Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors that Potently Reactivate Latent HIV
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines
2.2. Reagents
2.3. Evaluation of HIV-Latency Reversal in Cell Lines
2.4. Evaluation of Cytotoxicity
2.5. Real-Time qRT-PCR (Real-Time Quantitative Reverse Transcription PCR) and HIV-1 RNA Analysis
2.6. Evaluation of HIV Reactivation by Western Blot
2.7. Establishment of HIV Latency in Primary CD4+ T-Cells
2.8. Detection of gp120 Expression
2.9. Drug Interaction Analysis
3. Results
3.1. Evaluation of the Efficacy and Cytotoxicity of the LRAs
3.2. Combinations of PKCas and HDACis Do not Affect the Viability of Uninfected Cells
3.3. Combinations of LRAs Reactivate HIV Expression in Latently Infected Cells
3.4. Combinations of PKCas and HDACis Induce High Levels of gp120 Expression
3.5. Indolactam/AR-42 Induces CD4 Downregulation
3.6. Evaluation of HIV Activation in a Primary CD4+ T-Cell Model
3.7. Effect of LRAs Combinations on the Cellular Activation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Target | OM-10.1 | U1 | ACH-2 | J-Lat 10.6 | J-Lat A2 | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
EC50 1 | CC50 1 | EC50 1 | CC50 1 | EC50 1 | CC50 1 | EC50 1 | CC50 1 | EC50 1 | CC50 1 | ||
Prostratin | PKC | 0.41 ± 0.03 | >8 | 0.3 ± 0.03 | >8 | 0.31 ± 0.07 | >8 | 0.68 ± 0.01 | >8 | 0.87 ± 0.03 | >8 |
TPPB | PKC | 0.13 ± 0.01 | >8 | 0.21 ± 0.01 | >8 | 0.07 ± 0.01 | >8 | 0.51 ± 0.08 | >8 | 0.49 ± 0.03 | >8 |
(-)-Indolactam V | PKC | 0.09 ± 0.02 | >8 | 0.12 ± 0.02 | >8 | 0.18 ± 0.03 | >8 | 0.2 ± 0.04 | >8 | 0.32 ± 0.05 | >8 |
Belinostat | HDAC | 0.88 ± 0.4 | 2.7 ± 0.2 | 0.77 ± 0.01 | >8 | 0.44 ± 0.03 | 1.1 ± 0.2 | 0.94 ± 0.03 | 1.4 ± 0.06 | 0.94 ± 0.05 | 1.4 ± 0.02 |
PCI-24781 | HDAC | 0.35 ± 0.04 | 0.4 ± 0.02 | 0.46 ± 0.03 | ~8 | 0.37 ± 0.04 | 0.31 ± 0.02 | 0.45 ± 0.02 | 0.4 ± 0.02 | 0.38 ± 0.05 | 0.54 ± 0.03 |
Givinostat | HDAC | 0.45 ± 0.13 | 0.42 ± 0.01 | 0.63 ± 0.02 | ~4 | 0.32 ± 0.04 | 0.63 ± 0.03 | 0.88 ± 0.04 | 0.93 ± 0.04 | 0.7 ± 0.05 | 1.2 ± 0.02 |
AR-42 | HDAC | 0.53 ± 0.08 | 0.4 ± 0.01 | 0.26 ± 0.1 | ~8 | 0.24 ± 0.04 | 0.41 ± 0.01 | 0.55 ± 0.02 | 0.45 ± 0.02 | 0.44 ± 0.05 | 0.53 ± 0.05 |
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Curreli, F.; Ahmed, S.; Victor, S.M.B.; Debnath, A.K. Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors that Potently Reactivate Latent HIV. Viruses 2020, 12, 609. https://doi.org/10.3390/v12060609
Curreli F, Ahmed S, Victor SMB, Debnath AK. Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors that Potently Reactivate Latent HIV. Viruses. 2020; 12(6):609. https://doi.org/10.3390/v12060609
Chicago/Turabian StyleCurreli, Francesca, Shahad Ahmed, Sofia M. Benedict Victor, and Asim K. Debnath. 2020. "Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors that Potently Reactivate Latent HIV" Viruses 12, no. 6: 609. https://doi.org/10.3390/v12060609