- Open Access
9-aminoacridine Inhibition of HIV-1 Tat Dependent Transcription
© Guendel et al; licensee BioMed Central Ltd. 2009
- Received: 11 June 2009
- Accepted: 24 July 2009
- Published: 24 July 2009
As part of a continued search for more efficient anti-HIV-1 drugs, we are focusing on the possibility that small molecules could efficiently inhibit HIV-1 replication through the restoration of p53 and p21WAF1 functions, which are inactivated by HIV-1 infection. Here we describe the molecular mechanism of 9-aminoacridine (9AA) mediated HIV-1 inhibition. 9AA treatment resulted in inhibition of HIV LTR transcription in a specific manner that was highly dependent on the presence and location of the amino moiety. Importantly, virus replication was found to be inhibited in HIV-1 infected cell lines by 9AA in a dose-dependent manner without inhibiting cellular proliferation or inducing cell death. 9AA inhibited viral replication in both p53 wildtype and p53 mutant cells, indicating that there is another p53 independent factor that was critical for HIV inhibition. p21WAF1 is an ideal candidate as p21WAF1 levels were increased in both p53 wildtype and p53 mutant cells, and p21WAF1 was found to be phosphorylated at S146, an event previously shown to increase its stability. Furthermore, we observed p21WAF1 in complex with cyclin T1 and cdk9 in vitro, suggesting a direct role of p21WAF1 in HIV transcription inhibition. Finally, 9AA treatment resulted in loss of cdk9 from the viral promoter, providing one possible mechanism of transcriptional inhibition. Thus, 9AA treatment was highly efficient at reactivating the p53 – p21WAF1 pathway and consequently inhibiting HIV replication and transcription.
- ACH2 Cell
- Amino Moiety
- Acridine Hydrochloride
- p21WAF1 Level
- p21WAF1 Pathway
HIV-1 infection results in the alteration of numerous host factors and signaling cascades . In particular, it has been demonstrated that the p53 pathway plays an important role in HIV-1 infection [2, 3]. p53 is critical for protecting the integrity of the genome through regulating apoptosis [4–9] and the cell cycle, at both G1/S [10–14] and G2/M checkpoints [15–19]. Wild-type p53 has the ability to be a potent suppressor of HIV-1 Tat transcriptional activity [20, 21], whereas mutant p53 can activate HIV-1 transcription [22, 23]. An RGD-containing domain of Tat protein, Tat (65-80), was shown to play an important role in regulating the proliferative functions of a variety of cell lines, including a human adenocarcinoma cell line, A549. p53 activity was greatly reduced when cells were treated with Tat-(65–80) . On the other hand, Tat efficiently inhibits p53 transcriptional activity through blocking K320 acetylation . These above observations are at least partially explained by the discovery that Tat binds directly to p53 through the p53 dimerization domain . A model has been suggested where p53 could become inactivated in HIV-1 infected cells through binding to Tat and subsequently losing its ability to transactivate its downstream target gene p21WAF1 . While the interplay between p53 and HIV-1 Tat has been clearly demonstrated in vitro by a number of researchers, the in vivo interaction is less clearly defined and requires further analysis. Collectively, these observations indicate the possible role of p53 in the control of HIV-1 replication patterns and proviral latency .
One of the most well characterized transcriptional targets of p53 is the p21WAF1 gene. p21WAF1 was simultaneously characterized by a number of different researchers; it has been described as a target of p53 transactivation, a cyclin/cyclin-dependent kinase (cdk) inhibitor and a protein that is expressed in senescent fibroblasts [28–31]. In addition to its most well-known role as a cdk inhibitor (CKI) that can lead to cell cycle arrest, p21WAF1 is also well recognized to be involved in a variety of other physiological functions. These include the promotion of differentiation as well as the imposition of cellular senescence [32, 33]. The anti-proliferative functions of p21WAF1 are associated with its ability to bind to PCNA and block DNA synthesis. Nuclear p21WAF1 also participates in regulating several transcriptional responses, as well as regulating DNA methylation [34, 35]. While in the cytoplasm p21WAF1 also has important pro-proliferative and survival functions including promoting the formation of cyclin D/cdk4, 6 complexes [36–38] and negatively regulating Fas-mediated apoptosis through the inactivation of procaspase 3 [34, 35].
