A new small-molecule compound, Q308, silences latent HIV-1 provirus by suppressing Tat- and FACT-mediated transcription

2021 ◽  
Author(s):  
Chen-liang Zhou ◽  
Yi-fan Huang ◽  
Yi-bin Li ◽  
Tai-zhen Liang ◽  
Teng-yi Zheng ◽  
...  
Keyword(s):  
Small Molecule ◽  
Difficult Problem ◽  
Viral Reservoir ◽  
Functional Cure ◽  
Latently Infected ◽  
Small Molecule Compound ◽  
Infected Cells ◽  
Latent Hiv ◽  
Anti Hiv ◽  
Hiv 1

Eliminating the latent HIV reservoir remains a difficult problem for creating an HIV functional cure or achieving remission. The “block-and-lock” strategy aims to steadily suppress transcription of the viral reservoir and lock the HIV promoter in deep latency using latency-promoting agents (LPAs). However, to date, most of the investigated LPA candidates are not available for clinical trials, and some of them exhibit immune-related adverse reactions. The discovery and development of new, active, and safe LPA candidates for an HIV cure are necessary to eliminate residual HIV-1 viremia through the “block-and-lock” strategy. In this study, we demonstrated that a new small-molecule compound, Q308, silenced the HIV-1 provirus by inhibiting Tat-mediated gene transcription and selectively downregulating the expression levels of the facilitated chromatin transcription (FACT) complex. Strikingly, Q308 induced the preferential apoptosis in HIV-1 latently infected cells, indicating that Q308 may reduce the size of the viral reservoir and thus further prevent viral rebound. These findings highlight that Q308 is a novel and safe anti-HIV-1 inhibitor candidate for a functional cure.

scholarly journals VIP-SPOT: an Innovative Assay To Quantify the Productive HIV-1 Reservoir in the Monitoring of Cure Strategies

mBio ◽  
2021 ◽  
Author(s):  
Maria C. Puertas ◽  
Ángel Bayón-Gil ◽  
Maria C. Garcia-Guerrero ◽  
Maria Salgado ◽  
Víctor Urrea ◽  
...  
Keyword(s):  
The Body ◽  
Continuous Treatment ◽  
Viral Reservoir ◽  
Functional Cure ◽  
Viral Eradication ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Current efforts aimed at finding a definitive cure for HIV-1 infection are hampered mainly by the persistence of a viral reservoir in latently infected cells. While complete viral eradication from the body remains elusive, finding a functional cure to enable control of viremia without the need for continuous treatment is a key goal.

scholarly journals Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1798
Author(s):  
Grant R. Campbell ◽  
Stephen A. Spector
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Functional Cure ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.

scholarly journals The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells

Oncotarget ◽  
2017 ◽  
Vol 8 (55) ◽  
pp. 94104-94116 ◽  
Author(s):  
Hanyu Pan ◽  
Panpan Lu ◽  
Yinzhong Shen ◽  
Yanan Wang ◽  
Zhengtao Jiang ◽  
...  
Keyword(s):  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

scholarly journals A New Quinoline BRD4 Inhibitor Targets a Distinct Latent HIV-1 Reservoir for Reactivation from Other “Shock” Drugs

2018 ◽  
Vol 92 (10) ◽  
Author(s):  
Erik Abner ◽  
Mateusz Stoszko ◽  
Lei Zeng ◽  
Heng-Chang Chen ◽  
Andrea Izquierdo-Bouldstridge ◽  
...  
Keyword(s):  
Hdac Inhibitors ◽  
Jurkat Cells ◽  
Viral Reactivation ◽  
Viral Reservoir ◽  
Latently Infected ◽  
Core Histones ◽  
Latent Hiv ◽  
Expression Microarrays ◽  
Hiv 1

ABSTRACT Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol), that is able to reactivate viral transcription in several models of HIV latency, including J-Lat cells, through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or “shock” drugs, such as protein kinase C (PKC) agonists or histone deacetylase (HDAC) inhibitors. Here, we demonstrate that MMQO activates HIV-1 independently of the Tat transactivator. Gene expression microarrays in Jurkat cells indicated that MMQO treatment results in robust immunosuppression, diminishes expression of c-Myc, and causes the dysregulation of acetylation-sensitive genes. These hallmarks indicated that MMQO mimics acetylated lysines of core histones and might function as a bromodomain and extraterminal domain protein family inhibitor (BETi). MMQO functionally mimics the effects of JQ1, a well-known BETi. We confirmed that MMQO interacts with the BET family protein BRD4. Utilizing MMQO and JQ1, we demonstrate how the inhibition of BRD4 targets a subset of latently integrated barcoded proviruses distinct from those targeted by HDAC inhibitors or PKC pathway agonists. Thus, the quinoline-based compound MMQO represents a new class of BET bromodomain inhibitors that, due to its minimalistic structure, holds promise for further optimization for increased affinity and specificity for distinct bromodomain family members and could potentially be of use against a variety of diseases, including HIV infection. IMPORTANCE The suggested “shock and kill” therapy aims to eradicate the latent functional proportion of HIV-1 proviruses in a patient. However, to this day, clinical studies investigating the “shocking” element of this strategy have proven it to be considerably more difficult than anticipated. While the proportion of intracellular viral RNA production and general plasma viral load have been shown to increase upon a shock regimen, the global viral reservoir remains unaffected, highlighting both the inefficiency of the treatments used and the gap in our understanding of viral reactivation in vivo . Utilizing a new BRD4 inhibitor and barcoded HIV-1 minigenomes, we demonstrate that PKC pathway activators and HDAC and bromodomain inhibitors all target different subsets of proviral integration. Considering the fundamental differences of these compounds and the synergies displayed between them, we propose that the field should concentrate on investigating the development of combinatory shock cocktail therapies for improved reservoir reactivation.

