Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study

Steens, Jean Marc; Scherrer, Didier; Gineste, Paul; Barrett, Perry; Khuanchai, Supparatpino; Ratanasuwan, Winai; Ruxrungtham, Kiat; Tazi, Jamal; Murphy, Robert L.; Ehrlich, Hartmut J.

doi:10.1128/aac.00545-17

Cited by 20 publications

(13 citation statements)

References 21 publications

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“…The proper and timely assembly of such a Rev-dependent mRNP will determine the efficient association of the unspliced mRNA with the host machineries for nuclear export and translation initiation. Last but not least, the small molecule ABX464, currently under a phase II clinical trial, was shown to interfere with the Rev-CBP80 interaction (82,83). Therefore, results presented here will be useful either for the better understanding of the mechanism of action of this small molecule or for the rational design of new drugs targeting the Rev-CBP80-eIF4A complex.…”

Section: Discussionmentioning

confidence: 99%

A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

Toro-Ascuy

Rojas-Araya

García-de-Gracia

et al. 2018

Preprint

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33Gag synthesis from the full-length unspliced mRNA is critical for the production of the 34 viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While 35 most spliced mRNAs follow the canonical gene expression pathway in which the 36 recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex 37 (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA 38 relies on the viral protein Rev to reach the cytoplasm and recruit the host translational 39 machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving 40 nuclear export and translation of the unspliced mRNA. These functions of Rev are 41 supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the 42 nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box 43 RNA helicase eIF4AI, which translocates to the nucleus and cooperates with Rev to 44 promote Gag synthesis. Interestingly, molecular docking analyses revealed the assembly of 45 a Rev-CBP80-eIF4AI complex that is organized around the Rev response element (RRE). 46 Together, our results provide further evidence towards the understanding of the molecular 47 mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 48 replication. 49 50 51 52 53 54 55 56 57 58 59 60 61 62Human Immunodeficiency Virus type-1 (HIV-1) gene expression is a complex process that 64 leads to the synthesis of fifteen proteins from one single primary transcript (1,2). Once the 65 proviral DNA has been integrated into the host cell genome, the RNA polymerase II drives 66 the synthesis of a 9-kb, capped and polyadenylated pre-mRNA that undergoes alternative 67 splicing generating more than 100 different transcripts classified into three main 68 populations (3,4). The so-called 2-kb multiply spliced transcripts code for the key 69 regulatory proteins Tat and Rev and the accessory protein Nef and are the dominant viral 70 mRNA species at early stages of viral gene expression (1,2,5). Unlike cellular mRNAs or 71 the 2-kb transcripts, which are spliced to completion before they exit the nucleus, HIV-1 72 and other complex retroviruses produce an important fraction of viral transcripts that 73 remain incompletely spliced (2,6). These 4-kb transcripts are expressed during the 74 intermediate phase of gene expression and are used for the synthesis of the envelope 75 glycoprotein (Env) and the accessory proteins Vif, Vpr and Vpu (2,6). Finally, the full-76 length 9-kb pre-mRNA in its unspliced form also reaches the cytoplasm to be used as an 77 mRNA template during the late stages of viral gene expression for the synthesis of the 78 major structural proteins Gag and Gag-Pol (1,2,6). 79Gene expression in eukaryotic cells occurs through the intricate connection of different 80 processes including transcription, splicing, nuclear export, translation and mRNA decay 81 and is regulated by the specific recruitment of nuclear proteins that together form the 82 messenger ribonuc...

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Section: Discussionmentioning

confidence: 99%

A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

Toro-Ascuy

Rojas-Araya

García-de-Gracia

et al. 2018

Preprint

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“…The precise mechanism of action of these different kinase inhibitors remains unclear and again, overall enthusiasm for their use is tempered by the central role that these kinases play in cell mitosis, adhesion, migration, proliferation, and survival. Other previously identified latency-promoting agents include curaxin (CBL0100), a small molecule targeting the chromatin transcription complex (FACT) that efficiently blocks HIV-1 transcription in vitro and ex vivo [139]; levosimendan, which blocks viral replication through inhibition of the phosphoinositide 3-kinase pathway [140]; and ABX464, a drug that interacts with the Cap Binding Complex (CBC) and inhibits the Rev-dependent nuclear export of unspliced HIV transcripts [141]. ABX464 not only suppresses viral replication in vitro, but also delays viral rebound in humanized mice [141] and reduced viral reservoir size in early clinical studies [139,142].…”

