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
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, 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
Abstract
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.
Trial registration: ClinicalTrial.gov NCT02191657.
Conflict of interest statement
Competing Interests: The authors have read the journal's policy. The authors of this manuscript have the following competing interests: Cornell University, as former employer of HMHA, owns two patents that are cited in the Discussion under reference [24] and [105] and that directly relate to material pertinent to this article. Under applicable US law, the term for either patent is expiring or has expired. Rutgers University, as employer of HMHA, MBM, TP, BH, DS, BMC, former employer of PEP, and representative of ARH, owns patents and has filed patents and patent applications to protect aspects of the intellectual property that is disclosed in this manuscript. Rutgers University has granted option rights for its intellectual property to HMHA and MBM, which relates to material one might perceive as pertinent to this article: U.S. Patents 7,244,814 and 7,141,589; U.S. Patent applications 12/840,270; 13/271,190; 10/581,658; 10/527,453; 13/272,190; US Provisional applications 61/805,056 and 62/073,980. No financial interactions (employment, consultancy, compensations, grants, royalties, personal fees, fund raising, etc.) have occurred as a result of this option agreement. The contributions of ARH to this work predate the current employment by Eli Lilly and Company, Indianapolis, USA; the latter did not play a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript; did not provide financial support; and has been listed solely to identify “Current Affiliation” as stated. ApoPharma Inc., Toronto, Canada, the employer of MS, FT, and JC, holds FDA and EMA approvals for commercialization of deferiprone as medicinal chelator to treat iron overload in thalassemic patients, and also holds patents for deferiprone use and use of certain analogs for indications outside of those disclosed for HIV-AIDS in this manuscript. The clinical trial was funded by ApoPharma Inc., Toronto, Canada, whose employees MS, FT, and JC received funding in the form of salary. MS, FT, and JC also collaborated with university-employed colleagues (PEP and HMHA) on the design of that trial and independently collected the trial data. The university-employed scientists HMHA, BH, PEP, ARH, and BMC lead the statistical analysis of these data, unconditionally provided by ApoPharma, and independently decided on their publication, without involvement of any financial instruments or support by ApoPharma in the form of authors' salaries, consultation fees, non-financial assistance, or research materials other than medicine-grade deferiprone (see Materials and Methods). The contributions of MS, FT, and JC to this work occurred as part of their employment by ApoPharma Inc., Toronto, Canada, and by way of their employment may relate to that company’s patents, products in development, or marketed products. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
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References
- Taylor BS, Sobieszczyk ME, McCutchan FE, Hammer SM (2008) The challenge of HIV-1 subtype diversity. N Engl J Med 358: 1590–1602. 10.1056/NEJMra0706737
- Holtz CM, Mansky LM (2013) Variation of HIV-1 mutation spectra among cell types. J Virol 87: 5296–5299. 10.1128/JVI.03576-12
- Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z, et al. (2014) HIV-1 persistence in CD4 T cells with stem cell-like properties. Nat Med 20: 139–142. 10.1038/nm.3445
- Wensing AM, van de Vijver DA, Angarano G, Asjo B, Balotta C, Boeri E, et al. (2005) Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 192: 958–966.
- Herbeck JT, Muller V, Maust BS, Ledergerber B, Torti C, Di Giambenedetto S, et al. (2012) Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission. AIDS 26: 193–205. 10.1097/QAD.0b013e32834db418
- Kordelas L, Verheyen J, Esser S, Group EHIVA (2014) Shift of HIV tropism in stem-cell transplantation with CCR5 Delta32 mutation. N Engl J Med 371: 880–882.
- Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, et al. (2009) Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 360: 692–698. 10.1056/NEJMoa0802905
- Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, et al. (2011) Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood 117: 2791–2799. 10.1182/blood-2010-09-309591
- Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, et al. (2013) Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog 9: e1003347 10.1371/journal.ppat.1003347
- Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. (2014) Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370: 901–910. 10.1056/NEJMoa1300662
- Bureau of Disease Control, Prevention and Epidemiology HIV/STD/VH/TB Epidemiology Section, Michigan Department of Community Health (2014) Annual review of HIV trends in southeast Michigan (2008–2012). Overall trends in new HIV diagnoses in southeast Michigan. pp 1–5. Available:
- Department of Health, HIV/AIDS, Hepatitis, STD, and TB Administration, Government of the District of Columbia (2013) Annual Epidemiology & Surveillance Report 2012. pp 1–77. Available:
- United States State Department (2014) PEPFAR—The United States President's Emergency Plan for AIDS Relief—Countries. Office of U.S. Global AIDS Coordinator and the Bureau of Public Affairs. Washington, DC Available:
- Reese M (2015) Declaration of Public Health Emergency in Scott County, Indiana (Executive Order 15–05). Executive Department Indianapolis—State of Indiana. Available:
- Maddox L, Bush T, Moise M (2015) Epidemiology of HIV infection—Trends in Florida reported through 2014. Florida Department of Health, Division of Disease Control and Health Protection, HIV/AIDS Section. Tallahassee, FL Available:
- Editorial (2015) Alarming rise in HIV cases. Tampa Bay Times, July 10, 2015. Tampa Bay, FL Available:
- Group ISS, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. (2015) Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med 373: 795–807. 10.1056/NEJMoa1506816
- HHS Panel on Antiretroviral Guidelines for Adults and Adolescents (2015) Statement Regarding Results from the START and TEMPRANO Trials. U.S. Department of Health and Human Services, Office of AIDS Research Council. Available:
- World Health Organization (2015) Guideline on when to start antiretroviral therapy and on pre-exposure prophylasis for HIV. Geneva, Switzerland. Available:
- World Health Organization (2015) HIV / AIDS Factsheet No 360. Geneva, Switzerland. Available:
- United States State Department (2015) PEPFAR—Latest Results. Office of U.S. Global AIDS Coordinator and the Bureau of Public Affairs. Washington, DC Available:
- Joint United Nations Programme on HIV/AIDS (2014) Children and HIV. Geneva, Switzerland. Available at:
- Sloan CE, Champenois K, Choisy P, Losina E, Walensky RP, Schackman BR, et al. (2012) Newer drugs and earlier treatment: impact on lifetime cost of care for HIV-infected adults. AIDS 26: 45–56. 10.1097/QAD.0b013e32834dce6e
- United States State Department (2015) PEPFAR Funding Fact Sheet Fiscal Years 2014–2016. Office of U.S. Global AIDS Coordinator and the Bureau of Public Affairs. Washington, DC Available:
- Chun TW, Justement JS, Murray D, Hallahan CW, Maenza J, Collier AC, et al. (2010) Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS 24: 2803–2808. 10.1097/QAD.0b013e328340a239
- Fischer M, Hafner R, Schneider C, Trkola A, Joos B, Joller H, et al. (2003) HIV RNA in plasma rebounds within days during structured treatment interruptions. AIDS 17: 195–199.
- Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al. (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 9: 727–728.
- Andrus L, Szabo P, Grady RW, Hanauske AR, Huima-Byron T, Slowinska B, et al. (1998) Antiretroviral effects of deoxyhypusyl hydroxylase inhibitors: a hypusine-dependent host cell mechanism for replication of human immunodeficiency virus type 1 (HIV-1). Biochem Pharmacol 55: 1807–1818.
- Hanauske-Abel HM, Günzler V (1982) A stereochemical concept for the catalytic mechanism of prolyl hydroxlyase. Applicability to classification and design of inhibitors. J Theor Biol 94: 421–455.
- Hanauske-Abel HM (1983) Über einen stereochemischen Vorschlag für den katalytischen Mechanismus der Prolylhydroxylase, seine Anwendung zur Klassifizierung und Formulierung von Hemmstoffen sowie die Entwicklung und Erprobung eines 'maßgeschneiderten' neuartigen Inhibitors. Thesis, Department of Pharmacology and Toxicology, Philipps Universität, Marburg, Germany
- Hanauske-Abel HM, Popowicz AM (2003) The HAG mechanism: a molecular rationale for the therapeutic application of iron chelators in human diseases involving the 2-oxoacid utilizing dioxygenases. Curr Med Chem 10: 1005–1019.
- Abbruzzese A, Hanauske-Abel HM, Park MH, Henke S, Folk JE (1991) The active site of deoxyhypusyl hydroxylase: use of catecholpeptides and their component chelator and peptide moieties as molecular probes. Biochim Biophys Acta 1077: 159–166.
- McCaffrey TA, Pomerantz KB, Sanborn TA, Spokojny AM, Du B, Park MH, et al. (1995) Specific inhibition of eIF-5A and collagen hydroxylation by a single agent. Antiproliferative and fibrosuppressive effects on smooth muscle cells from human coronary arteries. J Clin Invest 95: 446–455.
- Park JH, Aravind L, Wolff EC, Kaevel J, Kim YS, Park MH (2006) Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci U S A 103: 51–56.
- Majamaa K, Hanauske-Abel HM, Gunzler V, Kivirikko KI (1984) The 2-oxoglutarate binding site of prolyl 4-hydroxylase. Identification of distinct subsites and evidence for 2-oxoglutarate decarboxylation in a ligand reaction at the enzyme-bound ferrous ion. Eur J Biochem 138: 239–245.
- Majamaa K, Turpeenniemi-Hujanen TM, Latipaa P, Gunzler V, Hanauske-Abel HM, Hassinen IE, et al. (1985) Differences between collagen hydroxylases and 2-oxoglutarate dehydrogenase in their inhibition by structural analogues of 2-oxoglutarate. Biochem J 229: 127–133.
- Tschank G, Raghunath M, Gunzler V, Hanauske-Abel HM (1987) Pyridinedicarboxylates, the first mechanism-derived inhibitors for prolyl 4-hydroxylase, selectively suppress cellular hydroxyprolyl biosynthesis. Decrease in interstitial collagen and Clq secretion in cell culture. Biochem J 248: 625–633.
- Hanauske-Abel HM (1991) Prolyl 4-hydroxylase, a target enzyme for drug development. Design of suppressive agents and the in vitro effects of inhibitors and proinhibitors. J Hepatol 13 Suppl 3: S8–15; discussion S16.
- Newfield RS, Giardina P, Grady RC, Hanauske-Abel HM (1996) Deferiprone, but not deferoxamine, inhibits biosynthesis of fibrillar procollagens in iron-overloaded thalassemic patients. Ped Res 39: 160.
- Newfield RS, Giardina P, Grady RC, Hanauske-Abel HM (1996) Deferiprone: An in vitro inhibitor of protein hydroxylases vital for matrix formation and cell proliferation. Ped Res 39: 160.
- Clement PM, Hanauske-Abel HM, Wolff EC, Kleinman HK, Park MH (2002) The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro. Int J Cancer 100: 491–498.
- Hoffart LM, Barr EW, Guyer RB, Bollinger JM Jr., Krebs C (2006) Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase. Proc Natl Acad Sci U S A 103: 14738–14743.
- Hanauske-Abel HM, Saxena D, Palumbo PE, Hanauske A-R, Luchessi AD, Cambiaghi TD, et al. (2013) Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection. PLOS ONE 8: e74414 10.1371/journal.pone.0074414
- Hanauske-Abel HM, Slowinska B, Zagulska S, Wilson RC, Staiano-Coico L, Hanauske AR, et al. (1995) Detection of a sub-set of polysomal mRNAs associated with modulation of hypusine formation at the G1-S boundary. Proposal of a role for eIF-5A in onset of DNA replication. FEBS Lett 366: 92–98.
- Hanauske-Abel HM, Grady RW, Hanauske AR, Andrus L, Szabo P (1998) Method of inhibiting viral replication in eukaryotic cells and of inducing apoptosis of virally infected cells. United States Patent 5,849,587.
- Hoque M, Hanauske-Abel HM, Palumbo P, Saxena D, D'Alliessi Gandolfi D, Park M, et al. (2009) Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A. Retrovirology 6: 90 10.1186/1742-4690-6-90
- Arrowsmith J, Miller P (2013) Phase II and Phase III attrition rates 2011–2012. Nat Rev Drug Discov 12: 569 10.1038/nrd4090
- Begley CG, Ellis LM (2012) Drug development: Raise standards for preclinical cancer research. Nature 483: 531–533. 10.1038/483531a
- Kontoghiorghes GJ, Goddard JG, Bartlett AN, Sheppard L (1990) Pharmacokinetic studies in humans with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Clin Pharmacol Ther 48: 255–261.
- Witvrouw M, Pannecouque C, Desmyter J, De Clercq E, Andries K (2000) In vitro evaluation of the effect of temporary removal of HIV drug pressure. Antiviral Res 46: 215–221.
- Nitanda T, Wang X, Somekawa K, Yuasa S, Baba M (2001) Three-drug combinations of emivirine and nucleoside reverse transcriptase inhibitors in vitro: long-term culture of HIV-1-infected cells and breakthrough viruses. Antivir Chem Chemother 12: 161–167.
- New DR, Maggirwar SB, Epstein LG, Dewhurst S, Gelbard HA (1998) HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism. J Biol Chem 273: 17852–17858.
- Gain P, Thuret G, Chiquet C, Dumollard JM, Mosnier JF, Burillon C, et al. (2002) Value of two mortality assessment techniques for organ cultured corneal endothelium: trypan blue versus TUNEL technique. Br J Ophthalmol 86: 306–310.
- Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, et al. (1995) Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1: 129–134.
- Montagnier L (2009) 25 years after HIV discovery: prospects for cure and vaccine (Nobel lecture). Angew Chem Int Ed Engl 48: 5815–5826. 10.1002/anie.200902130
- Fernandez Larrosa PN, Croci DO, Riva DA, Bibini M, Luzzi R, Saracco M, et al. (2008) Apoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathway. Retrovirology 5: 19 10.1186/1742-4690-5-19
- Venkatachari NJ, Buchanan WG, Ayyavoo V (2008) Human immunodeficiency virus (HIV-1) infection selectively downregulates PD-1 expression in infected cells and protects the cells from early apoptosis in vitro and in vivo. Virology 376: 140–153. 10.1016/j.virol.2008.03.015
- Klase Z, Winograd R, Davis J, Carpio L, Hildreth R, Heydarian M, et al. (2009) HIV-1 TAR miRNA protects against apoptosis by altering cellular gene expression. Retrovirology 6: 18 10.1186/1742-4690-6-18
- Georgiou NA, van der Bruggen T, Oudshoorn M, Hider RC, Marx JJ, van Asbeck BS (2002) Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis. Eur J Clin Invest 32 Suppl 1: 91–96.
- Sun Z, Cheng Z, Taylor CA, McConkey BJ, Thompson JE (2010) Apoptosis induction by eIF5A1 involves activation of the intrinsic mitochondrial pathway. J Cell Physiol 223: 798–809. 10.1002/jcp.22100
- Seko Y, Fujimura T, Yao T, Taka H, Mineki R, Okumura K, et al. (2015) Secreted tyrosine sulfated-eIF5A mediates oxidative stress-induced apoptosis. Sci Rep 5: 13737 10.1038/srep13737
- Beninati S, Abbruzzese A, Folk JE (1990) High-performance liquid chromatographic method for determination of hypusine and deoxyhypusine. Anal Biochem 184: 16–20.
- Bevec D, Klier H, Holter W, Tschachler E, Valent P, Lottspeich F, et al. (1994) Induced gene expression of the hypusine-containing protein eukaryotic initiation factor 5A in activated human T lymphocytes. Proc Natl Acad Sci U S A 91: 10829–10833.
- Li Q, Smith AJ, Schacker TW, Carlis JV, Duan L, Reilly CS, et al. (2009) Microarray Analysis of Lymphatic Tissue Reveals Stage-Specific, Gene Expression Signatures in HIV-1 Infection. The Journal of Immunology 183: 1975–1982. 10.4049/jimmunol.0803222
- Mo B, Vendrov AE, Palomino WA, DuPont BR, Apparao KB, Lessey BA (2006) ECC-1 cells: a well-differentiated steroid-responsive endometrial cell line with characteristics of luminal epithelium. Biol Reprod 75: 387–394.
- Mesquita PM, Cheshenko N, Wilson SS, Mhatre M, Guzman E, Fakioglu E, et al. (2009) Disruption of tight junctions by cellulose sulfate facilitates HIV infection: model of microbicide safety. J Infect Dis 200: 599–608. 10.1086/600867
- Rohan LC, Moncla BJ, Kunjara Na Ayudhya RP, Cost M, Huang Y, Gai F, et al. (2010) In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. PLoS One 5: e9310 10.1371/journal.pone.0009310
- Patel MV, Ghosh M, Fahey JV, Wira CR (2012) Uterine epithelial cells specifically induce interferon-stimulated genes in response to polyinosinic-polycytidylic acid independently of estradiol. PLoS One 7: e35654 10.1371/journal.pone.0035654
- Nazli A, Chan O, Dobson-Belaire WN, Ouellet M, Tremblay MJ, Gray-Owen SD, et al. (2010) Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog 6: e1000852 10.1371/journal.ppat.1000852
- Okamoto M, Makino M, Yamada K, Nakade K, Yuasa S, Baba M (1996) Complete inhibition of viral breakthrough by combination of MKC-442 with AZT during a long-term culture of HIV-1 infected cells. Antiviral Res 31: 69–77.
- Balzarini J, Perez-Perez MJ, Velazquez S, San-Felix A, Camarasa MJ, De Clercq E, et al. (1995) Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e., TSAO derivatives). Proc Natl Acad Sci U S A 92: 5470–5474.
- Balzarini J, De Clercq E (2001) Rapid alternation of drug therapy is highly efficient in suppressing the emergence of mutant drug-resistant HIV strains in cell culture. AIDS Res Hum Retroviruses 17: 1625–1634.
- Davey RT Jr., Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, et al. (1999) HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A 96: 15109–15114.
- National Department of Health, Republic of South Africa (2010) Clinical guidelines for the management of HIV & AIDS in adults and adolescents. pp. 1–42. Available:
- European Medicines Agency (2013) Ferriprox ™: Annex I—Summary of product characteristics. pp 1–56. Available:
- Food and Drug Administration (2011) Oncologic Drugs Advisory Committee Briefing Document: NDA # 21–825, Ferriprox® (deferiprone). pp 1–7. Available:
- Butler SL, Hansen MS, Bushman FD (2001) A quantitative assay for HIV DNA integration in vivo. Nat Med 7: 631–634.
- Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, et al. (2013) Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155: 540–551. 10.1016/j.cell.2013.09.020
- Alidjinou EK, Bocket L, Hober D (2015) Quantification of viral DNA during HIV-1 infection: A review of relevant clinical uses and laboratory methods. Pathol Biol (Paris) 63: 53–59.
- Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. (2011) Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 365: 1673–1683. 10.1056/NEJMoa1106152
- Limenta LM, Jirasomprasert T, Tankanitlert J, Svasti S, Wilairat P, Chantharaksri U, et al. (2008) UGT1A6 genotype-related pharmacokinetics of deferiprone (L1) in healthy volunteers. Br J Clin Pharmacol 65: 908–916. 10.1111/j.1365-2125.2008.03103.x
- Benoit-Biancamano MO, Connelly J, Villeneuve L, Caron P, Guillemette C (2009) Deferiprone glucuronidation by human tissues and recombinant UDP-glucuronosyltransferase 1A6: an in vitro investigation of genetic and splice variants. Drug Metab Dispos 37: 322–329. 10.1124/dmd.108.023101
- Bellanti F, Danhof M, Della Pasqua O (2014) Population pharmacokinetics of deferiprone in healthy subjects. Br J Clin Pharmacol 78: 1397–1406. 10.1111/bcp.12473
- Center for Drug Evaluation and Research, Food and Drug Administration, United States Department of Health and Human Services (2003) Guidance for Industry. Exposure-Response Relationships—Study Design, Data Analysis, and Regulatory Applications. April 2003 ed. pp. 1–28. Available at:
- Raboud JM, Montaner JS, Conway B, Haley L, Sherlock C, O'Shaughnessy MV, et al. (1996) Variation in plasma RNA levels, CD4 cell counts, and p24 antigen levels in clinically stable men with human immunodeficiency virus infection. J Infect Dis 174: 191–194.
- Paxton WB, Coombs RW, McElrath MJ, Keefer MC, Hughes J, Sinangil F, et al. (1997) Longitudinal analysis of quantitative virologic measures in human immunodeficiency virus-infected subjects with > or = 400 CD4 lymphocytes: implications for applying measurements to individual patients. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. J Infect Dis 175: 247–254.
- Modjarrad K, Chamot E, Vermund SH (2008) Impact of small reductions in plasma HIV RNA levels on the risk of heterosexual transmission and disease progression. AIDS 22: 2179–2185. 10.1097/QAD.0b013e328312c756
- Saag MS, Holodniy M, Kuritzkes DR, O'Brien WA, Coombs R, Poscher ME, et al. (1996) HIV viral load markers in clinical practice. Nat Med 2: 625–629.
- Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, et al. (2004) The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 63: 214–219.
- Gotzsche PC, Hansen M, Stoltenberg M, Svendsen A, Beier J, Faarvang KL, et al. (1996) Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis. Scand J Rheumatol 25: 194–199.
- Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB, et al. (2004) Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum 51: 738–745.
- Stadler WM (2007) The randomized discontinuation trial: a phase II design to assess growth-inhibitory agents. Mol Cancer Ther 6: 1180–1185.
- Kopec JA, Abrahamowicz M, Esdaile JM (1993) Randomized discontinuation trials: utility and efficiency. J Clin Epidemiol 46: 959–971.
- Karrison TG, Ratain MJ, Stadler WM, Rosner GL (2012) Estimation of progression-free survival for all treated patients in the randomized discontinuation trial design. Am Statistician 66: 155–162.
- Frost SD, Martinez-Picado J, Ruiz L, Clotet B, Brown AJ (2002) Viral dynamics during structured treatment interruptions of chronic human immunodeficiency virus type 1 infection. J Virol 76: 968–979.
- Harrigan PR, Whaley M, Montaner JS (1999) Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy. AIDS 13: F59–62.
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (2009) Table for grading the severity of adult and pediatric adverse events, version 1.0 of December 2004 with clarification of August 2009. Available:
- National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases (2007) Adult Toxicity Table. Available:
- Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, et al. (2006) Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 47: 362–367.
- Center for Drug Evaluation and Research, Food and Drug Administration, United States Department of Health and Human Services (2005) Guidance for Industry—Clinical Evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. pp 1–16. Available:
- Center for Drug Evaluation and Research, Food and Drug Administration, United States Department of Health and Human Services (2009) Guidance for Industry—Antiviral Product Development—Conducting and Submitting Virology Studies to the Agency. pp 1–14. Available at:
- Committee for Medicinal Products for Human Use, European Medicines Agency (2013) Guideline on the clinical development of medicinal products for the treatment of HIV infection. pp. 1–18. Available at:
- Yasue M, Kawamura N, Sakakibara J (1970) [Syntheses of N-substituted-3-glucosyloxy-2-methyl-4-pyridones and their aglycones]. Yakugaku Zasshi 90: 1222–1225.
- Kontoghiorghes GJ (1985) New orally active iron chelators. Lancet 1: 817.
- Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, et al. (2004) Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 89: 1187–1193.
- Sohn YS, Breuer W, Munnich A, Cabantchik ZI (2008) Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications. Blood 111: 1690–1699.
- Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, et al. (2009) Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies. Blood Cells Mol Dis 42: 247–251. 10.1016/j.bcmd.2009.01.002
- Piga A, Gaglioti C, Fogliacco E, Tricta F (2003) Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica 88: 489–496.
- Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, et al. (2006) Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood 107: 3733–3737.
- Pepe A, Meloni A, Capra M, Cianciulli P, Prossomariti L, Malaventura C, et al. (2011) Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica 96: 41–47. 10.3324/haematol.2009.019042
- Telfer P, Coen PG, Christou S, Hadjigavriel M, Kolnakou A, Pangalou E, et al. (2006) Survival of medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980–2004. Haematologica 91: 1187–1192.
- Modell B, Khan M, Darlison M, Westwood MA, Ingram D, Pennell DJ (2008) Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson 10: 42 10.1186/1532-429X-10-42
- Tochigi Y, Yamashiki N, Ohgiya S, Ganaha S, Yokota H (2005) Isoform-specific expression and induction of UDP-glucuronosyltransferase in immunoactivated peritoneal macrophages of the rat. Drug Metab Dispos 33: 1391–1398.
- Schäfer B, Hauber I, Bunk A, Heukeshoven J, Dusedau A, Bevec D, et al. (2006) Inhibition of multidrug-resistant HIV-1 by interference with cellular S-adenosylmethionine decarboxylase activity. J Infect Dis 194: 740–750.