Dilazep synergistically reactivates latent HIV-1 in latently infected cells

2014 ◽  
Vol 41 (11) ◽  
pp. 7697-7704 ◽  
Author(s):  
Hanxian Zeng ◽  
Sijie Liu ◽  
Pengfei Wang ◽  
Xiying Qu ◽  
Haiyan Ji ◽  
...  
Keyword(s):  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

scholarly journals Efficient inhibition of HIV using CRISPR/Cas13d nuclease system

2021 ◽  
Author(s):  
Hoang Nguyen ◽  
Hannah Wilson ◽  
Sahana Jayakumar ◽  
Viraj Kulkarni ◽  
Smita Kulkarni
Keyword(s):  
T Cells ◽  
Alternative Treatment ◽  
Treatment Modality ◽  
Rna Viruses ◽  
Guide Rnas ◽  
Rna Targeting ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

Recently discovered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas13 proteins are programmable RNA-guided ribonucleases that target single-stranded RNA (ssRNA). CRISPR/Cas13 mediated RNA targeting has emerged as a powerful tool for detecting and eliminating RNA viruses. Here, we demonstrate the effectiveness of CRISPR/Cas13d to inhibit HIV-1 replication. We designed guide RNAs (gRNAs) targeting highly conserved regions of HIV-1. RfxCas13d (CasRx) in combination with HIV-specific gRNAs efficiently inhibited HIV-1 replication in cell line models. Furthermore, simultaneous targeting of four distinct sites in the HIV-1 transcript resulted in robust inhibition of HIV-1 replication. We also show the effective HIV-1 inhibition in primary CD4+ T-cells and suppression of HIV-1 reactivated from latently infected cells using the CRISPR/Cas13d system. Our study demonstrates the utility of the CRISPR/Cas13d nuclease system to target acute and latent HIV infection and provides an alternative treatment modality against HIV.

scholarly journals New Approaches to Dendritic Cell-Based Therapeutic Vaccines Against HIV-1 Infection

2022 ◽  
Vol 12 ◽  
Author(s):  
Marisierra Espinar-Buitrago ◽  
Ma Angeles Muñoz-Fernández
Keyword(s):  
Immunological Synapse ◽  
T Cell Response ◽  
Viral Reservoir ◽  
Therapeutic Vaccines ◽  
Viral Loads ◽  
Response Capacity ◽  
Latently Infected ◽  
Infected Cells ◽  
Antigen Presenting ◽  
Hiv 1

Due to the success of combined antiretroviral therapy (cART) in recent years, the pathological outcome of Human Immunodeficiency Virus type 1 (HIV-1) infection has improved substantially, achieving undetectable viral loads in most cases. Nevertheless, the presence of a viral reservoir formed by latently infected cells results in patients having to maintain treatment for life. In the absence of effective eradication strategies against HIV-1, research efforts are focused on obtaining a cure. One of these approaches is the creation of therapeutic vaccines. In this sense, the most promising one up to now is based on the establishing of the immunological synapse between dendritic cells (DCs) and T lymphocytes (TL). DCs are one of the first cells of the immune system to encounter HIV-1 by acting as antigen presenting cells, bringing about the interaction between innate and adaptive immune responses mediated by TL. Furthermore, TL are the end effector, and their response capacity is essential in the adaptive elimination of cells infected by pathogens. In this review, we summarize the knowledge of the interaction between DCs with TL, as well as the characterization of the specific T-cell response against HIV-1 infection. The use of nanotechnology in the design and improvement of vaccines based on DCs has been researched and presented here with a special emphasis.

scholarly journals FISHing Out the Hidden Enemy: Advances in Detecting and Measuring Latent HIV-Infected Cells

