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microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection
RNA interference plays a significant role in manipulating cellular and viral mechanisms to maintain latency during HIV-1 infection. HIV-1 produces several microRNAs including one from the TAR element which alter the host's response to infection. Since cyclin/cdk complexes are important for vira...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Library Publishing Media
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902143/ https://www.ncbi.nlm.nih.gov/pubmed/20628499 |
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author | Carpio, Lawrence Klase, Zachary Coley, William Guendel, Irene Choi, Sarah Van Duyne, Rachel Narayanan, Aarthi Kehn-Hall, Kylene Meijer, Laurent Kashanchi, Fatah |
author_facet | Carpio, Lawrence Klase, Zachary Coley, William Guendel, Irene Choi, Sarah Van Duyne, Rachel Narayanan, Aarthi Kehn-Hall, Kylene Meijer, Laurent Kashanchi, Fatah |
author_sort | Carpio, Lawrence |
collection | PubMed |
description | RNA interference plays a significant role in manipulating cellular and viral mechanisms to maintain latency during HIV-1 infection. HIV-1 produces several microRNAs including one from the TAR element which alter the host's response to infection. Since cyclin/cdk complexes are important for viral transcription, these studies focus on the possible cdk inhibitors that inhibit viral transcription, without affecting normal cellular mechanisms. Roscovitine and Flavopiridol are well-studied cdk inhibitors that are effective at suppressing their target cdks at a low IC50. These cdk inhibitors and possibly future generations of drugs are affected by microRNA mechanisms. From our studies, we developed a third generation derivative called CR8#13. In cells that lack Dicer there was a higher level of basal viral LTR-reporter transcription. When drugs, specifically Flavopiridol and CR8#13 were added, the transcriptional inhibition of the LTR was less potent in cells that lacked Dicer. Also, after transfection with HIV-1 clone (pNL4.3), CR8 and CR8#13 derivatives were shown to be more effective viral transcription inhibitors in cell lines that contained Dicer (T-cells) as compared to Dicer deficient lines (monocytes). We next asked whether the addition of CR8 or CR8#13 could possibly increase levels of TAR microRNA in HIV-1 LTR containing cells. We demonstrate that the 3'TAR microRNA is produced in higher amounts after drug treatment, resulting in microRNA recruitment to the LTR. MicroRNA recruitment results in chromatin alteration, changes in Pol II phosphorylation and viral transcription inhibition. In conclusion, our results indicate that viral microRNA, specifically the TAR microRNA produced from the HIV-1 LTR is responsible for maintaining latent infections by manipulating host cell mechanisms to limit transcription from the viral LTR promoter. With the microRNA machinery present, cdk inhibitors are able to significantly increase the amount of TAR microRNA, leading to downregulation of viral LTR transcription. |
format | Text |
id | pubmed-2902143 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Library Publishing Media |
record_format | MEDLINE/PubMed |
spelling | pubmed-29021432010-09-14 microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection Carpio, Lawrence Klase, Zachary Coley, William Guendel, Irene Choi, Sarah Van Duyne, Rachel Narayanan, Aarthi Kehn-Hall, Kylene Meijer, Laurent Kashanchi, Fatah J RNAi Gene Silencing Research Article RNA interference plays a significant role in manipulating cellular and viral mechanisms to maintain latency during HIV-1 infection. HIV-1 produces several microRNAs including one from the TAR element which alter the host's response to infection. Since cyclin/cdk complexes are important for viral transcription, these studies focus on the possible cdk inhibitors that inhibit viral transcription, without affecting normal cellular mechanisms. Roscovitine and Flavopiridol are well-studied cdk inhibitors that are effective at suppressing their target cdks at a low IC50. These cdk inhibitors and possibly future generations of drugs are affected by microRNA mechanisms. From our studies, we developed a third generation derivative called CR8#13. In cells that lack Dicer there was a higher level of basal viral LTR-reporter transcription. When drugs, specifically Flavopiridol and CR8#13 were added, the transcriptional inhibition of the LTR was less potent in cells that lacked Dicer. Also, after transfection with HIV-1 clone (pNL4.3), CR8 and CR8#13 derivatives were shown to be more effective viral transcription inhibitors in cell lines that contained Dicer (T-cells) as compared to Dicer deficient lines (monocytes). We next asked whether the addition of CR8 or CR8#13 could possibly increase levels of TAR microRNA in HIV-1 LTR containing cells. We demonstrate that the 3'TAR microRNA is produced in higher amounts after drug treatment, resulting in microRNA recruitment to the LTR. MicroRNA recruitment results in chromatin alteration, changes in Pol II phosphorylation and viral transcription inhibition. In conclusion, our results indicate that viral microRNA, specifically the TAR microRNA produced from the HIV-1 LTR is responsible for maintaining latent infections by manipulating host cell mechanisms to limit transcription from the viral LTR promoter. With the microRNA machinery present, cdk inhibitors are able to significantly increase the amount of TAR microRNA, leading to downregulation of viral LTR transcription. Library Publishing Media 2010-05-29 /pmc/articles/PMC2902143/ /pubmed/20628499 Text en ©The Authors http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an open access article, published under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/). This license permits non-commercial use, distribution and reproduction of the article, provided the original work is appropriately acknowledged with correct citation details. |
spellingShingle | Research Article Carpio, Lawrence Klase, Zachary Coley, William Guendel, Irene Choi, Sarah Van Duyne, Rachel Narayanan, Aarthi Kehn-Hall, Kylene Meijer, Laurent Kashanchi, Fatah microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection |
title | microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection |
title_full | microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection |
title_fullStr | microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection |
title_full_unstemmed | microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection |
title_short | microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection |
title_sort | microrna machinery is an integral component of drug-induced transcription inhibition in hiv-1 infection |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902143/ https://www.ncbi.nlm.nih.gov/pubmed/20628499 |
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