Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial.
<h4>Unlabelled</h4>Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the o...
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Public Library of Science (PLoS)
2016-01-01
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| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0154842&type=printable |
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| author | Deepti Saxena Michael Spino Fernando Tricta John Connelly Bernadette M Cracchiolo Axel-Rainer Hanauske Darlene D'Alliessi Gandolfi Michael B Mathews Jonathan Karn Bart Holland Myung Hee Park Tsafi Pe'ery Paul E Palumbo Hartmut M Hanauske-Abel |
| author_facet | Deepti Saxena Michael Spino Fernando Tricta John Connelly Bernadette M Cracchiolo Axel-Rainer Hanauske Darlene D'Alliessi Gandolfi Michael B Mathews Jonathan Karn Bart Holland Myung Hee Park Tsafi Pe'ery Paul E Palumbo Hartmut M Hanauske-Abel |
| author_sort | Deepti Saxena |
| collection | DOAJ |
| description | <h4>Unlabelled</h4>Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 μM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug's half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster ('polyproline')-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound.<h4>Trial registration</h4>ClinicalTrial.gov NCT02191657. |
| format | Article |
| id | doaj-art-e17e5bea35ab4969b437207695534e81 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-e17e5bea35ab4969b437207695534e812025-08-20T02:15:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01115e015484210.1371/journal.pone.0154842Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial.Deepti SaxenaMichael SpinoFernando TrictaJohn ConnellyBernadette M CracchioloAxel-Rainer HanauskeDarlene D'Alliessi GandolfiMichael B MathewsJonathan KarnBart HollandMyung Hee ParkTsafi Pe'eryPaul E PalumboHartmut M Hanauske-Abel<h4>Unlabelled</h4>Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 μM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug's half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster ('polyproline')-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound.<h4>Trial registration</h4>ClinicalTrial.gov NCT02191657.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0154842&type=printable |
| spellingShingle | Deepti Saxena Michael Spino Fernando Tricta John Connelly Bernadette M Cracchiolo Axel-Rainer Hanauske Darlene D'Alliessi Gandolfi Michael B Mathews Jonathan Karn Bart Holland Myung Hee Park Tsafi Pe'ery Paul E Palumbo Hartmut M Hanauske-Abel Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial. PLoS ONE |
| title | Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial. |
| title_full | Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial. |
| title_fullStr | Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial. |
| title_full_unstemmed | Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial. |
| title_short | Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial. |
| title_sort | drug based lead discovery the novel ablative antiretroviral profile of deferiprone in hiv 1 infected cells and in hiv infected treatment naive subjects of a double blind placebo controlled randomized exploratory trial |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0154842&type=printable |
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