scholarly journals Short Communication: The Broad-Spectrum Histone Deacetylase Inhibitors Vorinostat and Panobinostat Activate Latent HIV in CD4+ T Cells In Part Through Phosphorylation of the T-Loop of the CDK9 Subunit of P-TEFb

2016 ◽  
Vol 32 (2) ◽  
pp. 169-173 ◽  
Author(s):  
Md Saha Jamaluddin ◽  
Pei-Wen Hu ◽  
Yih Jan ◽  
Edward B. Siwak ◽  
Andrew P. Rice
Keyword(s):  
T Cells ◽  
Histone Deacetylase ◽  
Broad Spectrum ◽  
Cd4 T Cells ◽  
Histone Deacetylase Inhibitors ◽  
Short Communication ◽  
Latent Hiv

scholarly journals Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ T cells

2013 ◽  
Vol 69 (1) ◽  
pp. 28-33 ◽  
Author(s):  
Liang Shan ◽  
Sifei Xing ◽  
Hung-Chih Yang ◽  
Hao Zhang ◽  
Joseph B. Margolick ◽  
...  
Keyword(s):  
T Cells ◽  
Histone Deacetylase ◽  
Cd4 T Cells ◽  
Histone Deacetylase Inhibitors ◽  
Latent Hiv ◽  
Hiv 1

The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression in CD4+ T-cells and monocytes and induces latent HIV-1 expression in vitro

Cytokine ◽  
2009 ◽  
Vol 48 (1-2) ◽  
pp. 61
Author(s):  
Shay Matalon ◽  
Brent E. Palmer ◽  
Marcel F. Nold ◽  
Antonio Furlan ◽  
Gianluca Fossati ◽  
...  
Keyword(s):  
T Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Cd4 T Cells ◽  
Ccr5 Expression ◽  
Deacetylase Inhibitor ◽  
Latent Hiv ◽  
Hiv 1

scholarly journals Cellular Gene Modulation of HIV-Infected CD4 T Cells in Response to Serial Treatment with the Histone Deacetylase Inhibitor Vorinostat

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Jill W. Maxwell ◽  
Shane D. Falcinelli ◽  
Alexey Nefedov ◽  
Corin Dorfmeier ◽  
Guoxin Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Histone Deacetylase ◽  
Cd4 T Cells ◽  
Histone Deacetylase Inhibitors ◽  
Transcriptional Response ◽  
Hiv Latency ◽  
Hiv Rna ◽  
Transcriptional Changes

ABSTRACT Histone deacetylase inhibitors (HDACi) are the most widely studied HIV latency-reversing agents (LRAs). The HDACi suberoylanilide hydroxamic acid (vorinostat [VOR]) has been employed in several clinical HIV latency reversal studies, as well as in vitro models of HIV latency, and has been shown to effectively induce HIV RNA and protein expression. Despite these findings, response to HDACi can vary, particularly with intermittent dosing, and information is lacking on the relationship between the host transcriptional response and HIV latency reversal. Here, we report on global gene expression responses to VOR and examine the longevity of the transcriptional response in various cellular models. We found that many genes are modulated at 6 h post-VOR treatment in HCT116, Jurkat, and primary resting CD4 T cells, yet return to baseline levels after an 18-h VOR-free period. With repeat exposure to VOR in resting CD4 T cells, we found similar and consistent transcriptional changes at 6 h following each serial treatment. In addition, serial exposure in HIV-infected suppressed donor CD4 T cells showed consistent transcriptional changes after each exposure to VOR. We identified five host genes that were strongly and consistently modulated following histone deacetylase (HDAC) inhibition; three (H1F0, IRGM, and WIPI49) were upregulated, and two (PHF15 and PRDM10) were downregulated. These genes demonstrated consistent modulation in peripheral blood mononuclear cell (PBMC) samples from HIV-positive (HIV+) participants who received either single or multiple doses of 400 mg of VOR. Interestingly, the host transcriptional response did not predict induction of cell-associated HIV RNA, suggesting that other cellular factors play key roles in HIV latency reversal in vivo despite robust HDACi pharmacological activity. IMPORTANCE Histone deacetylase inhibitors are widely studied HIV latency-reversing agents (LRAs). VOR, an HDACi, induces histone acetylation and chromatin remodeling and modulates host and HIV gene expression. However, the relationship between these events is poorly defined, and clinical studies suggest diminished HIV reactivation in resting CD4 T cells with daily exposure to VOR. Our study provides evidence that VOR induces a consistent level of host cell gene transcription following intermittent exposure. In addition, in response to VOR exposure a gene signature that was conserved across single and serial exposures both in vitro and in vivo was identified, indicating that VOR can consistently and reproducibly modulate transcriptional host responses. However, as the HIV response to HDACi declines over time, other factors modulate viral reactivation in vivo despite robust HDAC activity. The identified host gene VOR biomarkers can be used for monitoring the pharmacodynamic activity of HDAC inhibitors.

