title: Identification of a methylated oligoribonucleotide as a potent inhibitor of HIV-1 reverse transcription complex.
abstract: Upon HIV-1 infection of a target cell, the viral reverse transcriptase (RT) copies the genomic RNA to synthesize the viral DNA. The genomic RNA is within the incoming HIV-1 core where it is coated by molecules of nucleocapsid (NC) protein that chaperones the reverse transcription process. Indeed, the RT chaperoning properties of NC extend from the initiation of cDNA synthesis to completion of the viral DNA. New and effective drugs against HIV-1 continue to be required, which prompted us to search for compounds aimed at inhibiting NC protein. Here, we report that the NC chaperoning activity is extensively inhibited in vitro by small methylated oligoribonucleotides (mODN). These mODNs were delivered intracellularly using a cell-penetrating-peptide and found to impede HIV-1 replication in primary human cells at nanomolar concentrations. Extensive analysis showed that viral cDNA synthesis was severely impaired by mODNs. Partially resistant viruses with mutations in NC and RT emerged after months of passaging in cell culture. A HIV-1 molecular clone (NL4.3) bearing these mutations was found to replicate at high concentrations of mODN, albeit with a reduced fitness. Small, methylated ODNs such as mODN-11 appear to be a new type of highly potent inhibitor of HIV-1.
authors: Laboretro, INSERM #758, ENS Lyon, 46 allée d'Italie, 69364 Lyon, Laboratoire de Biophotonique et Pharmacologie, UMR 7213 CNRS, Université de Strasboug, Illkirch, France.
authors: Boyan
authors: B
authors: Grigorov
authors: Anne
authors: A
authors: Bocquin
authors: Caroline
authors: C
authors: Gabus
authors: Sergey
authors: S
authors: Avilov
authors: Yves
authors: Y
authors: Mély
authors: Audrey
authors: A
authors: Agopian
authors: Gilles
authors: G
authors: Divita
authors: Marina
authors: M
authors: Gottikh
authors: Myriam
authors: M
authors: Witvrouw
authors: Jean-Luc
authors: JL
authors: Darlix
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008745:Methylation; D009154:Mutation; D009843:Oligoribonucleotides / Q000737:chemistry*; D048348:Reverse Transcription; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D018076:DNA, Complementary; C071884:NCP7 protein, Human immunodeficiency virus 1; D009843:Oligoribonucleotides; D054301:gag Gene Products, Human Immunodeficiency Virus; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase