Deep sequencing of virus-infected cells reveals HIV-encoded small RNAs

Schopman, Nick C.T.; Willemsen, Marcel; Liu, Ying Poi; Bradley, Ted; Kampen, Antoine H van; Baas, Frank; Berkhout, Ben; Haasnoot, Joost

doi:10.1093/nar/gkr719

Cited by 124 publications

(139 citation statements)

References 53 publications

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“…The low amount of TAR and RRE vsiRNAs identified by various groups may prove to be of importance during a relatively short time frame at the beginning of HIV-1 RNA expression. 49,[72][73][74][75] The displacement of endogenous miRNAs into the RISC mediated by TAR or RRE competition may contribute to mechanisms leading to changes in gene expression and associated pathogenicity in patients.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

et al. 2015

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Several proteins and RNAs expressed by mammalian viruses have been reported to interfere with RNA interference (RNAi) activity. We investigated the ability of the HIV-1-encoded RNA elements Trans-Activation Response (TAR) and RevResponse Element (RRE) to alter RNAi. MicroRNA let7-based assays showed that RRE is a potent suppressor of RNAi activity, while TAR displayed moderate RNAi suppression. We demonstrate that RRE binds to TAR-RNA Binding Protein (TRBP), an essential component of the RNA Induced Silencing Complex (RISC). The binding of TAR and RRE to TRBP displaces small interfering (si)RNAs from binding to TRBP. Several stem-deleted RRE mutants lost their ability to suppress RNAi activity, which correlated with a reduced ability to compete with siRNA-TRBP binding. A lentiviral vector expressing TAR and RRE restricted RNAi, but RNAi was restored when Rev or GagPol were coexpressed. Adenoviruses are restricted by RNAi and encode their own suppressors of RNAi, the Virus-Associated (VA) RNA elements. RRE enhanced the replication of wild-type and VA-deficient adenovirus. Our work describes RRE as a novel suppressor of RNAi that acts by competing with siRNAs rather than by disrupting the RISC. This function is masked in lentiviral vectors co-expressed with viral proteins and thus will not affect their use in gene therapy. The potent RNAi suppressive effects of RRE identified in this study could be used to enhance the expression of RNAi restricted viruses used in oncolysis such as adenoviruses.

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Section: Discussionmentioning

confidence: 99%

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

et al. 2015

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“…As a counterdefense mechanism, many viral genomes encode suppressors of RNAi that inhibit various steps of siRNA biogenesis and function (van Rij et al, 2006, Li et al, 2002, Nayak et al, 2010). vsiRNAs have also been identified in mammalian cells infected with RNA viruses (Schopman et al, 2012); however, it is not yet known whether such RNAs have gene silencing functions or whether the siRNA pathway is required for antiviral immunity in mammals.…”

Section: Exo-sirnasmentioning

confidence: 99%

Gene regulation by non-coding RNAs

Patil

Zhou

Rana

2013

Critical Reviews in Biochemistry and Molecular Biology

156

110

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The past two decades have seen an explosion in research on noncoding RNAs and their physiological and pathological functions. Several classes of small (20–30 nucleotides) and long (>200 nucleotides) noncoding RNAs have been firmly established as key regulators of gene expression in myriad processes ranging from embryonic development to innate immunity. In this review, we focus on our current understanding of the molecular mechanisms underlying the biogenesis and function of small interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs). In addition, we briefly review the relevance of small and long noncoding RNAs to human physiology and pathology and their potential to be exploited as therapeutic agents.

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“…In addition, the HIV-1 genome also encodes several small, regulatory non-coding RNAs (ncRNAs) 4 and probably microRNAs (miRNAs) that can regulate host gene expression (11)(12)(13)(14)(15)(16)(17). Tat is an essential regulatory protein that directs efficient elongation of the HIV-1 genome.…”

mentioning

confidence: 99%

“…Later, Jeang and co-workers found TAR-specific sequences and 125 other HIV-1 ncRNAs in the total RNA pools from HIV-1-infected cells and reported that the TAR RNA was the most abundant ncRNA (12). Recently, Schopman et al (11) detected numerous small RNAs that correspond to the HIV-1 RNA genome. Finally, multiple experimental data indicate that the exosomes play key roles in the miRNA transfer to recipient cells (26,38,39).…”

mentioning

confidence: 99%

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Sampey

Saifuddin

Schwab

et al. 2016

Journal of Biological Chemistry

181

273

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HIV-1 infection results in a chronic illness because longterm highly active antiretroviral therapy can lower viral titers to an undetectable level. However, discontinuation of therapy rapidly increases virus burden. Moreover, patients under highly active antiretroviral therapy frequently develop various metabolic disorders, neurocognitive abnormalities, and cardiovascular diseases. We have previously shown that exosomes containing trans-activating response (TAR) element RNA enhance susceptibility of undifferentiated naive cells to HIV-1 infection. This study indicates that exosomes from HIV-1-infected primary cells are highly abundant with TAR RNA as detected by RT-real time PCR. Interestingly, up to a million copies of TAR RNA/l were also detected in the serum from HIV-1-infected humanized mice suggesting that TAR RNA may be stable in vivo. Incubation of exosomes from HIV-1-infected cells with primary macrophages resulted in a dramatic increase of proinflammatory cytokines, IL-6 and TNF-␤, indicating that exosomes containing TAR RNA could play a direct role in control of cytokine gene expression. The intact TAR molecule was able to bind to PKR and TLR3 effectively, whereas the 5 and 3 stems (TAR microRNAs) bound best to TLR7 and -8 and none to PKR. Binding of TAR to PKR did not result in its phosphorylation, and therefore, TAR may be a dominant negative decoy molecule in cells. The TLR binding through either TAR RNA or TAR microRNA potentially can activate the NF-B pathway and regulate cytokine expression. Collectively, these results imply that exosomes containing TAR RNA could directly affect the proinflammatory cytokine gene expression and may explain a possible mechanism of inflammation observed in HIV-1-infected patients under cART.

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Deep sequencing of virus-infected cells reveals HIV-encoded small RNAs

Cited by 124 publications

References 53 publications

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

Gene regulation by non-coding RNAs

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

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