title: Mutagen-mediated enhancement of HIV-1 replication in persistently infected cells.
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.
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Jiménez
authors.forename: Isabel
authors.initials: I
authors.lastname: Olivares
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: de Ávila Lucas
authors.forename: Víctor
authors.initials: V
authors.lastname: Toledano
authors.forename: Mónica
authors.initials: M
authors.lastname: Gutiérrez-Rivas
authors.forename: Ramón
authors.initials: R
authors.lastname: Lorenzo-Redondo
authors.forename: Ana
authors.initials: A
authors.lastname: Grande-Pérez
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
authors.forename: Cecilio
authors.initials: C
authors.lastname: López-Galíndez
mesh_terms: D002460:Cell Line; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation / Q000187:drug effects; D059645:Mutation Rate; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*; D000093542:Gemcitabine
chemical_list: D009153:Mutagens; D012367:RNA, Viral; D003841:Deoxycytidine; C074071:5-hydroxy-2'-deoxycytidine; D005472:Fluorouracil; D000093542:Gemcitabine