title: 5,6-Dihydro-5-aza-2'-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors.
abstract: The nucleoside analog 5,6-dihydro-5-aza-2'-deoxycytidine (KP-1212) has been investigated as a first-in-class lethal mutagen of human immunodeficiency virus type-1 (HIV-1). Since a prodrug monotherapy did not reduce viral loads in Phase II clinical trials, we tested if ribonucleotide reductase inhibitors (RNRIs) combined with KP-1212 would improve antiviral activity. KP-1212 potentiated the activity of gemcitabine and resveratrol and simultaneously increased the viral mutant frequency. G-to-C mutations predominated with the KP-1212-resveratrol combination. These observations represent the first demonstration of a mild anti-HIV-1 mutagen potentiating the antiretroviral activity of RNRIs and encourage the clinical translation of enhanced viral mutagenesis in treating HIV-1 infection.
authors.affiliation: Institute for Molecular Virology, University of Minnesota, 18-242 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA; Molecular and Cellular Developmental Biology & Genetics Graduate Program, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Rawson
authors.forename: Richard H
authors.initials: RH
authors.lastname: Heineman
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Beach
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Martin
authors.forename: Erica K
authors.initials: EK
authors.lastname: Schnettler
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dapp
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Louis M
authors.initials: LM
authors.lastname: Mansky
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017930:Genes, Reporter / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000077185:Resveratrol; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D019380:Anti-HIV Agents; D003841:Deoxycytidine; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D000077185:Resveratrol; D012264:Ribonucleotide Reductases; D013267:Stilbenes; D014764:Viral Proteins; D000097573:Red Fluorescent Protein; C588297:5,6-dihydro-5-aza-2'-deoxycytidine
keywords: 2′,2′-difluoro-2′-deoxycytidine; 2′,2′-difluoro-2′-deoxyuridine; 5,6-Dihydro-5-aza-2′-deoxycytidine; 5-AZC; 5-aza-5,6,-dihydro-2′-deoxycytidine; 5-azacytidine; DMSO; Error catastrophe; KP-1212; Lethal mutagenesis; MOI; NRTI; RNRI; Resveratrol; SD; dFdC; dFdU; dimethylsulfoxide; multiplicity of infection; nucleoside reverse transcriptase inhibitor; ribonucleotide reductase inhibitor; standard deviation