As the regulation of the p53 and p21WAF1 pathways by HIV-1 infection has become a point of great interest, it might be possible to combat HIV-1 infection through the restoration of the p53 and p21WAF1 pathways using small molecules, such as 9-aminoacridine (9AA). 9AA was originally identified as an anti-bacterial agent, but more recently has gained notice as a potential treatment for cancer, viral, and prion diseases [39–41]. Enthusiasm for 9AA was initially dampened due to observed toxicity that was suggested to be due to DNA intercalating properties and possible topoisomerase II poisoning [42–44]. However, later studies have demonstrated that 9AA can be utilized in a selective manner, especially for virally infected cells. In a 2008 study, up to 20 μM 9AA was utilized with no toxicity observed in uninfected cell lines or PBMCs . In addition, an independent group demonstrated that 9AA treatment did not induced phosphorylation of histone H2A.X or activate the DNA response kinases ATM or ATR, all of which are indicators of DNA damage . 9AA was not found to cause DNA damage by poisoning topoisomerase II as had been previously suggested . Therefore, it appears that 9AA activates p53 through a mechanism different than DNA damage induced p53. 9AA treatment of renal carcinoma cells and HTLV-1 infected T-cells demonstrated NF-κB inhibition and p53 activation, with NF-κB inhibition being upstream of p53 activation [41, 45, 46]. 9AA triggered cell death is dependent on p53, as p53 siRNA blocks 9AA induced cell death . More recently, Guo et al. demonstrated through proteomics analysis downregulation of p110γ, the catalytic subunit of the phosphoinositide 3-kinase (PI3K) family upon 9AA treatment of renal carcinoma cells . Follow-up studies indicated that AKT and the mammalian target of rapamycin (mTOR) signaling were inhibited, which contributed to p110γ downregulation, and possibly p53 and NF-κB alterations.
Previously we have shown that 9AA efficiently reactivates the p53 and p21WAF1 pathways in HIV-1 infected cells . Specifically, we observed increased S15 phosphorylation of p53 and increased p21WAF1 protein levels. p53-pS15 was not detected in complex with Tat, freeing p53 from Tat inhibition. Importantly, virus replication was found to be inhibited in HIV infected PBMCs by 9AA in a dose-dependent manner. Here we investigate further the mechanism of 9AA HIV-1 inhibition. We show that 9AA treatment resulted in inhibition of Tat dependent HIV-1 transcription, without inhibition of cellular proliferation. Using various 9AA derivatives we determined that the amino moiety of 9AA is critical for the observed transcriptional inhibition. We observed for the first time p21WAF1 in complex with p-TEFb (cyclin T1 and cdk9) in vitro, suggesting a role of p21WAF1 in HIV-1 transcription and 9AA mediated inhibition of viral transcription. Finally, we observed loss of the critical transcriptional cofactor, cdk9, from the LTR following 9AA treatment, indicating that this is one possible mechanism of 9AA mediated viral inhibition. Thus, 9AA treatment is highly efficient at reactivating p53 and p21WAF1 pathways and inhibiting HIV replication.
ACH2 and J1.1 are latently HIV-1 infected T-cell lines. ACH2, J1.1, CEM, and Jurkat cells were grown in RPMI-1640 media containing 10% fetal bovine serum (FBS), 1% L-glutamine, and 1% streptomycin/penicillin. TZM-bl cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% FBS, 1% L-glutamine, and 1% streptomycin/penicillin. All cells were incubated at 37°C and 5% CO2.