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Vinayaka R. Prasad ◽  
Ganjam V. Kalpana
Keyword(s):  
Immune Surveillance ◽  
Gag Protein ◽  
Link Type ◽  
Latently Infected ◽  
Hiv Eradication ◽  
Infected Cells ◽  
Latent Hiv ◽  
Cell Host Microbe ◽  
Unique Cell ◽  
Hiv 1

ABSTRACT The indomitable aspect of HIV-1 infection is not that HIV-1 proviral DNA is integrated into host DNA but that it can also turn itself off, remaining invisible to drug or immune surveillance. Thus, the goals of eradication include ways to precisely excise HIV-1 DNA or wake up the silent HIV-1 provirus and eliminate the infected cells thus identified. Methods to identify and fish out the latently infected cells or to delineate their characteristics are being rapidly developed. In 2016, Baxter et al. (A. E. Baxter, J. Niessl, R. Fromentin, J. Richard, F. Porichis, R. Charlebois, M. Massanella, N. Brassard, N. Alsahafi, G. G. Delgado, J. P. Routy, B. D. Walker, A. Finzi, N. Chomont, and D. E. Kaufmann, Cell Host Microbe 20:368–380, 2016, https://doi.org/10.1016/j.chom.2016.07.015 ) and Martrus et al. (G. Martrus, A. Niehrs, R. Cornelis, A. Rechtien, W. García-Beltran, M. Lütgehetmann, C. Hoffmann, and M. Altfeld, J Virol 90:9018–9028, 2016, https://doi.org/10.1128/JVI.01448-16 ) reported using the fluorescence in situ hybridization-flow cytometry technique to identify and quantify cells expressing HIV-1 RNA and Gag protein, as well as bearing unique cell surface markers. In a recent article in mBio, Grau-Expósito et al. (J. Grau-Expósito, C. Serra-Peinado, L. Miguel, J. Navarro, A. Curran, J. Burgos, I. Ocaña, E. Ribera, A. Torrella, B. Planas, R. Badía, J. Castellví, V. Falcó, M. Crespo, and M. J. Buzon, mBio 8:e00876-17, 2017, https://doi.org/10.1128/mBio.00876-17 !) reported a similar method that they claim to be more sensitive. With these methods, researchers are one step closer to measuring latent reservoirs and eliminating critical barriers to HIV eradication.

scholarly journals Humanized Mouse Model of HIV-1 Latency with Enrichment of Latent Virus in PD-1+and TIGIT+CD4 T Cells

2019 ◽  
Vol 93 (10) ◽  
Author(s):  
George N. Llewellyn ◽  
Eduardo Seclén ◽  
Stephen Wietgrefe ◽  
Siyu Liu ◽  
Morgan Chateau ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Ex Vivo ◽  
Latent Reservoir ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACTCombination anti-retroviral drug therapy (ART) potently suppresses HIV-1 replication but does not result in virus eradication or a cure. A major contributing factor is the long-term persistence of a reservoir of latently infected cells. To study this reservoir, we established a humanized mouse model of HIV-1 infection and ART suppression based on an oral ART regimen. Similar to humans, HIV-1 levels in the blood of ART-treated animals were frequently suppressed below the limits of detection. However, the limited timeframe of the mouse model and the small volume of available samples makes it a challenging model with which to achieve full viral suppression and to investigate the latent reservoir. We therefore used anex vivolatency reactivation assay that allows a semiquantitative measure of the latent reservoir that establishes in individual animals, regardless of whether they are treated with ART. Using this assay, we found that latently infected human CD4 T cells can be readily detected in mouse lymphoid tissues and that latent HIV-1 was enriched in populations expressing markers of T cell exhaustion, PD-1 and TIGIT. In addition, we were able to use theex vivolatency reactivation assay to demonstrate that HIV-specific TALENs can reduce the fraction of reactivatable virus in the latently infected cell population that establishesin vivo, supporting the use of targeted nuclease-based approaches for an HIV-1 cure.IMPORTANCEHIV-1 can establish latent infections that are not cleared by current antiretroviral drugs or the body’s immune responses and therefore represent a major barrier to curing HIV-infected individuals. However, the lack of expression of viral antigens on latently infected cells makes them difficult to identify or study. Here, we describe a humanized mouse model that can be used to detect latent but reactivatable HIV-1 in both untreated mice and those on ART and therefore provides a simple system with which to study the latent HIV-1 reservoir and the impact of interventions aimed at reducing it.

scholarly journals Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

2020 ◽  
Author(s):  
Iart Luca Shytaj ◽  
Francesco Andrea Procopio ◽  
Mohammad Tarek ◽  
Irene Carlon-Andres ◽  
Hsin-Yao Tang ◽  
...  
Keyword(s):  
Pentose Phosphate ◽  
Viral Reactivation ◽  
People Living With Hiv ◽  
Cellular Models ◽  
Downstream Effectors ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Living With Hiv ◽  
Hiv 1

AbstractHIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic and metabolomic analysis, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, the antioxidant NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people-living-with-HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

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