Regulation of host gene expression by HIV-1 TAR microRNAs

Dominique L Ouellet,John J Rossi,Jimmy Vigneault-Edwards,Patrick Provost,Isabelle Plante,John C Burnett,Lise-Andrée Gobeil,Kevin Létourneau

doi:10.1186/1742-4690-10-86

Abstract

BackgroundThe transactivating response (TAR) element of human immunodeficiency virus type 1 (HIV-1) is the source of two functional microRNAs (miRNAs), miR-TAR-5p and miR-TAR-3p. The objective of this study was to characterize the post-transcriptional regulation of host messenger RNAs (mRNAs) relevant to HIV-1 pathogenesis by HIV-1 TAR miRNAs.ResultsWe demonstrated that TAR miRNAs derived from HIV-1 can incorporate into host effector Argonaute protein complexes, which is required if these miRNAs are to regulate host mRNA expression. Bioinformatic predictions and reporter gene activity assays identified regulatory elements complementary and responsive to miR-TAR-5p and miR-TAR-3p in the 3’ untranslated region (UTR) of several candidate genes involved in apoptosis and cell survival. These include Caspase 8, Aiolos, Ikaros and Nucleophosmin (NPM)/B23. Analyses of Jurkat cells that stably expressed HIV-1 TAR or contained a full-length latent HIV provirus suggested that HIV-1 TAR miRNAs could regulate the expression of genes in T cells that affect the balance between apoptosis and cell survival.ConclusionsHIV-1 TAR miRNAs may contribute to the replication cycle and pathogenesis of HIV-1, by regulating host genes involved in the intricate balance between apoptosis and infected cell, to induce conditions that promote HIV-1 propagation and survival.

Highlights

The transactivating response (TAR) element of human immunodeficiency virus type 1 (HIV-1) is the source of two functional microRNAs, miR-TAR-5p and miR-TAR-3p
We found that HIV-1 TAR miRNAs target and modulate the expression of host cell messenger RNAs (mRNAs) for Caspase 8, an initiator protein of the extrinsic apoptosis pathway [38], the Aiolos and Ikaros, transcription factors involved in hematopoiesis, immunity and cell fate [39], and Nucleophosmin (NPM)/B23, a multifunctional nucleolar protein [40]
TAR miRNAs are incorporated into Argonaute protein complexes Argonaute proteins are the core components of the RNA silencing complexes (RISC) and exert their repressive effects on specific mRNAs that are targeted by small RNA species, e.g. miRNAs or small interfering RNAs

Summary

Introduction

The transactivating response (TAR) element of human immunodeficiency virus type 1 (HIV-1) is the source of two functional microRNAs (miRNAs), miR-TAR-5p and miR-TAR-3p. Ago can act on messenger RNAs (mRNAs), that have complementary sequences to the loaded guide miRNA, and block protein expression by repressing mRNA translation or inducing mRNA degradation [9]. Cellular mRNAs that have sequences complementary to HIV-1 miRNAs in their 3’ UTRs, and are potential regulatory targets of these viral miRNAs, have been identified [27]. A viral miRNA, miR-BART-5 derived from the Epstein-Barr virus (EBV) [30], targets the mRNA of the host cell p53 up-regulator of apoptosis (PUMA), to reduce the likelihood of the EBV-infected cells from undergoing apoptosis-induced cell death [31]. Since TAR miRNAs have been recently detected in exosomes released from HIV-1 infected cells, their distributions within the noninfected cell population might be enhanced [32]

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