- Hauber I, Bevec D, Heukeshoven J, Kratzer F, Horn F, Choidas A, et al. (2005) Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. J Clin Invest 115: 76–85.
- Schroeder M, Kolodzik A, Pfaff K, Priyadarshini P, Krepstakies M, Hauber J, et al. (2014) In silico design, synthesis, and screening of novel deoxyhypusine synthase inhibitors targeting HIV-1 replication. ChemMedChem 9: 940–952. 10.1002/cmdc.201300481
- Chiang PK, McCann PP, Lane JR, Pankaskie MC, Burke DS, Mayers DL (1996) Antihuman Immunodeficiency Virus (HIV-1) Activities of Inhibitors of Polyamine Pathways. J Biomed Sci 3: 78–81.
- Jin X, McGrath MS, Xu H (2015) Inhibition of HIV expression and integration in macrophages by methylglyoxal-bis-guanylhydrazone. J Virol 89: 11176–11189. 10.1128/JVI.01692-15
- Gordon RK, Ginalski K, Rudnicki WR, Rychlewski L, Pankaskie MC, Bujnicki JM, et al. (2003) Anti-HIV-1 activity of 3-deaza-adenosine analogs. Inhibition of S-adenosylhomocysteine hydrolase and nucleotide congeners. Eur J Biochem 270: 3507–3517.
- Mayers DL, Mikovits JA, Joshi B, Hewlett IK, Estrada JS, Wolfe AD, et al. (1995) Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3'-azido-3'-deoxythymidine-resistant HIV-1 strains. Proc Natl Acad Sci U S A 92: 215–219.
- Marasco CJ Jr., Kramer DL, Miller J, Porter CW, Bacchi CJ, Rattendi D, et al. (2002) Synthesis and evaluation of analogues of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine as inhibitors of tumor cell growth, trypanosomal growth, and HIV-1 infectivity. J Med Chem 45: 5112–5122.
- Hoffman BD, Hanauske-Abel HM, Flint A, Lalande M (1991) A new class of reversible cell cycle inhibitors. Cytometry 12: 26–32.
- Watson PA, Hanauske-Abel HH, Flint A, Lalande M (1991) Mimosine reversibly arrests cell cycle progression at the G1-S phase border. Cytometry 12: 242–246.
- Hanauske-Abel HM, Park MH, Hanauske AR, Popowicz AM, Lalande M, Folk JE (1994) Inhibition of the G1-S transition of the cell cycle by inhibitors of deoxyhypusine hydroxylation. Biochim Biophys Acta 1221: 115–124.
- Han Z, Sakai N, Bottger LH, Klinke S, Hauber J, Trautwein AX, et al. (2015) Crystal Structure of the Peroxo-diiron(III) Intermediate of Deoxyhypusine Hydroxylase, an Oxygenase Involved in Hypusination. Structure 23: 882–892. 10.1016/j.str.2015.03.002
- Ross EM, Gilman AG (1985) Pharmacodynamics: Mechanism of drug action and the relationship between drug concentration and effect In: Gilman AG, Goodman LS, Rall TW, Murad F, editors. The pharmacological basis of therapeutics. New York: MacMillan; pp. 35–48.
- Frey AG, Nandal A, Park JH, Smith PM, Yabe T, Ryu MS, et al. (2014) Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase. Proc Natl Acad Sci U S A 111: 8031–8036. 10.1073/pnas.1402732111
- Mémin E, Hoque M, Jain MR, Heller DS, Li H, Cracchiolo B, et al. (2013) Blocking eIF5A modification in cervical cancer cells alters the expression of cancer-related genes and suppresses cell proliferation. Cancer Res 74: 552–562. 10.1158/0008-5472.CAN-13-0474
- Minden MD, Hogge DE, Weir SJ, Kasper J, Webster DA, Patton L, et al. (2014) Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am J Hematol 89: 363–368. 10.1002/ajh.23640
- Fujimura K, Wright T, Strnadel J, Kaushal S, Metildi C, Lowy AM, et al. (2014) A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer. Cancer Res 74: 6671–6681. 10.1158/0008-5472.CAN-14-1031
- Park MH, Clement PM, Hanauske-Abel HM, Wolff EC, Kleinman HK, Cracchiolo BM (2006) Methods of inhibiting formation of vascular channels and methods of inhibiting proliferation. United States Patent 7,141,589
- Chawla B, Kumar RR, Tyagi N, Subramanian G, Srinivasan N, Park MH, et al. (2012) A unique modification of the eukaryotic initiation factor 5A shows the presence of the complete hypusine pathway in Leishmania donovani. PLoS One 7: e33138 10.1371/journal.pone.0033138
- Atemnkeng VA, Pink M, Schmitz-Spanke S, Wu XJ, Dong LL, Zhao KH, et al. (2013) Deoxyhypusine hydroxylase from Plasmodium vivax, the neglected human malaria parasite: molecular cloning, expression and specific inhibition by the 5-LOX inhibitor zileuton. PLoS One 8: e58318 10.1371/journal.pone.0058318
- Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, et al. (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373: 117–122.
- Piatak M Jr., Saag MS, Yang LC, Clark SJ, Kappes JC, Luk KC, et al. (1993) High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259: 1749–1754.
- Schüpbach J, Gunthard H, Joos B, Fischer M, Boni J, Tomasik Z, et al. (2005) HIV-1 p24 may persist during long-term highly active antiretroviral therapy, increases little during short treatment breaks, and its rebound after treatment stop correlates with CD4(+) T cell loss. J Acquir Immune Defic Syndr 40: 250–256.
- Spear JB, Benson CA, Pottage JC Jr., Paul DA, Landay AL, Kessler HA (1988) Rapid rebound of serum human immunodeficiency virus antigen after discontinuing zidovudine therapy. J Infect Dis 158: 1132–1133.
- Kappes JC, Saag MS, Shaw GM, Hahn BH, Chopra P, Chen S, et al. (1995) Assessment of antiretroviral therapy by plasma viral load testing: standard and ICD HIV-1 p24 antigen and viral RNA (QC-PCR) assays compared. J Acquir Immune Defic Syndr Hum Retrovirol 10: 139–149.
- Merigan TC, Skowron G, Bozzette SA, Richman D, Uttamchandani R, Fischl M, et al. (1989) Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. A phase I and II study. Ann Intern Med 110: 189–194.
