Evaluation of the Innate Immune Modulator Acitretin as a Strategy To Clear the HIV Reservoir

García-Vidal, Edurne; Castellví, Marc; Pujantell, Maria; Badía, Roger; Jou, Antoni; Gómez, Lucía; Puig, Teresa; Clotet, Bonaventura; Ballana, Ester; Riveira-Muñoz, Eva; Esté, José A.

doi:10.1128/aac.01368-17

Cited by 26 publications

(20 citation statements)

References 38 publications

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“…Cell death was driven by RIG-I-mediated increases in the pro-apoptotic protein Bax, which can trigger caspase-mediated apoptosis (Li et al, 2016). Unfortunately, these findings were not replicated in a subsequent study that also evaluated latently infected cells lines and patient derived cells (Garcia-Vidal et al, 2017). …”

Section: Pro-apoptotic Compounds To Clear Hiv Latently Infected T-cellsmentioning

confidence: 95%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

327

351

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Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is lifelong. HIV persists during ART due to long lived and proliferating latently infected CD4+ T-cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.

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Section: Pro-apoptotic Compounds To Clear Hiv Latently Infected T-cellsmentioning

confidence: 95%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

327

351

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“…Furthermore, the RIG-I agonist acitretin, an FDA-approved retinoic acid derivative, was recently shown to reactivate latent HIV and induce the selective apoptosis of latently HIV infected cells in vitro (21). 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).…”

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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“…We observed parallels in CD4 + T cells from RA-stimulated cultures where the apoptosis marker CD10 was elevated in α4β7 expressing effector and TEMRA cells. Future studies are required to understand and validate the interdependence between α4β7 expression, RIG-1 signaling and stability of the viral reservoir as some study groups argue that Acitretin does not cause optimal activation and subsequent apoptosis of latently-infected cells [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected Cells

Olwenyi

Acharya

Routhu

et al. 2020

Cells

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The accurate estimation and eradication of Human Immunodeficiency Virus (HIV) viral reservoirs is limited by the incomplete reactivation of cells harboring the latent replication-competent virus. We investigated whether the in vitro and in vivo addition of retinoic acid (RA) enhances virus replication and improves the detection of latent virus. Peripheral blood mononuclear cells (PBMCs) from naive and anti-retroviral therapy (ART)-treated SIV-infected rhesus macaques (RMs) were cultured in vitro with anti-CD3/CD28 + IL-2 in the presence/absence of RA. Viral RNA and p27 levels were quantified using RT-qPCR and ELISA, respectively. Viral reservoirs were estimated using the Tat/Rev-Induced Limited Dilution Assay (TILDA) and Quantitative Viral Outgrowth Assay (QVOA). In vitro and in vivo measures revealed that there was also an increase in viral replication in RA-treated versus without RA conditions. In parallel, the addition of RA to either CD3/CD28 or phorbol myristate acetate (PMA)/ionomycin during QVOA and TILDA, respectively, was shown to augment reactivation of the replication-competent viral reservoir in anti-retroviral therapy (ART)-suppressed RMs as shown by a greater than 2.3-fold increase for QVOA and 1 to 2-fold increments for multi-spliced RNA per million CD4+ T cells. The use of RA can be a useful approach to enhance the efficiency of current protocols used for in vitro and potentially in vivo estimates of CD4+ T cell latent reservoirs. In addition, flow cytometry analysis revealed that RA improved estimates of various viral reservoir assays by eliciting broad CD4 T-cell activation as demonstrated by elevated CD25 and CD38 but reduced CD69 and PD-1 expressing cells.

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Evaluation of the Innate Immune Modulator Acitretin as a Strategy To Clear the HIV Reservoir

Cited by 26 publications

References 38 publications

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

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

Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected Cells

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