Novel Latency Reversal Agents for HIV-1 Cure

Spivak, Adam M.; Planelles, Vicente

doi:10.1146/annurev-med-052716-031710

Cited by 136 publications

(145 citation statements)

References 111 publications

(146 reference statements)

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“…It has been suggested that reactivation of latent virus followed by an intensive course of ART can represent a therapeutic strategy to eradicate the virus. Several compounds including TLR agonists have been proposed as candidates with conflicting results 88 . In recent studies, TLR7 agonist GS-9620 induced pDC-mediated reactivation of latent HIV in PBMCs isolated from HIV patients on ART and delayed viral rebound in simian-human immunodeficiency virus (SHIV)-infected monkeys when administered with broadly neutralizing antibodies 89,90 .…”

Section: Discussionmentioning

confidence: 99%

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

et al. 2020

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During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.

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Section: Discussionmentioning

confidence: 99%

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

et al. 2020

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“…Clinical trials of chronically infected patients found that IFN-α therapy fails to suppress HIV-1 replication and causes severe side-effects, including toxicity, ART failure and progression to AIDS [100]. Some novel methods and therapeutic strategies that can overcome viral latency have been developed such as HDAC, disulfiram, galectin-9, ingenol-3-angelate, prostratin, 5-azadC, bryostatin-1, and Runx1 [100, 101]. TLR7/8 agonists induce production of IFN-α that effectively inhibits HIV-1 replication in activated lymphocytes, macrophages or latently infected monocytic cell lines [102, 103].…”

Section: Current Potential Applications Of Type I Ifn Classesmentioning

confidence: 99%

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

Gong

Zhao

et al. 2018

Cell Physiol Biochem

130

108

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The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.

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“…Prostratin), epigenetic modulators (e.g. HDAC or bromodomain inhibitors), and modulators of the PI3K or mTOR signaling pathways [3][4][5][6] . However, to date, clinical trials of existing LRAs have not demonstrated successful reduction of the latent reservoir 7 .…”

Section: Mainmentioning

confidence: 99%

FOXO1 promotes HIV Latency by suppressing ER stress in T cells

Vallejo-Gracia

Chen

Perrone

et al. 2020

Preprint

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Quiescence is a hallmark of CD4 + T cells latently infected with HIV-1. While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. Here we report that FOXO1, a key regulator of T-cell quiescence, promotes latency and suppresses productive HIV infection. In resting T cells, FOXO1 inhibition induces ER stress and activates two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Both factors associate with HIV chromatin and are necessary for HIV reactivation. Indeed, inhibition of PKR-like endoplasmic reticulum kinase (PERK), a known link between ER stress and ATF4, and calcineurin, a calcium-dependent regulator of NFAT, synergistically suppress HIV reactivation induced by FOXO1 inhibition. Thus, our studies uncover a novel link between FOXO1, ER stress, and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.Luciferase Reporter Assay. For reactivation of latent HIV-1 provirus, cells were counted and collected as pellets by centrifugation at 1500 rpm for 10 min. Cells were then plated in 96-well U-bottom plates at 1×10 6 per 200 μl in the presence of 30 μM Raltegravir (Santa Cruz Biotechnology) and the indicated activator. Cells were harvested 72 h after stimulation, washed one time with PBS, and lysed in 60 μl of Passive Lysis Buffer (Promega). After 15 min of lysis, the luciferase activity in cell extracts was quantified with a SpectraMax i3x Multi-Mode plate reader (Molecular Devices, USA) after mixing 20 μl of lysate with 100 μl of substrate (Luciferase Assay System-Promega). Relative light units (RLU) were normalized to protein content determined by DC Protein assay (BIO-RAD).Synergy Bliss model. To analyze drug combinatorial effects, we used the Bliss independence model from the SynergyFinder web application (https://synergyfinder.fimm.fi) 79 . The Bliss score (∆faxy) is the difference between the calculated reactivation value if the two drugs act independently and the observed combined reactivation values. Synergy is defined as ∆faxy > 0, while ∆faxy < 0 indicates antagonism. Positive Bliss scores represent dose combinations which have greater than additive effect 25 .

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Novel Latency Reversal Agents for HIV-1 Cure

Cited by 136 publications

References 111 publications

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

FOXO1 promotes HIV Latency by suppressing ER stress in T cells

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