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

Yamamoto, Takuya; Kanuma, Tomohiro; Takahama, Shokichi; Okamura, Tomonori; Moriishi, Eiko; Ishii, Ken J.; Terahara, Kazutaka; Yasutomi, Yasuhiro

doi:10.1038/s41598-019-42253-3

Cited by 29 publications

(28 citation statements)

References 68 publications

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“…TL8-506 is 500x more active on HEL-Blue hTLR8 than TLR7-transfected HEK293 (HEK-Blue™ hTLR7) cells (EC50 ¼ 30 nM vs 15 mM). TL8-506 is 50x and 25x more potent in inducing NF-kB activation in TLR8-transfeceted HEK293 cells than resiquimod and 3M À 002 (EC50 ¼ 30 nM vs 1500 nM and 800 nM respectively) [174,175]. (Fig.…”

Section: Pyrimidine and Purine Base Derivativesmentioning

confidence: 92%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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a b s t r a c tThe discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

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Section: Pyrimidine and Purine Base Derivativesmentioning

confidence: 92%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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“…CD4 ؉ T CM cell isolation. T CM cells were isolated, grown, and infected as described elsewhere (23). Human peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated by Ficoll-Hypaque (Lympholyte; Cedarlane) gradient centrifugation.…”

Section: Methodsmentioning

confidence: 99%

“…However, a subsequent study that evaluated acitretin as an LRA in latently infected cell lines and patient-derived samples failed to extend these observations (22). A recent study demonstrated that the STING agonists 2=3=-cGAMP and cyclic di-AMP were able to decrease the amount of simian immunodeficiency virus (SIV) Gag in the DNA of peripheral blood mononuclear cells (PBMCs) obtained from monkeys exhibiting natural SIV control at 40 weeks postinfection (23). However, only cyclic di-AMP reactivated latent HIV in a primary CD4 ϩ T cell model of HIV-1 latency established after activation through the T cell receptor and the subsequent return to quiescence.…”

mentioning

confidence: 99%

Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators

Palermo

Acchioni

Carlo

et al. 2019

J Virol

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The presence of T cell reservoirs in which human immunodeficiency virus (HIV) establishes latency by integrating into the host genome represents a major obstacle to an HIV cure and has prompted the development of strategies aimed at the eradication of HIV from latently infected cells. The “shock-and-kill” strategy is one of the most pursued approaches to the elimination of viral reservoirs. Although several latency-reversing agents (LRAs) have shown promising reactivation activity, they have failed to eliminate the cellular reservoir. In this study, we evaluated a novel immune system-mediated approach to clearing the HIV reservoir, based on a combination of innate immune stimulation and epigenetic reprogramming. The combination of the STING agonist cGAMP (cyclic GMP-AMP) and the FDA-approved histone deacetylase inhibitor resminostat resulted in a significant increase in HIV proviral reactivation and specific apoptosis in HIV-infected cells in vitro. Reductions in the proportion of HIV-harboring cells and the total amount of HIV DNA were also observed in CD4+ central memory T (TCM) cells, a primary cell model of latency, where resminostat alone or together with cGAMP induced high levels of selective cell death. Finally, high levels of cell-associated HIV RNA were detected ex vivo in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from individuals on suppressive antiretroviral therapy (ART). Although synergism was not detected in PBMCs with the combination, viral RNA expression was significantly increased in CD4+ T cells. Collectively, these results represent a promising step toward HIV eradication by demonstrating the potential of innate immune activation and epigenetic modulation for reducing the viral reservoir and inducing specific death of HIV-infected cells. IMPORTANCE One of the challenges associated with HIV-1 infection is that despite antiretroviral therapies that reduce HIV-1 loads to undetectable levels, proviral DNA remains dormant in a subpopulation of T lymphocytes. Numerous strategies to clear residual virus by reactivating latent virus and eliminating the reservoir of HIV-1 (so-called “shock-and-kill” strategies) have been proposed. In the present study, we use a combination of small molecules that activate the cGAS-STING antiviral innate immune response (the di-cyclic nucleotide cGAMP) and epigenetic modulators (histone deacetylase inhibitors) that induce reactivation and HIV-infected T cell killing in cell lines, primary T lymphocytes, and patient samples. These studies represent a novel strategy for HIV eradication by reducing the viral reservoir and inducing specific death of HIV-infected cells.

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“…In computer science, supercomputers with well-designed evolutionary algorithms, through trial and error approaches, should be employed to program cell robots[ 5 ]. The development of "surrogate target cells" for HIV infections will lead to "HIV suicide" because they cannot replicate and reproduce[ 8 ].…”

Section: Resultsmentioning

confidence: 99%

Hypothesis of design of biological cell robot as human immunodeficiency virus vaccine

Xie

Yang

Liao

2020

WJV

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High genetic variability of human immunodeficiency virus (HIV) has been a major intractable challenge to the practical design of vaccines. But a recent pioneer study published in PNAS Xenobots, is likely to revolutionize HIV prevention as it presented the world's first living robot made of cells. In the advent of this discovery, we herein discuss the possibility of using living biological cell robots to target HIV-infected T lymphocytes, and the prospects of this approach being a new HIV vaccine. We capture the current research status and trend of advances in biological cell robots' design as a new HIV vaccine. The key differences between this novel vaccine and other HIV vaccines are highlighted.

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

Cited by 29 publications

References 68 publications

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators

Hypothesis of design of biological cell robot as human immunodeficiency virus vaccine

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