HIV Latency: Should We Shock or Lock?

Darcis, Gilles; Driessche, Benoît Van; Lint, Carine Van

doi:10.1016/j.it.2016.12.003

Cited by 137 publications

(149 citation statements)

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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%

“…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). Once the viral load is under the control, LPAs alone would continue to reinforce the deep and irreversible latency of HIV-1 and the permanent silencing of HIV-1 proviruses even without cART, which would eventually lead to the elimination of HIV-1 latent reservoir and a functional cure of HIV-1.…”

Section: Introductionmentioning

confidence: 99%

“…It would also allow the disruption of cART and the reduction of its side effects (Mousseau et al, 2015b). Recently several potential LPAs have been identified (Darcis et al, 2017). For example, one promising LPA is didehydro-Cortistatin A (dCA), which selectively inhibits HIV-1 Tat-mediated viral transcription (Mousseau et al, 2012).…”

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%

Section: Introductionmentioning

confidence: 99%

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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“…We postulated that the lack of occasional low-grade transcription caused by dCA may induce epigenetic changes that lock the HIV promoter in a sustainable latent state. Based on dCA’s mode of action, we have postulated a strategy of HIV-1 cure termed “Block-and-Lock”, where a specific HIV-1 transcriptional inhibitor would promote a durable state of latency, less susceptible to spontaneous reactivation during ART and when ART is discontinued [126–128]. …”

Section: The Super Elongation Complexmentioning

confidence: 99%

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

Mousseau

Valente

2017

CPD

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Background The viral transactivator Tat protein is a key modulator of HIV-1 replication, as it regulates transcriptional elongation from the integrated proviral genome. Tat recruits the human transcription elongation factor b, and other host proteins, such as the super elongation complex, to activate the cellular RNA polymerase II, normally stalled shortly after transcription initiation at the HIV promoter. By means of a complex set of interactions with host cellular factors, Tat determines the fate of viral activity within the infected cell. The virus will either actively replicate to promote dissemination in blood and tissues, or become dormant mostly in memory CD4+ T cells, as part of a small but long-living latent reservoir, the main obstacle for HIV eradication. Objective In this review, we summarize recent advances in the understanding of the multi-step mechanism that regulates Tat-mediated HIV-1 transcription and RNA polymerase II release, to promote viral transcription elongation. Early events of the human transcription elongation factor b release from the inhibitory 7SK small nuclear ribonucleoprotein complex and its recruitment to the HIV promoter will be discussed. Specific roles of the super elongation complex subunits during transcription elongation, and insight on recently identified cellular factors and mechanisms regulating HIV latency will be detailed. Conclusion Understanding the complexity of HIV transcriptional regulation by host factors may open the door for development of novel strategies to eradicate the resilient latent reservoir.

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H uman Immunodeficiency Virus ( HIV )

Geretti

2017

Encyclopedia of Life Sciences

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Human immunodeficiency virus (HIV) is the aetiological agent of the acquired immune deficiency syndrome (AIDS). Without treatment, most subjects develop severe disease and die within approximately 10 years of the infection. HIV‐related disease has two interrelated mechanisms of pathogenesis: immune activation with inflammation and progressive immune deficiency. Antiretroviral therapy (ART) effectively suppresses HIV replication and prevents disease progression and death. Treatment regimens are mainly based on combinations of three antiretroviral agents with two different mechanisms of action, chosen from drug classes that target different steps in the virus replication cycle. People that maintain excellent adherence to treatment enjoy long and healthy lives and are at little risk of developing drug resistance or transmitting the infection to contacts. During ART, however, HIV persists by integrating within the deoxyribonucleic acid (DNA) of long‐lived memory CD4 T cells. Research is actively pursuing strategies to cure HIV infection by eradicating or silencing integrated virus and inducing immune control. Key Concepts HIV infection is a zoonosis that resulted from transmission to humans of viruses found in African monkeys and apes. Circulating strains are characterised by an incredible amount of genetic variation, upon which evolutionary forces can act. The natural course of HIV infection is characterised by progressive immune dysfunction. The impact of HIV on the immune system comprises chronic immune activation, abnormal T‐cell responses and cytokine production, progressive T‐cell exhaustion and CD4 cell loss occurring mostly through apoptosis. Antiretroviral treatment is lifelong. Consistently high levels of adherence are required to prevent virus escape and emergence of drug resistance. HIV has found several ways of evading immune responses and exploits physiological processes to ensure persistence in infected hosts. Integrated virus can persist long term in a dormant state, ready to reactivate under the appropriate circumstances. This reservoir is invisible to the immune system and unresponsive to antiretroviral therapy. How the HIV reservoir is maintained despite antiretroviral therapy is not completely understood. Mechanisms may include expansion through proliferation of latently infected CD4 T cells without virus production and replenishment through ongoing virus production in body compartments where antiretroviral drugs have reduced penetration or activity. The most effective way of containing the spread of HIV combines prevention of acquisition through personal protective measures and prophylactic use of antiretroviral therapy and prevention of transmission through prompt diagnosis and early treatment of those who become infected. There is cautious optimism, based on emerging research data, that both a prophylactic vaccine and a cure for those already infected may 1 day become available.

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HIV Latency: Should We Shock or Lock?

Cited by 137 publications

References 100 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

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

H uman Immunodeficiency Virus ( HIV )

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