Small Molecule Compounds and Antibodies
9-aminoacridine was obtained from Sigma, 2-aminoacridine and 4-aminoacridine from KaironKem, acridine hydrochloride from TCI, and 4-aminoquinoline from Tyger Scientific. p21WAF1, phospho-p21WAF1 (S146), cdk2, cyclin T, and actin antibodies were obtained from Santa Cruz Biotechnology. Cdk9 antibody was obtained from Biodesign International. p53, phospho-p53 (S15), AKT (pan), phospho-AKT (S473), phospho-AKT (T308), GSK3-β (pan), phospho-GSK3-β (S9) antibodies were obtained from Cell Signaling.
Plasmids (LTR-CAT and/or CMV-Tat) were transfected by electroporation using a Bio-Rad Gene Pulser (Bio-Rad, Richmond, CA) at 960 μF and 230 volts. Two hours after transfection drug treatment was initiated. After 48 hours, cells were lysed and chloramphenicol acetyltransferase (CAT) activity was determined. Briefly, a standard reaction was performed by adding the cofactor acetyl coenzyme A to a microcentrifuge tube containing cell extract (50 ug) and radiolabeled (14C) chloramphenicol in a final volume of 30 μl and incubating the mixture at 37°C for 1 hour. The reaction mixture was then extracted with ethyl acetate and separated by thin-later chromatography on silica gel plates (Baker-flex silica gel thin-later chromatography plates) in a chloroform-methanol (19:1) solvent. The resolved reaction products were then detected by exposing the plate to a PhosphoImager cassette.
TZM-bl cells were transfected with pc-Tat (0.5 ug) using the Attractene reagent (Qiagen) according to the manufacturers' instructions. TZM-bl cells contain an integrated copy of the firefly luciferase gene under the control of the HIV-1 promoter (obtained through the NIH AIDS Research and Reference Reagent Program). The next day, cells were treated with DMSO or the indicated compound. Forty-eight hours post drug treatment, luciferase activity of the firefly luciferase was measured with the BrightGlo Luciferase Assay (Promega). Luminescence was read from a 96 well plate on an EG&G Berthold luminometer.
Chromatin Immunoprecipitation Assay (ChIP)
ACH2 cells were treated with 2.5 uM 9AA and processed 48 hours later for ChIP. For ChIP, approximately 5 × 106 cells were used per IP. Cells were cross-linked with 1.0% formaldehyde at 37°C for 10 minutes, pelleted, washed, and cells lysed using SDS lysis buffer (1% SDS, 10 mM EDTA, 50 mM Tris-HCl, pH 8.0, one tablet complete protease inhibitor cocktail per 50 ml) on ice for 10 mins. Cells were sonicated on ice for 6 cycles to obtain an average DNA length of 500 to 1200 bp. Lysate was clarified by centrifugation at 14,000 rpm for 10 minutes at 4°C. Supernatant was then diluted 10 fold in ChIP dilution buffer (0.01% SDS, 1.1% Triton X-100, 1.2 mM EDTA, 16.7 mM Tris-HCl, pH 8.0, 167 mM NaCl) and pre-cleared with a mixture of protein A/G agarose (blocked previously with 1 mg/ml salmon sperm DNA and 1 mg/ml BSA) at 4°C for 1 hour. Pre-cleared chromatin was incubated with 10 μg of antibody at 4°C overnight. Next day, 60 μl of a 30% slurry of blocked protein A/G agarose was added and complexes incubated for 2 hours. Immune complexes were recovered by centrifugation and washed once with low salt buffer (0.1% SDS, 1% Triton X-100, 2 mM EDTA, 20 mM Tris-HCl, pH 8.0, 150 mM NaCl), twice with high salt buffer (0.1% SDS, 1% Triton X-100 2 mM EDTA, 20 mM Tris-HCl, pH 8.0, 500 mM NaCl), once with LiCl buffer (0.25 M LiCl, 1% NP-40, 1% deoxycholate, 1 mM EDTA, 10 mM Tris-HCl, pH 8.0), and once with TE buffer. Immune complexes were eluted twice with elution buffer (1% SDS, 0.1 M NaHCO3) and incubating at room temperature for 15 minutes on a rotating wheel. Cross-links were reversed by adding 20 μl of 5 M NaCl and incubating elutes at 65°C overnight. The next day, proteinase K (100 μg/ml final concentration) was added and samples incubated at 55°C for 1 hour. Samples were extracted with phenol:chloroform twice and ethanol precipitated overnight. Pellets were then washed with 70% ethanol, dried, resuspended in 50 μl of TE, and assayed by PCR. Thirty-five cycles of PCR were performed in 50 μl with 10 μl of immunoprecipitated material, 0.1 μM of primers, 0.2 mM dNTPs, and 1.0 unit of Taq DNA polymerase. Finally, PCR products were electrophoresed on 2% agarose gels and visualized by ethidium bromide staining.