scholarly journals Histone deacetylase inhibitors butyrate and bufexamac inhibit de novo HIV-1 infection in CD4 T-cells

2020 ◽  
Author(s):  
Lin Chen ◽  
Ariane Zutz ◽  
Julia Phillippou-Massier ◽  
Tim Liebner ◽  
Oliver T. Keppler ◽  
...  
Keyword(s):  
T Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
De Novo ◽  
Treatment Strategies ◽  
Proteome Analysis ◽  
Global Changes ◽  
Hiv Replication ◽  
Latent Hiv ◽  
Hiv 1

AbstractWhile current combined antiretroviral therapy (cART) allows control of HIV replication in patients and effectively suppresses plasma viral loads, it is unable to target latent reservoirs, which are responsible for virus rebound after discontinuation of therapy. Several histone deacetylase inhibitors (HDACIs) have been shown to target reservoirs and to reactivate latent HIV. While this effect is highly desired, it carries the risk that HIV-1 may be reactivated in tissue compartments were cART concentrations are insufficient and thus leading to de novo infections in this sites. To address this concern, we evaluated the effect of different HDACIs for their ability to reverse HIV latency and to modulate de novo infections. Two of the inhibitors, sodium butyrate and bufexamac, significantly inhibited de novo HIV-1 infection in activated CD4+ T-cells. Transcriptome and proteome analysis indicated global changes of protein abundancies, exhibited reduced proliferation of CD4+ T-cells, and revealed butyrate-based proteasomal degradation of EP300, an important factor for HIV-1 replication. Our results disclose new potential treatment strategies and minimizes the concern of potential reservoir reseeding by HDACIs.

scholarly journals Combinations of Histone Deacetylase Inhibitors with Distinct Latency Reversing Agents Variably Affect HIV Reactivation and Susceptibility to NK Cell-Mediated Killing of T Cells That Exit Viral Latency

2021 ◽  
Vol 22 (13) ◽  
pp. 6654
Author(s):  
Daniela A. Covino ◽  
Maria G. Desimio ◽  
Margherita Doria
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Nk Cell ◽  
Hiv Reservoir ◽  
Nkg2d Ligands ◽  
Latent Hiv ◽  
Reversing Agents

The ‘shock-and-kill’ strategy to purge the latent HIV reservoir relies on latency-reversing agents (LRAs) to reactivate the provirus and subsequent immune-mediated killing of HIV-expressing cells. Yet, clinical trials employing histone deacetylase inhibitors (HDACis; Vorinostat, Romidepsin, Panobinostat) as LRAs failed to reduce the HIV reservoir size, stressing the need for more effective latency reversal strategies, such as 2-LRA combinations, and enhancement of the immune responses. Interestingly, several LRAs are employed to treat cancer because they up-modulate ligands for the NKG2D NK-cell activating receptor on tumor cells. Therefore, using in vitro T cell models of HIV latency and NK cells, we investigated the capacity of HDACis, either alone or combined with a distinct LRA, to potentiate the NKG2D/NKG2D ligands axis. While Bortezomib proteasome inhibitor was toxic for both T and NK cells, the GS-9620 TLR-7 agonist antagonized HIV reactivation and NKG2D ligand expression by HDACis. Conversely, co-administration of the Prostratin PKC agonist attenuated HDACi toxicity and, when combined with Romidepsin, stimulated HIV reactivation and further up-modulated NKG2D ligands on HIV+ T cells and NKG2D on NK cells, ultimately boosting NKG2D-mediated viral suppression by NK cells. These findings disclose limitations of LRA candidates and provide evidence that NK cell suppression of reactivated HIV may be modulated by specific 2-LRA combinations.

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