- Ioannidis JP, Havlir DV, Tebas P, Hirsch MS, Collier AC, Richman DD (2000) Dynamics of HIV-1 viral load rebound among patients with previous suppression of viral replication. AIDS 14: 1481–1488.
- Garcia F, Plana M, Vidal C, Cruceta A, O'Brien WA, Pantaleo G, et al. (1999) Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS 13: F79–86.
- Ortiz GM, Nixon DF, Trkola A, Binley J, Jin X, Bonhoeffer S, et al. (1999) HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 104: R13–18.
- Cohen AR, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F (2000) Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 108: 305–312.
- Neufeld EJ (2010) Update on iron chelators in thalassemia. Hematology Am Soc Hematol Educ Program 2010: 451–455. 10.1182/asheducation-2010.1.451
- Hanauske-Abel HM, McCaffrey TA, Grady RW (1998) Method for the treatment of fibroproliferative disorders by the application of inhibitors of protein hydroxylation. United States Patent 5,789,426
- Hirasawa K, Yoshida O, Fujinami T, Sohma K, Watanabe A (2000) Adenine-induced selective apoptosis toward HIV chronically infected cells in vitro. Biochem Biophys Res Commun 273: 1025–1032.
- Swingler S, Mann AM, Zhou J, Swingler C, Stevenson M (2007) Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein. PLoS Pathog 3: 1281–1290.
- Perez OD, Nolan GP, Magda D, Miller RA, Herzenberg LA (2002) Motexafin gadolinium (Gd-Tex) selectively induces apoptosis in HIV-1 infected CD4+ T helper cells. Proc Natl Acad Sci U S A 99: 2270–2274.
- Guendel I, Agbottah ET, Kehn-Hall K, Kashanchi F (2010) Inhibition of human immunodeficiency virus type-1 by cdk inhibitors. AIDS Res Ther 7: 7 10.1186/1742-6405-7-7
- Berro R, de la Fuente C, Klase Z, Kehn K, Parvin L, Pumfery A, et al. (2007) Identifying the membrane proteome of HIV-1 latently infected cells. J Biol Chem 282: 8207–8218.
- Vocero-Akbani AM, Heyden NV, Lissy NA, Ratner L, Dowdy SF (1999) Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein. Nat Med 5: 29–33.
- Wang Z, Tang Z, Zheng Y, Yu D, Spear M, Iyer SR, et al. (2010) Development of a nonintegrating Rev-dependent lentiviral vector carrying diphtheria toxin A chain and human TRAF6 to target HIV reservoirs. Gene Ther 17: 1063–1076. 10.1038/gt.2010.53
- Imaz A, Falco V, Ribera E (2011) Antiretroviral salvage therapy for multiclass drug-resistant HIV-1-infected patients: from clinical trials to daily clinical practice. AIDS Rev 13: 180–193.
- Collins I, Cairns J, Le Coeur S, Pagdi K, Ngampiyaskul C, Layangool P, et al. (2013) Five-year trends in antiretroviral usage and drug costs in HIV-infected children in Thailand. J Acquir Immune Defic Syndr 64: 95–102. 10.1097/QAI.0b013e318298a309
- Stadeli KM, Richman DD (2013) Rates of emergence of HIV drug resistance in resource-limited settings: a systematic review. Antivir Ther 18: 115–123. 10.3851/IMP2437
- Stover J, Korenromp EL, Blakley M, Komatsu R, Viisainen K, Bollinger L, et al. (2011) Long-term costs and health impact of continued global fund support for antiretroviral therapy. PLoS One 6: e21048 10.1371/journal.pone.0021048
- Pennings PS, Kryazhimskiy S, Wakeley J (2014) Loss and recovery of genetic diversity in adapting populations of HIV. PLoS Genet 10: e1004000 10.1371/journal.pgen.1004000
- Lazdins JK, Alteri E, Klimkait T, Woods-Cook K, Walker MR, Goutte G, et al. (1991) Lack of effect of desferrioxamine on in-vitro HIV-1 replication. Lancet 338: 1341–1342.
- Salhi Y, Costagliola D, Rebulla P, Dessi C, Karagiorga M, Lena-Russo D, et al. (1998) Serum ferritin, desferrioxamine, and evolution of HIV-1 infection in thalassemic patients. J Acquir Immune Defic Syndr Hum Retrovirol 18: 473–478.
- De Clercq E (1995) Antiviral therapy for human immunodeficiency virus infections. Clin Microbiol Rev 8: 200–239.
- Liang WS, Maddukuri A, Teslovich TM, de la Fuente C, Agbottah E, Dadgar S, et al. (2005) Therapeutic targets for HIV-1 infection in the host proteome. Retrovirology 2: 20
- Narayanan A, Kehn-Hall K, Bailey C, Kashanchi F (2011) Analysis of the roles of HIV-derived microRNAs. Expert Opin Biol Ther 11: 17–29. 10.1517/14712598.2011.540564
- Coley W, Kehn-Hall K, Van Duyne R, Kashanchi F (2009) Novel HIV-1 therapeutics through targeting altered host cell pathways. Expert Opin Biol Ther 9: 1369–1382. 10.1517/14712590903257781
- Bruey JM, Ducasse C, Bonniaud P, Ravagnan L, Susin SA, Diaz-Latoud C, et al. (2000) Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2: 645–652.
- Wainberg Z, Oliveira M, Lerner S, Tao Y, Brenner BG (1997) Modulation of stress protein (hsp27 and hsp70) expression in CD4+ lymphocytic cells following acute infection with human immunodeficiency virus type-1. Virology 233: 364–373.
- Selliah N, Finkel TH (2001) Biochemical mechanisms of HIV induced T cell apoptosis. Cell Death Differ 8: 127–136.
- Weaver JG, Tarze A, Moffat TC, Lebras M, Deniaud A, Brenner C, et al. (2005) Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor. J Clin Invest 115: 1828–1838.
- Fulda S, Galluzzi L, Kroemer G (2010) Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 9: 447–464. 10.1038/nrd3137
- Lee MO, Moon SH, Jeong HC, Yi JY, Lee TH, Shim SH, et al. (2013) Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci U S A 110: E3281–3290. 10.1073/pnas.1303669110
- Lori F, Malykh A, Cara A, Sun D, Weinstein JN, Lisziewicz J, et al. (1994) Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science 266: 801–805.