Western Blot Analysis
Cell extracts were resolved by SDS PAGE on a 4-20% tris-glycine gel (Invitrogen). Proteins were transferred to Immobilon membranes (Millipore) at 200 mA for 2 hours. Membranes were blocked with Dulbecco's phosphate-buffered saline (PBS) 0.1% Tween-20 + 3% BSA. Primary antibody against specified antibodies was incubated with the membrane in PBS + 0.1% Tween-20 overnight at 4°C. Membranes were washed two times with PBS + 0.1% Tween-20 and incubated with HRP-conjugated secondary antibody for one hour. Presence of secondary antibody was detected by SuperSignal West Dura Extended Duration Substrate (Pierce). Luminescence was visualized on a Kodak 1D image station.
Supernatants from ACH2 and J1.1 cells were collected to test for the presence of virus on day 7 post 9AA treatment. Viral supernatants (10 μl) were incubated in a 96-well plate with reverse transcriptase (RT) reaction mixture containing 1× RT buffer (50 mM Tris-HCl, 1 mM DTT, 5 mM MgCl2, 20 mM KCl), 0.1% Triton, poly(A) (1 U/ml), pd(T) (1 U/ml), and [3H]TTP. The mixture was incubated overnight at 37°C, and 10 ml of the reaction mix was spotted on a DEAE Filtermat paper, washed four times with 5% Na2HPO4, three times with water, and then dried completely. RT activity was measured in a Betaplate counter (Wallac, Gaithersburg, MD).
GST Pulldown Assays
GST tagged proteins were purified as described previously . GST-p21 (1 μg), GST-p21 (N) (1 μg), GST-p21 (C) (1 μg), or GST (1 μg) proteins were added to 2 mg of CEM extracts from various cell lines and rotated overnight at 4°C. The next day complexes were washed twice with TNE150 + 0.1% NP-40 and once with TNE50 + 0.1%NP-40. Complexes were run on 4–20% Tris-glycine gel. Western blots were performed with anti-cdk9 (Biodesign), anti-cyclin T, and anti-cdk2 (Santa Cruz) antibodies.
Five thousand cells were plated per well in a 96-well plate and the next day cells were treated with various concentrations of compounds (1, 10, 50 μM) or DMSO. Forty-eight hours later, 10 μl MTT reagent (50 mg/ml) was added to each well and plates incubated at 37°C for 2 hours. Next, 100 μl of DMSO was added to each well and plate was shaken for 15 minutes at room temperature. The assay was read at 570 nM.
