cells to induce cytopathic effects and/or elicit cytotoxic T lymphocyte (CTL)/NK cell-mediated immune responses to kill these cells. We believe that not only the reactivation of latently-infected cells, but also the induction of strong CTL responses, would be required for this. Here, we used typical immune activators that target pattern recognition receptors (PRRs). For our experimental model, we identified eight SIV-infected cynomolgus monkeys that became natural controllers of viremia. Although plasma viral loads were undetectable, we could measure SIV-DNA by qPCR in peripheral blood mononuclear cells (PBMCs). Using these PBMCs, we screened 10 distinct PRR ligands to measure IFN-α and IFN-γ production. Among these, STING ligands, cGAMP and c-di-AMP, and the TLR7/8 agonist R848 markedly increased cytokine levels. Both R848 and STING ligands could reactivate latently-infected cells in both cynomolgus monkeys and human PBMCs in vitro . Furthermore, c-di-AMP increased the frequency of SIV Gag-specific CD8 + T cells including polyfunctional CD8 + T cells, as compared to that in untreated control or R848-treated cells. Together, STING ligands might be candidates for HIV treatment.