- Vila J, Nugier F, Bargues G, Vallet T, Peyramond D, Hamedi-Sangsari F, et al. (1997) Absence of viral rebound after treatment of HIV-infected patients with didanosine and hydroxycarbamide. Lancet 350: 635–636.
- Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, Siliciano R, et al. (1999) Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 340: 1683–1684.
- Lisziewicz J, Jessen H, Finzi D, Siliciano RF, Lori F (1998) HIV-1 suppression by early treatment with hydroxyurea, didanosine, and a protease inhibitor. Lancet 352: 199–200.
- Lori F, Rosenberg E, Lieberman J, Foli A, Maserati R, Seminari E, et al. (1999) Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters. AIDS Res Hum Retroviruses 15: 1333–1338.
- Amaru Calzada A, Pedrini O, Finazzi G, Leoni F, Mascagni P, Introna M, et al. (2013) Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2(V617F) myeloproliferative neoplasm patients. Exp Hematol 41: 253–260 e252. 10.1016/j.exphem.2012.10.013
- Schrell UM, Rittig MG, Anders M, Kiesewetter F, Marschalek R, Koch UH, et al. (1997) Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibition of primary human meningioma cells in culture and in meningioma transplants by induction of the apoptotic pathway. J Neurosurg 86: 845–852.
- Nyholm S, Thelander L, Graslund A (1993) Reduction and loss of the iron center in the reaction of the small subunit of mouse ribonucleotide reductase with hydroxyurea. Biochemistry 32: 11569–11574.
- Kayyali R, Porter JB, Liu ZD, Davies NA, Nugent JH, Cooper CE, et al. (2001) Structure-function investigation of the interaction of 1- and 2-substituted 3-hydroxypyridin-4-ones with 5-lipoxygenase and ribonucleotide reductase. J Biol Chem 276: 48814–48822.
- Peil L, Starosta AL, Lassak J, Atkinson GC, Virumae K, Spitzer M, et al. (2013) Distinct XPPX sequence motifs induce ribosome stalling, which is rescued by the translation elongation factor EF-P. Proc Natl Acad Sci U S A 110: 15265–15270. 10.1073/pnas.1310642110
- Tanner DR, Cariello DA, Woolstenhulme CJ, Broadbent MA, Buskirk AR (2009) Genetic identification of nascent peptides that induce ribosome stalling. J Biol Chem 284: 34809–34818. 10.1074/jbc.M109.039040
- Starosta AL, Lassak J, Peil L, Atkinson GC, Virumae K, Tenson T, et al. (2014) Translational stalling at polyproline stretches is modulated by the sequence context upstream of the stall site. Nucleic Acids Res 42: 10711–10719. 10.1093/nar/gku768
- Ingolia NT, Lareau LF, Weissman JS (2011) Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147: 789–802. 10.1016/j.cell.2011.10.002
- Uemura S, Aitken CE, Korlach J, Flusberg BA, Turner SW, Puglisi JD (2010) Real-time tRNA transit on single translating ribosomes at codon resolution. Nature 464: 1012–1017. 10.1038/nature08925
- Graille M, Seraphin B (2012) Surveillance pathways rescuing eukaryotic ribosomes lost in translation. Nat Rev Mol Cell Biol 13: 727–735. 10.1038/nrm3457
- Becker T, Armache JP, Jarasch A, Anger AM, Villa E, Sieber H, et al. (2011) Structure of the no-go mRNA decay complex Dom34-Hbs1 bound to a stalled 80S ribosome. Nat Struct Mol Biol 18: 715–720. 10.1038/nsmb.2057
- Gutierrez E, Shin BS, Woolstenhulme CJ, Kim JR, Saini P, Buskirk AR, et al. (2013) eIF5A promotes translation of polyproline motifs. Mol Cell 51: 35–45. 10.1016/j.molcel.2013.04.021
- Korber BT, Foley BT, Kuiken CL, Pillai SK, Sodroski JG (2014) Numbering Positions in HIV Relative to HXB2CG.
- Kuo LS, Baugh LL, Denial SJ, Watkins RL, Liu M, Garcia JV, et al. (2012) Overlapping effector interfaces define the multiple functions of the HIV-1 Nef polyproline helix. Retrovirology 9: 47 10.1186/1742-4690-9-47
- Tarafdar S, Poe JA, Smithgall TE (2014) The accessory factor Nef links HIV-1 to Tec/Btk kinases in an Src homology 3 domain-dependent manner. J Biol Chem 289: 15718–15728. 10.1074/jbc.M114.572099
- Asamitsu K, Morishima T, Tsuchie H, Kurimura T, Okamoto T (1999) Conservation of the central proline-rich (PxxP) motifs of human immunodeficiency virus type 1 Nef protein during the disease progression in two hemophiliac patients. FEBS Lett 459: 399–404.
- Donahue JP, Vetter ML, Mukhtar NA, D'Aquila RT (2008) The HIV-1 Vif PPLP motif is necessary for human APOBEC3G binding and degradation. Virology 377: 49–53. 10.1016/j.virol.2008.04.017
- Fitzon T, Leschonsky B, Bieler K, Paulus C, Schroder J, Wolf H, et al. (2000) Proline residues in the HIV-1 NH2-terminal capsid domain: structure determinants for proper core assembly and subsequent steps of early replication. Virology 268: 294–307.
- Garrus JE, von Schwedler UK, Pornillos OW, Morham SG, Zavitz KH, Wang HE, et al. (2001) Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 107: 55–65.
- Yost SA, Marcotrigiano J (2013) Viral precursor polyproteins: keys of regulation from replication to maturation. Curr Opin Virol 3: 137–142. 10.1016/j.coviro.2013.03.009
- Smith MS, Brian EL, Pagano JS (1987) Resumption of virus production after human immunodeficiency virus infection of T lymphocytes in the presence of azidothymidine. J Virol 61: 3769–3773.
- Schinazi RF, Lloyd RM Jr., Nguyen MH, Cannon DL, McMillan A, Ilksoy N, et al. (1993) Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother 37: 875–881.
- Jonckheere H, Witvrouw M, De Clercq E, Anne J (1998) Lamivudine resistance of HIV type 1 does not delay development of resistance to nonnucleoside HIV type 1-specific reverse transcriptase inhibitors as compared with wild-type HIV type 1. AIDS Res Hum Retroviruses 14: 249–253.