9AA inhibits HIV-1 Tat dependent transcription
To determine if viral transcription inhibition also occurred on a fully chromatinized promoter, we utilized TZM-bl cells, which have an integrated LTR-luciferase reporter construct. TZM-bl cells were transfected with Tat and treated with various concentrations of 9AA or 100 nM flavopiridol the following day. Luciferase assays revealed that 9AA inhibited LTR transcription in a dose dependent manner, with 1 μM showing greater than 50% inhibition and 2.5 μM showing complete transcriptional inhibition (Figure 1B). We were interested if 9AA derivatives would display similar transcriptional inhibition ability. Four commercially available 9AA derivates were purchased (Figure 1C). Compounds 2-aminoacridine (2AA) and 4-aminoacridine (4AA) differ from 9AA only in the location of the amino moiety, while acridine hydrochloride (AH) lacks the amino group. 4-aminoquinoline (4AQ) retains the amino moiety in the same position as 9AA, but lacks the third aromatic ring. Luciferase assays performed with these compounds indicated that the presence and location of the amino moiety is critical for the activity of 9AA, as both AH and 4AA did not inhibit HIV-1 transcription (Figure 1D). Surprisingly, cells treated with 2AA exhibited an increase in viral transcription at both 1 μM and 10 μM. 4AQ treated cells showed limited viral transcription inhibition at 1 μM and approximately 50% inhibition at 1 μM. These results demonstrate the importance of both the presence and location of the amino moiety for the activity of 9AA and also show that, while improving 9AA activity, the third aromatic ring is not essential. The inhibition demonstrated by 9AA is specific to this class of compounds, as other amino acridines did not display activity to the same extent. In addition, they demonstrate that 9AA inhibits HIV-1 transcription in a specific manner.
9AA inhibits viral replication in cells with mutant p53
9AA does not inhibit proliferation in uninfected cells
9AA induces AKT activity and stabilization of p21WAF1
p21WAF1 binds to cyclin T and cdk9 in vitro
9AA treatment results in loss of cdk9 from the viral LTR
In this study we have demonstrated that 9AA is an HIV-1 transcriptional inhibitor that acts without inducing cell death or inhibiting cellular proliferation of uninfected cells. Interestingly, we observed 9AA inhibition of HIV-1 replication in both p53 wildtype and p53 mutant cells. However, in both cell types p21WAF1 levels were increased following 9AA treatment. Unexpectedly, we found increased AKT activity upon 9AA treatment as well as phosphorylation of p21WAF1 at S146, a known target of AKT, which induces p21WAF1 stability. We also observed p21WAF1 in complex with cdk9/cyclin T in vitro, suggesting that p21WAF1 may act as an inhibitor of cdk9/cylin T1 kinase activity. Finally, we found that cdk9 was removed from the viral LTR following 9AA treatment, indicating one mechanism for loss of viral transcription.
The interplay between p53 and HIV-1 is of significant interest to the HIV-1 field. Specifically, p53 and Tat antagonize each other, resulting in inhibition of Tat transcription by p53 and downregulation of p53 dependent transcription by Tat . In addition, the activation of p53 is known to induce apoptosis in response to gp120 [2, 64, 65], where cell death can be induced by through mTOR-mediated phosphorylation of p53 on S15 and subsequent phosphorylation of p53 on S46 [65, 66]. p53 phosphorylation on S15 was observed following 9AA treatment, however cell death was not observed at low levels of compound treatment. S15 phosphorylation is a priming event necessary for other p53 post-translational modifications, with the end result of p53 activation. Therefore, our results indicate that 9AA treatment activates p53 and inhibits HIV-1 without inducing apoptosis. Conversely there has also been data indicating that knockdown of p53 through RNA interference results in a marked reduction in Tat-induced transcription . One potential explanation for the discrepancy is that the above mentioned study examined acutely infected cells, whereas many of the other investigators used chronic or latently infected models, where the status of p53 is unknown. In addition, our current results point toward both p53 dependent and p53 independent activation of p21Waf1 by 9AA treatment. We believe that p21Waf1 may be the key protein in regulating cyclin/cdk complexes in these chronically or latently infected cells.
