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The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency.

Mousseau G, Kessing CF, Fromentin R, Trautmann L, Chomont N, Valente ST - MBio (2015)

Bottom Line: Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs.Based on the mode of action of didehydro-cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir.Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA.

No MeSH data available.


Related in: MedlinePlus

Hypothetical approach to a functional HIV cure. (1) Upon HIV infection, there is a sharp increase of the viral load in circulating plasma of infected individuals. (2) The viral load sharply decreases to below the limit of detection (<50 copies/ml) during an ART regimen, but episodes of detectable viremia “blips” are commonly observed. Most of the infected cells remain latently infected, and if ART is discontinued (3), there is an immediate resurgence of virus correlating with CD4+ T cell reactivation (4). The addition of a Tat inhibitor such as dCA to an ART regimen could promote and maintain a state of latency, possibly allowing for ART interruption without viral rebound. dCA may also prevent reservoir replenishment. With time, patients may potentially observe a reduction in the size of the viral reservoir and relief from chronic inflammation caused by ongoing low-level virus production.
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fig8: Hypothetical approach to a functional HIV cure. (1) Upon HIV infection, there is a sharp increase of the viral load in circulating plasma of infected individuals. (2) The viral load sharply decreases to below the limit of detection (<50 copies/ml) during an ART regimen, but episodes of detectable viremia “blips” are commonly observed. Most of the infected cells remain latently infected, and if ART is discontinued (3), there is an immediate resurgence of virus correlating with CD4+ T cell reactivation (4). The addition of a Tat inhibitor such as dCA to an ART regimen could promote and maintain a state of latency, possibly allowing for ART interruption without viral rebound. dCA may also prevent reservoir replenishment. With time, patients may potentially observe a reduction in the size of the viral reservoir and relief from chronic inflammation caused by ongoing low-level virus production.

Mentions: Our results highlight an alternative approach to the “kick and kill” strategy. In this model (Fig. 8), a Tat inhibitor blocks the Tat feedback loop that is initiated after low-level basal reactivation and drives the viral promoter into more complete transcriptional inhibition. dCA treatment combined with ART would delay or halt viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells could result in a continuous decay of this pool over time, possibly culminating in a sterilizing cure. It was previously demonstrated that the decay of the viral reservoir in patients with no “blips,” or episodes of clinically detectable viremia, was faster than in patients with blips (6, 91). These results argue that reducing low-level viremia and replenishment may reduce the half-life of the viral reservoir and reinforce the rationale for the inclusion of a Tat inhibitor in eradication strategies.


The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency.

Mousseau G, Kessing CF, Fromentin R, Trautmann L, Chomont N, Valente ST - MBio (2015)

Hypothetical approach to a functional HIV cure. (1) Upon HIV infection, there is a sharp increase of the viral load in circulating plasma of infected individuals. (2) The viral load sharply decreases to below the limit of detection (<50 copies/ml) during an ART regimen, but episodes of detectable viremia “blips” are commonly observed. Most of the infected cells remain latently infected, and if ART is discontinued (3), there is an immediate resurgence of virus correlating with CD4+ T cell reactivation (4). The addition of a Tat inhibitor such as dCA to an ART regimen could promote and maintain a state of latency, possibly allowing for ART interruption without viral rebound. dCA may also prevent reservoir replenishment. With time, patients may potentially observe a reduction in the size of the viral reservoir and relief from chronic inflammation caused by ongoing low-level virus production.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495168&req=5

fig8: Hypothetical approach to a functional HIV cure. (1) Upon HIV infection, there is a sharp increase of the viral load in circulating plasma of infected individuals. (2) The viral load sharply decreases to below the limit of detection (<50 copies/ml) during an ART regimen, but episodes of detectable viremia “blips” are commonly observed. Most of the infected cells remain latently infected, and if ART is discontinued (3), there is an immediate resurgence of virus correlating with CD4+ T cell reactivation (4). The addition of a Tat inhibitor such as dCA to an ART regimen could promote and maintain a state of latency, possibly allowing for ART interruption without viral rebound. dCA may also prevent reservoir replenishment. With time, patients may potentially observe a reduction in the size of the viral reservoir and relief from chronic inflammation caused by ongoing low-level virus production.
Mentions: Our results highlight an alternative approach to the “kick and kill” strategy. In this model (Fig. 8), a Tat inhibitor blocks the Tat feedback loop that is initiated after low-level basal reactivation and drives the viral promoter into more complete transcriptional inhibition. dCA treatment combined with ART would delay or halt viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells could result in a continuous decay of this pool over time, possibly culminating in a sterilizing cure. It was previously demonstrated that the decay of the viral reservoir in patients with no “blips,” or episodes of clinically detectable viremia, was faster than in patients with blips (6, 91). These results argue that reducing low-level viremia and replenishment may reduce the half-life of the viral reservoir and reinforce the rationale for the inclusion of a Tat inhibitor in eradication strategies.

Bottom Line: Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs.Based on the mode of action of didehydro-cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir.Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA.

No MeSH data available.


Related in: MedlinePlus