- Mellors JW, Bazmi HZ, Schinazi RF, Roy BM, Hsiou Y, Arnold E, et al. (1995) Novel mutations in reverse transcriptase of human immunodeficiency virus type 1 reduce susceptibility to foscarnet in laboratory and clinical isolates. Antimicrob Agents Chemother 39: 1087–1092.
- Niewerth M, Kunze D, Seibold M, Schaller M, Korting HC, Hube B (2003) Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob Agents Chemother 47: 1805–1817.
- Subissi A, Monti D, Togni G, Mailland F (2010) Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent. Drugs 70: 2133–2152. 10.2165/11538110-000000000-00000
- Lupetti A, Danesi R, Campa M, Del Tacca M, Kelly S (2002) Molecular basis of resistance to azole antifungals. Trends Mol Med 8: 76–81.
- Almeida B, Sampaio-Marques B, Carvalho J, Silva MT, Leao C, Rodrigues F, et al. (2007) An atypical active cell death process underlies the fungicidal activity of ciclopirox olamine against the yeast Saccharomyces cerevisiae. FEMS Yeast Res 7: 404–412.
- Morgan AA, Rubenstein E (2013) Proline: the distribution, frequency, positioning, and common functional roles of proline and polyproline sequences in the human proteome. PLoS One 8: e53785 10.1371/journal.pone.0053785
- Choi IY, Lim JH, Kim C, Song HY, Ju C, Kim WK (2013) 4-hydroxy-2(E)-Nonenal facilitates NMDA-Induced Neurotoxicity via Triggering Mitochondrial Permeability Transition Pore Opening and Mitochondrial Calcium Overload. Exp Neurobiol 22: 200–207. 10.5607/en.2013.22.3.200
- Song D, Song Y, Hadziahmetovic M, Zhong Y, Dunaief JL (2012) Systemic administration of the iron chelator deferiprone protects against light-induced photoreceptor degeneration in the mouse retina. Free Radic Biol Med 53: 64–71. 10.1016/j.freeradbiomed.2012.04.020
- Kim SN, Ahn YH, Kim SG, Park SD, Cho-Chung YS, Hong SH (2001) 8-Cl-cAMP induces cell cycle-specific apoptosis in human cancer cells. Int J Cancer 93: 33–41.
- Bissonnette N, Hunting DJ (1998) p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage. Oncogene 16: 3461–3469.
- Park DS, Morris EJ, Greene LA, Geller HM (1997) G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. J Neurosci 17: 1256–1270.
- Gorospe M, Wang X, Guyton KZ, Holbrook NJ (1996) Protective role of p21(Waf1/Cip1) against prostaglandin A2-mediated apoptosis of human colorectal carcinoma cells. Mol Cell Biol 16: 6654–6660.
- Farinelli SE, Greene LA (1996) Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support. J Neurosci 16: 1150–1162.
- Boehme SA, Lenardo MJ (1993) Ligand-induced apoptosis of mature T lymphocytes (propriocidal regulation) occurs at distinct stages of the cell cycle. Leukemia 7 Suppl 2: S45–49.
- Boehme SA, Lenardo MJ (1993) Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle. Eur J Immunol 23: 1552–1560.
- Hadziahmetovic M, Song Y, Wolkow N, Iacovelli J, Grieco S, Lee J, et al. (2011) The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration. Invest Ophthalmol Vis Sci 52: 959–968. 10.1167/iovs.10-6207
- Josefsson L, King MS, Makitalo B, Brannstrom J, Shao W, Maldarelli F, et al. (2011) Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. Proc Natl Acad Sci U S A 108: 11199–11204. 10.1073/pnas.1107729108
- Hauber I, Hofmann-Sieber H, Chemnitz J, Dubrau D, Chusainow J, Stucka R, et al. (2013) Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice. PLoS Pathog 9: e1003587 10.1371/journal.ppat.1003587
- Hu W, Kaminski R, Yang F, Zhang Y, Cosentino L, Li F, et al. (2014) RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc Natl Acad Sci U S A 111: 11461–11466. 10.1073/pnas.1405186111
- Johnson VA, Calvez V, Gunthard HF, Paredes R, Pillay D, Shafer RW, et al. (2013) Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med 21: 6–14.
- Fahey JV, Schaefer TM, Channon JY, Wira CR (2005) Secretion of cytokines and chemokines by polarized human epithelial cells from the female reproductive tract. Hum Reprod 20: 1439–1446.
- Richardson JM, Kaushic C, Wira CR (1995) Polymeric immunoglobin (Ig) receptor production and IgA transcytosis in polarized primary cultures of mature rat uterine epithelial cells. Biol Reprod 53: 488–498.
- Huang XP, Spino M, Thiessen JJ (2006) Transport kinetics of iron chelators and their chelates in Caco-2 cells. Pharm Res 23: 280–290.
- Schooley RT, Ramirez-Ronda C, Lange JM, Cooper DA, Lavelle J, Lefkowitz L, et al. (1996) Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group. J Infect Dis 173: 1354–1366.
- Fiscus SA, Hughes MD, Lathey JL, Pi T, Jackson B, Rasheed S, et al. (1998) Changes in virologic markers as predictors of CD4 cell decline and progression of disease in human immunodeficiency virus type 1-infected adults treated with nucleosides. AIDS Clinical Trials Group Protocol 175 Team. J Infect Dis 177: 625–633.
- Palumbo PE, Raskino C, Fiscus S, Pahwa S, Schutzbank T, Spector SA, et al. (1999) Virologic and immunologic response to nucleoside reverse-transcriptase inhibitor therapy among human immunodeficiency virus-infected infants and children. J Infect Dis 179: 576–583.
- The Health Professsions Council of South Africa, Government of the Republic of South Africa (2008) Guidelines for good practice in the health care professions. Seeking Patients' Informed Consent. pp. 1–18. Available at:
- Eberhard Y, McDermott SP, Wang X, Gronda M, Venugopal A, Wood TE, et al. (2009) Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood 114: 3064–3073. 10.1182/blood-2009-03-209965
- Müller G (2003) Medicinal chemistry of target family-directed masterkeys. Drug Discov Today 8: 681–691.
Source: PubMed