Recently, Zhang et al. investigated p21WAF1 as a potential molecular barrier for HIV-1 infection of stem cells . Hematopoietic stem cells were previously demonstrated to be highly resistant to HIV-1 infection [69–71]. In this study, p21WAF1 was revealed to restrict HIV-1 infection in primitive hematopoietic cells. By knockdown of the endogenous p21WAF1 levels using siRNAs, the stem cells became highly susceptible to HIV-1 infection. Further, it was shown that the effect of p21WAF1 is specific as the silencing of other p21WAF1 related proteins, p27 and p18 had no effect on HIV-1 infection. Based on these results it was suggested that p21WAF1 may be a possible restriction factor, like TRIM5 and APOBEC3G genes [72–76]. Interestingly, previous research showed that high-titer infection of HIV-1 in T lymphocytes resulted in a loss of the endogenous p21WAF1 , further demonstrating the importance of p21WAF1 in HIV-1 biology.
Our results indicate that p21WAF1 can be induced upon 9AA treatment independently of p53. In fact, p21WAF1 can be induced by a wide array of transcription factors independent of p53 including Sp1/Sp3, BRCA1, E2F-1/E2F-3, Smad3/4, STAT1, STAT3, STAT5, C/EBPα, and C/EBPβ . In addition, there are a number of transcription factors that are involved in the repression of p21WAF1 transcription including c-myc, c-jun, and Id1 . A number of theses factors also have an influence on HIV-1 transcription, including Sp1, C/EBPs, and c-myc . Therefore future studies will be focused on identifying signaling pathways that are altered upstream of p21WAF1 induction following 9AA treatment.
Surprisingly we observed an increased in AKT activity and GSK3-β phosphorylation following 9AA treatment in both p53 wildtype and p53 mutant cells. At first glance these results seemed puzzling; however there are a number of mechanisms that could explain this observation. MDM2 is a p53 transcriptional target that also functions in a feedback loop to regulate p53 levels through inducing p53 proteasomal degradation [80–84]. In order for MDM2 to target p53 to the proteasome it must be phosphorylated within its central domain . Interestingly, MDM2 is phosphorylated by GSK3, resulting in decreased p53 stability . In addition, Boehme et al. found that p53 is stabilized following DNA damage due to DNA PK mediated activation of AKT, phosphorylation and inhibition of GSK3, and consequently inhibition of MDM2 . Therefore in p53 wildtype cells, AKT activation could serve to increase the stability of p53 through the downstream inhibition of MDM2. In both p53 wildtype and mutant cells we observed p21WAF1 phosphorylation at S146, which has been shown to enhance stability of p21WAF1 as well as disrupt the interaction of p21WAF1 with PCNA [61, 88]. S146 phosphorylation was originally described as an AKT event , but can also be induced by PKC which is downstream of AKT . Hela cells treated with siRNA against PKCδ display reduced p21WAF1 stability . Finally, mTOR has been shown to phosphorylate S15 of p53 [64, 65], which is enhanced following 9AA treatment. Our results demonstrate that two substrates of mTOR, p53 S15 and AKT S473 display increased phosphorylation following 9AA treatment. Collectively, these results suggest that AKT and mTOR are activated following 9AA treatment and may help stabilize p53-p21WAF1 activation.
Finally, we have begun to dissect particular structural features that are critical for 9AA's mechanism of action through the use of 9AA derivatives. Our studies have shown that the amino moiety is critical for transcriptional inhibition as loss or movement of this moiety results in loss of 9AA activity. Furthermore, removal of the third aromatic ring of 9AA only partially diminishes 9AA's activity, indicating that it is not a critical structural feature. Future studies will further define the structure activity relationships of this class of molecules in search for a more potent and specific transcriptional inhibitor.
We would like to thank the members of the Kashanchi lab for experiments and assistance with the manuscript. We would also like to thank Dr. Anindya Dutta (University of Virginia) for the GST-p21WAF1 plasmid constructs.
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