title: Inhibition of human immunodeficiency virus type 1 transcription by N-aminoimidazole derivatives.
abstract: This study describes the mechanism of antiviral action of the N-aminoimidazole derivatives which exclusively inhibit retroviruses such as HIV-1, HIV-2, SIV and MSV. These antiretroviral compounds, with lead prototype NR-818, were found to inhibit HIV-1 replication at the transcriptional level. Analysis of each individual step of viral transcription, including transcriptional activation mediated by NF-kappaB, the chromatin remodeling process at the viral promoter and viral mRNA transcription mediated by RNAPII, showed that NR-818 was able to prolong the binding of NF-kappaB to its consensus sequence. The compound also increased the acetylation of histones H3 and H4 within the nucleosome nuc-1 at the transcription initiation site and inhibited the recruitment of viral Tat and the phosphorylation of the RNA polymerase II C-terminal domain (RNAPII CTD) at the viral promoter upon stimulation of latently HIV-1-infected cell lines. As a result, viral mRNA expression and subsequent viral p24 production in stimulated latently HIV-1-infected cell lines was suppressed by NR-818. These data suggest that the N-aminoimidazole derivatives effectively inhibit the reactivation of HIV-1 and may contribute to the control of the latent HIV-1 reservoir.
authors: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors: Miguel
authors: M
authors: Stevens
authors: Jan
authors: J
authors: Balzarini
authors: Irene M
authors: IM
authors: Lagoja
authors: Bernard
authors: B
authors: Noppen
authors: Katrien
authors: K
authors: François
authors: Arthur
authors: A
authors: Van Aerschot
authors: Piet
authors: P
authors: Herdewijn
authors: Erik
authors: E
authors: De Clercq
authors: Christophe
authors: C
authors: Pannecouque
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015696:Gene Products, tat / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D017735:Virus Latency; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D007093:Imidazoles; D054322:tat Gene Products, Human Immunodeficiency Virus