title: Combination of a mutagenic agent with a reverse transcriptase inhibitor results in systematic inhibition of HIV-1 infection.
abstract: Mutagenic treatments resulted in occasional, not systematic, human immunodeficiency virus type 1 (HIV-1) extinction. To study the possibility that a combination of an antiretroviral inhibitor, to reduce the viral replicative load, and a mutagenic agent could be more effective in producing viral extinction than a mutagenic agent alone, we have compared the efficiency of extinction of HIV-1 by the mutagenic deoxyribonucleoside analogue 5-hydroxydeoxycytidine (5-OHdC) alone and in combination with the HIV-1 nucleoside reverse transcriptase (RT) inhibitor AZT. Serial passages in peripheral mononuclear cells (PBMC) or MT-4 cells of primary HIV-1 isolates or HIV-1 NL4-3 in the presence of a single drug (AZT 0.01 microM or 5-OHdC 2 mM) failed to systematically extinguish high fitness HIV-1 replication after 16 serial transfers. However, systematic extinction of HIV-1 was observed when a combination of the mutagenic agent 5-OHdC and AZT was used. These results demonstrate that combinations of mutagenic agents and antiretroviral inhibitors have the potential to drive HIV-1 into extinction.
authors.affiliation: Fundacio irsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tapia
authors.forename: Guerau
authors.initials: G
authors.lastname: Fernàndez
authors.forename: Mariona
authors.initials: M
authors.lastname: Parera
authors.forename: Gemma
authors.initials: G
authors.lastname: Gómez-Mariano
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Miguel
authors.initials: M
authors.lastname: Quiñones-Mateu
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martínez
mesh_terms: D002460:Cell Line; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D009153:Mutagens / Q000008:administration & dosage*; D009154:Mutation / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage
chemical_list: D009153:Mutagens; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D015215:Zidovudine; C074071:5-hydroxy-2'-deoxycytidine