Section: Pharmacologic Inhibition Of Host Factorsmentioning

confidence: 99%

“…Other previously identified latency-promoting agents include curaxin (CBL0100), a small molecule targeting the chromatin transcription complex (FACT) that efficiently blocks HIV-1 transcription in vitro and ex vivo [139]; levosimendan, which blocks viral replication through inhibition of the phosphoinositide 3-kinase pathway [140]; and ABX464, a drug that interacts with the Cap Binding Complex (CBC) and inhibits the Rev-dependent nuclear export of unspliced HIV transcripts [141]. ABX464 not only suppresses viral replication in vitro, but also delays viral rebound in humanized mice [141] and reduced viral reservoir size in early clinical studies [139,142]. Again however, the question remains whether the beneficial antiviral effects of these drugs outweigh the potentially harmful consequences of a long-lasting and systemic suppression of the respective cellular pathways.…”

Section: Pharmacologic Inhibition Of Host Factorsmentioning

confidence: 99%

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

Schwarzer

Gramatica

Greene

2020

Viruses

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Human immunodeficiency virus (HIV-1) indefinitely persists, despite effective antiretroviral therapy (ART), within a small pool of latently infected cells. These cells often display markers of immunologic memory and harbor both replication-competent and -incompetent proviruses at approximately a 1:100 ratio. Although complete HIV eradication is a highly desirable goal, this likely represents a bridge too far for our current and foreseeable technologies. A more tractable goal involves engineering a sustained viral remission in the absence of ART--a "functional cure." In this setting, HIV remains detectable during remission, but the size of the reservoir is small and the residual virus is effectively controlled by an engineered immune response or other intervention. Biological precedence for such an approach is found in the post-treatment controllers (PTCs), a rare group of HIV-infected individuals who, following ART withdrawal, do not experience viral rebound. PTCs are characterized by a small reservoir, greatly reduced inflammation, and the presence of a poorly understood immune response that limits viral rebound. Our goal is to devise a safe and effective means for replicating durable post-treatment control on a global scale. This requires devising methods to reduce the size of the reservoir and to control replication of this residual virus. In the following sections, we will review many of the approaches and tools that likely will be important for implementing such a "reduce and control" strategy and for achieving a PTC-like sustained HIV remission in the absence of ART.

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“…Following Maraviroc, small-molecule CCR5 antagonists, aplaviroc, and vicriviroc are currently being evaluated in phase 2b clinical trials for HIV therapy [ 19 ]. A small-molecule ABX464 that inhibits HIV replication is also expected to enter phase 2b trials in 2018 [ 20 ]. Despite the advancement of biological and chemical engineering technology, it remains a huge challenge to deliver a safe, stable, and functional molecule into the host system to completely eradicate the residing virus [ 6 ].…”

Section: Current Hiv Treatmentsmentioning

confidence: 99%

“…The production cost is the key factor for anti-HIV antibody therapy due to the smaller market in viral diseases compared to cancer diseases [ 21 ]. There is also a rising concern following the increasing number of FDA-approved small-molecule inhibitors for HIV/AIDS therapy [ 10 , 13 , 18 , 20 ]. Although the antibody- and molecule-based therapeutics have different antiviral mechanisms, the comparison and competition between the antiviral antibodies and the substantial number of small-molecule inhibitors in the market is unavoidable.…”

Section: Challenges In Antibody-based Therapiesmentioning

confidence: 99%

Antibody-Mediated Therapy against HIV/AIDS: Where Are We Standing Now?

Awi

Teow

2018

Journal of Pathogens

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Acquired immunodeficiency syndrome (AIDS) cases are on the rise globally. To date, there is still no effective measure to eradicate the causative agent, human immunodeficiency virus (HIV). Highly active antiretroviral therapy (HAART) is being used in HIV/AIDS management, but it results in long-term medication and has major drawbacks such as multiple side effects, high cost, and increasing the generation rate of escape mutants. In addition, HAART does not control HIV-related complications, and hence more medications and further management are required. With this, other alternatives are urgently needed. In the past, small-molecule inhibitors have shown potent antiviral effects, and some of them are now being evaluated in clinical trials. The challenges in developing these small molecules for clinical use include the off-target effect, poor stability, and low bioavailability. On the other hand, antibody-mediated therapy has emerged as an important therapeutic modality for anti-HIV therapeutics development. Many antiviral antibodies, namely, broad neutralizing antibodies (bnAbs) against multiple strains of HIV, have shown promising effects in vitro and in animal studies; further studies are ongoing in clinical trials to evaluate their uses in clinical applications. This short review aims to discuss the current development of therapeutic antibodies against HIV and the challenges in adopting them for clinical use.

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Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study

Cited by 20 publications

References 21 publications

A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

Antibody-Mediated Therapy against HIV/AIDS: Where Are We Standing Now?

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