Targeting HIV Transcription: The Quest for a Functional Cure

Mousseau, Guillaume; Mediouni, Sonia; Valente, Susana T.

doi:10.1007/82_2015_435

Cited by 61 publications

(80 citation statements)

References 135 publications

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“…Since the “shock and kill” strategy still requires significant efforts to solve the above issues, other alternative strategies have been explored to reach an HIV-1 cure (Darcis et al, 2017; Mousseau et al, 2015b). One is to “block” the occasional reactivation of HIV-1 proviruses so that integrated proviruses are “locked” in a deep and permanent latency.…”

Section: Introductionmentioning

confidence: 99%

“…Since no drug component in cART inhibits HIV-1 transcription, there is still sporadically reactivated HIV-1 expression (“blip”) that continues the replenishment of HIV-1 latent reservoir and maintains its persistence. For the “block and lock” strategy, latency-promoting agents (LPAs) will be complemented with cART regimen to suppress resurrected viral transcription and reduce the residual viremia (Darcis et al, 2017; Mousseau et al, 2015b). Such combination treatment will facilitate the decay of HIV-1 latent reservoir and significantly reduce its size (Darcis et al, 2017; Mousseau et al, 2015b).…”

Section: Introductionmentioning

confidence: 99%

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Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

et al. 2017

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Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged “block and lock” approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

et al. 2017

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“…3.) basal HIV replication in patients under current cART therapy, which is believed to play a role in co-morbidities (as also stated in 101 ). Reducing the latent reservoir could be an alternative strategy for the 'purge and kill' strategy put forward the last decade 103 .…”

Section: Targeting the P-tefb-tat Interactionmentioning

confidence: 93%

“…Moreover, compounds interfering with the release of viral particles from HIV reservoirs are unavailable, which makes Tat-PTEFb an attractive target in order to reduce transactivation of HIV replication of already infected cells (also recently reviewed in 101 ). Furthermore, Tat seems to be the main determinant to control latency 102 .…”

Section: Targeting the P-tefb-tat Interactionmentioning

confidence: 99%

Targeting Virus-host Interactions of HIV Replication

Weydert¹,

Rijck²,

Christ³

et al. 2015

CTMC

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Cellular proteins that are hijacked by HIV in order to complete its replication cycle, form attractive new targets for antiretroviral therapy. In particular, the protein-protein interactions between these cellular proteins (cofactors) and viral proteins are of great interest to develop new therapies. Research efforts have led to the validation of different cofactors and some successes in therapeutic applications. Maraviroc, the first cofactor inhibitor approved for human medicinal use, provided a proof of concept. Furthermore, compounds developed as Integrase-LEDGF/p75 interaction inhibitors (LEDGINs) have advanced to early clinical trials. Other compounds targeting cofactors and cofactor-viral protein interactions are currently under development. Likewise, interactions between cellular restriction factors and their counteracting HIV protein might serve as interesting targets in order to impair HIV replication. In this respect, compounds targeting the Vif-APOBEC3G interaction have been described. In this review, we focus on compounds targeting the Integrase-LEDGF/p75 interaction, the Tat-P-TEFb interaction and the Vif-APOBEC3G interaction. Additionally we give an overview of currently discovered compounds presumably targeting cellular cofactor-HIV protein interactions.

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“…To activate viral transcription, Tat binds to the transactivation response (TAR) element, which is a 59-nucleotide stem-loop in viral RNA (29, 273). Subsequently, Tat recruits pTEFb (a structural complex with CDK9 and cyclin T1), SWI/SNF chromatin-remodeling complexes, and other cellular cofactors to the HIV-1 promoter (268,274). In this process, p300 acts synergistically with INI1 and BRG1 to activate the HIV-1 promoter (269).…”

Section: Tat-p300/swi/snf-integrase Associationmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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Targeting HIV Transcription: The Quest for a Functional Cure

Cited by 61 publications

References 135 publications

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

Targeting Virus-host Interactions of HIV Replication

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

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