Mutagen-mediated enhancement of HIV-1 replication in persistently infected cells |
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Authors: | Sánchez-Jiménez Carmen Olivares Isabel de Ávila Lucas Ana Isabel Toledano Víctor Gutiérrez-Rivas Mónica Lorenzo-Redondo Ramón Grande-Pérez Ana Domingo Esteban López-Galíndez Cecilio |
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Institution: | a Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spainb Centro de Biología Molecular “Severo Ochoa”, (CSIC-UAM), Campus de Cantoblanco, Madrid, Spainc Área de Genética, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, Málaga, Spaind Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain |
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Abstract: | Lethal mutagenesis, a new antiviral strategy to extinguish virus through elevated mutation rates, was explored in H61-D cells an HIV-1 persistently infected lymphoid cell line. Three mutagenic agents: 5-hydroxy-2′-deoxycytidine (5-OHdC), 5-fluorouracil (5-FU) and 2,2′-difluoro-2′-deoxycytidine (gemcitabine) were used. After 54 passages, treatments with 5-FU and gemcitabine reduced virus infectivity, p24 and RT activity. Treatment with the pyrimidine analog 5-OHdC resulted in increases of p24 production, RT activity and infectivity. Rise in viral replication by 5-OHdC during HIV-1 persistence is in contrast with its inhibitory effect in acute infections. Viral replication enhancement by 5-OHdC was associated with an increase in intracellular HIV-1 RNA mutations. Mechanisms of HIV-1 replication enhancement by 5-OHdC are unknown but some potential factors are discussed. Increase of HIV-1 replication by 5-OHdC cautions against the use, without previous analyses, of mutagenic nucleoside analogs for AIDS treatment. |
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Keywords: | HIV-1 Lethal mutagenesis Viral replication HIV-1 persistent cell line Nucleoside analogs 5-hydroxy-2&prime -deoxycytidine (5-OHdC) 5-fluorouracil (5-FU) 2&prime 2&prime -difluoro-2&prime -deoxycytidine (gemcitabine) |
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