Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase |
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| Affiliation: | 1. Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA;2. Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, 515 Delaware Street SE, Minneapolis, MN 55455, USA;3. Department of Microbiology and Immunology, Medical School, University of Minnesota, 689 23rd Avenue SE, Minneapolis, MN 55455, USA;4. Molecular, Cellular, Developmental Biology & Genetics Graduate Program, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA;5. Department of Computer Science and Engineering, University of Minnesota, 4-192 Keller Hall, 200 Union Street SE, Minneapolis, MN 55455, USA;6. Division of Biostatistics, School of Public Health, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA;7. Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA;8. Emory Center for AIDS Research, Emory University, 1518 Clifton Road NE, Suite 8050, Atlanta, GA 30322, USA;1. Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain;2. Unidad de cultivos celulares, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), C/ Dr. Esquerdo 46, 28007 Madrid, Spain;3. Unidad de Citometria y Sorter, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), C/ Dr. Esquerdo 46, 28007 Madrid, Spain;4. Departamento de Inmunología, Facultad de Medicina, Universidad de Córdoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain;5. Servicio de Enfermedades Infecciosas, Hospital Universitario Ramón y Cajal and IRYCIS, Ctra. de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain;1. Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China;2. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China;3. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA;1. Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, Prospekt Entuziastov 13, 410049 Saratov, Russia;2. N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospekt 47, 119991 Moscow, Russia;3. Chernyshevsky Saratov State University, 83 Ulitsa Astrakhanskaya, Saratov 410012, Russia;1. Department of Microbiology, University of São Paulo Biomedical Sciences Institute, São Paulo, Brazil;2. Butantan Institute, São Paulo, Brazil;3. Department of Parasitic and Infectious Diseases, University of São Paulo School of Medicine, São Paulo, Brazil;4. Hospital Israelita Albert Einstein, São Paulo, Brazil;5. LIM-03, Central Laboratories Division, Clinics Hospital, São Paulo School of Medicine, University of São Paulo, São Paulo, Brazil;6. LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil;1. Trek Therapeutics, PBC, 125 Cambridge Park Drive, Suite 301, Cambridge, MA 02140, USA;2. Department of Pathology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA;3. Southern Research, 431 Aviation Way, Frederick, MD 21701, USA;1. Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia;2. Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia;3. Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia |
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| Abstract: | Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2′-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5-aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity. |
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| Keywords: | Lethal mutagenesis Error catastrophe Viral mutagenesis Retrovirus 5-Azacytidine Resveratrol Drug synergy HIV-1 |
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