TY - JOUR
T1 - Mutagen-mediated enhancement of HIV-1 replication in persistently infected cells
AU - Sánchez-Jiménez, Carmen
AU - Olivares, Isabel
AU - de Ávila Lucas, Ana Isabel
AU - Toledano, Víctor
AU - Gutiérrez-Rivas, Mónica
AU - Lorenzo-Redondo, Ramón
AU - Grande-Pérez, Ana
AU - Domingo, Esteban
AU - López-Galíndez, Cecilio
N1 - Funding Information:
Technical support from Maria Rosa López-Huertas, Maite Coiras, and José Alcamí for the NFκB analysis and José Maria Rojas for the methylation experiments is greatly appreciated. Miguel Angel Martínez is thanked for helpful suggestions and the critical reading of the manuscript and Rafael Fernández Muñoz by statistical analysis in ribonucleotide pools and two anonymous reviewers for the helpful comments. Work in CNM is supported by grants SAF 2007–61036 and SAF 2010–17226 , by Fundacion para la Investigacion y Prevencion del SIDA en España (FIPSE) grants 36558/06 , 36641/07 , 36779/08 , 360766/09 and in part by the Red Temática Cooperativa de Investigación en SIDA (Red de grupos 173) of the Fondo de Investigaciones Sanitarias de la Seguridad Social (FISss) . Support by grant BFU2007-65080BMC from MICINN to AG-P is acknowledged. Work at CBMSO is supported by grants BFU2008-02816/BMC, FIPSE 36558/06 and Fundación Ramón Areces. CIBERehd is funded by Instituto de Salud Carlos III.
PY - 2012/3/15
Y1 - 2012/3/15
N2 - 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.
AB - 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.
KW - 2 ,2 -difluoro-2 -deoxycytidine (gemcitabine)
KW - 5-fluorouracil (5-FU)
KW - 5-hydroxy-2 -deoxycytidine (5-OHdC)
KW - HIV-1
KW - HIV-1 persistent cell line
KW - Lethal mutagenesis
KW - Nucleoside analogs
KW - Viral replication
UR - http://www.scopus.com/inward/record.url?scp=84857032188&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857032188&partnerID=8YFLogxK
U2 - 10.1016/j.virol.2011.12.016
DO - 10.1016/j.virol.2011.12.016
M3 - Article
C2 - 22265575
AN - SCOPUS:84857032188
SN - 0042-6822
VL - 424
SP - 147
EP - 153
JO - Virology
JF - Virology
IS - 2
ER -
