Dataset Information

HIV evades RNA interference directed at TAR by an indirect compensatory mechanism.

ABSTRACT: HIV can rapidly evolve when placed under selective pressure, including immune surveillance or the administration of antiretroviral drugs. Typically, a variant protein allows HIV to directly evade the selective pressure. Similarly, HIV has escaped suppression by RNA interference (RNAi) directed against viral RNAs by acquiring mutations at the target region that circumvent RNAi-mediated inhibition while conserving necessary viral functions. However, when we directed RNAi against the viral TAR hairpin, which plays an indispensable role in viral transcription, resistant strains were recovered, but none carried a mutation at the target site. Instead, we isolated several strains carrying promoter mutations that indirectly compensated for the RNAi by upregulating viral transcription. Combining RNAi with the application of an antiviral drug blocked replication of such mutants. Evolutionary tuning of viral transcriptional regulation may serve as a general evasion mechanism that may be targeted to improve the efficacy of antiviral therapy.

SUBMITTER: Leonard JN

PROVIDER: S-EPMC2742160 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HIV evades RNA interference directed at TAR by an indirect compensatory mechanism.

Leonard Joshua N JN Shah Priya S PS Burnett John C JC Schaffer David V DV

Cell host & microbe 20081101 5

HIV can rapidly evolve when placed under selective pressure, including immune surveillance or the administration of antiretroviral drugs. Typically, a variant protein allows HIV to directly evade the selective pressure. Similarly, HIV has escaped suppression by RNA interference (RNAi) directed against viral RNAs by acquiring mutations at the target region that circumvent RNAi-mediated inhibition while conserving necessary viral functions. However, when we directed RNAi against the viral TAR hair ...[more]

PMID: 18996348

Similar Datasets

Project description:The HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus, Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of acetylpromazine bound to the bulge of TAR RNA, to dock compounds from the Enamine database containing over two million individual compounds. The docking procedure identified 173 compounds that were further analyzed for the inhibition of HIV-1 infection. The top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50 = 2.97 μM), T0516-4834 (IC50 = 0.2 μM) and T5628834 (IC50 = 3.46 μM), were further tested for HIV-1 transcription inhibition. Only the T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas the T6780107 compound inhibited equally basal and Tat-induced transcription and the T5628834 compound only inhibited basal HIV-1 transcription. The compounds were tested for the inhibition of translation and showed minimal (<25%) effect. The T0516-4834 compound also showed the strongest inhibition of HIV-1 RNA expression and p24 production in CEM T cells and peripheral blood mononuclear cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound significantly disrupted Tat-TAR RNA interaction. Additionally, of the three tested compounds, T5628834 and, to a lesser extent, T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. None of the three compounds showed significant inhibition of the cellular CDK9 and cyclin T1 levels. In silico modelling showed that the T0516-4834 compound interacted with TAR RNA by binding to the bulge formed by U23, U25, C39, G26,C39 and U40 residues. Taken together, our study identified a novel benzoxazole compound that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection, suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.

Dataset Information

HIV evades RNA interference directed at TAR by an indirect compensatory mechanism.

Publications

HIV evades RNA interference directed at TAR by an indirect compensatory mechanism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets