Shock and kill, but don't miss the target

Herbein, Georges

doi:10.1016/j.ebiom.2020.102906

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…Several steps of the HIV pathogenesis that involve Akt can be targeted by treatments. The use of PI3K/Akt inhibitors can help modulate the latency/reactivation of the virus and cell survival, as part of new therapeutic approaches and thereby complete the conventional "shock and kill" and "block and lock" strategies (Figure 2) (Herbein, 2020). In the "shock and kill" strategy, viral reactivation from latency is induced by latency reversing agents (LRAs) while infected cells are killed by cellular immunity.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

CounterAKTing HIV: Toward a “Block and Clear” Strategy?

Pasquereau

Herbein

2022

Front. Cell. Infect. Microbiol.

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The protein kinase B or Akt is a central regulator of survival, metabolism, growth and proliferation of the cells and is known to be targeted by various viral pathogens, including HIV-1. The central role of Akt makes it a critical player in HIV-1 pathogenesis, notably by affecting viral entry, latency and reactivation, cell survival, viral spread and immune response to the infection. Several HIV proteins activate the PI3K/Akt pathway, to fuel the progression of the infection. Targeting Akt could help control HIV-1 entry, viral latency/replication, cell survival of infected cells, HIV spread from cell-to-cell, and the immune microenvironment which could ultimately allow to curtail the size of the HIV reservoir. Beside the “shock and kill” and “block and lock” strategies, the use of Akt inhibitors in combination with latency inducing agents, could favor the clearance of infected cells and be part of new therapeutic strategies with the goal to “block and clear” HIV.

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Section: Perspectives and Conclusionmentioning

confidence: 99%

CounterAKTing HIV: Toward a “Block and Clear” Strategy?

Pasquereau

Herbein

2022

Front. Cell. Infect. Microbiol.

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“…Latently infected viral reservoirs remain a major hurdle that must be overcome to achieve HIV cure. 2,721,83 Several strategies have been used to combat HIV-1 latency including gene editing to disrupt the HIV genome, [84][85][86] "shock and kill" to reactivate latent HIV-1 with HIV-1 latency-reversing agents, 23,87,88 and blocking viral reactivation to maintain HIV-1 in a state of prolonged silencing. 22,89 HIV-1 Tat is essential for HIV-1 replication, has been implicated in the establishment and reversal of HIV-1 latency, 30,90,91 and HIV-1 latencyreversing agents can act through HIV-1 Tat posttranslational modifications.…”

Section: Discussionmentioning

confidence: 99%

HIV‐1 Tat endocytosis and retention in endolysosomes affects HIV‐1 Tat‐induced LTR transactivation in astrocytes

et al. 2022

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The presence of latent HIV‐1 reservoirs in the periphery and brain represents a major obstacle to curing HIV‐1 infection. As an essential protein for HIV‐1 viral replication, HIV‐1 Tat, mostly intracellular, has been implicated in latent HIV‐1 infection. From HIV‐1 infected cells, HIV‐1 Tat is actively secreted and bystander cells uptake the released Tat whereupon it is endocytosed and internalized into endolysosomes. However, to activate the HIV‐1 LTR promoter and increase HIV‐1 replication, HIV‐1 Tat must first escape from the endolysosomes and then enter the nucleus. Here, we tested the hypothesis that HIV‐1 Tat can accumulate in endolysosomes and contribute to the activation of latent HIV‐1 in astrocytes. Using U87MG astrocytoma cells expressing HIV‐1 LTR‐driven luciferase and primary human astrocytes we found that exogenous HIV‐1 Tat enters endolysosomes, resides in endolysosomes for extended periods of time, and induces endolysosome de‐acidification as well as enlargement. The weak base chloroquine promoted the release of HIV‐1 Tat from endolysosomes and induced HIV‐1 LTR transactivation. Similar results were observed by activating endolysosome Toll‐like receptor 3 (TLR3) and TLR7/8. Conversely, pharmacological block of TLRs and knocking down expression levels of TLR3 and TLR7, but not TLR8, prevented endolysosome leakage and attenuated HIV‐1 Tat‐mediated HIV‐1 LTR transactivation. Our findings suggest that HIV‐1 Tat accumulation in endolysosomes may play an important role in controlling HIV‐1 transactivation.

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“…One such strategy relies on the use of latency-reversing agents (LRAs) that target repressors of HIV-1 gene expression, thereby inducing a controlled activation of the latent reservoirs of the virus. 4 , 5 , 6 …”

Section: Introductionmentioning

confidence: 99%