Low TRBP Levels Support an Innate Human Immunodeficiency Virus Type 1 Resistance in Astrocytes by Enhancing the PKR Antiviral Response

Ong, Chi L.; Thorpe, Janine; Gorry, Paul R; Bannwarth, Sylvie; Jaworowski, Anthony; Howard, Jane L.; Chung, Sean W. L.; Campbell, Sally; Christensen, Helen S.; Clerzius, Guerline; Mouland, Andrew J.; Gatignol, Anne; Purcell, Damian F. J.

doi:10.1128/jvi.79.20.12763-12772.2005

Cited by 76 publications

(103 citation statements)

References 62 publications

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“…Moreover, their interaction with PKR has functional implications in inflammation, stress response, viral infection, and oncogenesis (20,34,(42)(43)(44). Although TRBP and PACT directly interact with each other (Fig.…”

Section: Discussionmentioning

confidence: 99%

Human TRBP and PACT Directly Interact with Each Other and Associate with Dicer to Facilitate the Production of Small Interfering RNA

Kok

Ching

et al. 2007

Journal of Biological Chemistry

214

219

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Mammalian Dicer interacts with double-stranded RNA-binding protein TRBP or PACT to mediate RNA interference and micro-RNA processing. TRBP and PACT are structurally related but exert opposite regulatory activities on PKR. It is not understood whether TRBP and PACT are simultaneously required for Dicer. Here we show that TRBP directly interacts with PACT in vitro and in mammalian cells. TRBP and PACT form a triple complex with Dicer and facilitate the production of small interfering RNA (siRNA) by Dicer. Knockdown of both TRBP and PACT in cultured cells leads to significant inhibition of gene silencing mediated by short hairpin RNA but not by siRNA, suggesting that TRBP and PACT function primarily at the step of siRNA production. Taken together, these findings indicate that human TRBP and PACT directly interact with each other and associate with Dicer to stimulate the cleavage of double-stranded or short hairpin RNA to siRNA. Our work significantly alters the current model for the assembly and function of the Dicer-containing complex that generates siRNA and micro-RNA in human. RNA interference (RNAi)2 is an evolutionarily conserved mechanism for gene silencing mediated through small RNAs of ϳ22 nucleotides in length (1). At least two classes of small RNAs have been described in mammals, micro-RNAs (miRNA) produced from hairpin precursors and small interfering RNAs (siRNAs) derived from long double-stranded RNAs (dsRNAs) (2). Both miRNAs and siRNAs are generated by RNase III-type nuclease Dicer, and they are assembled into effector complex termed RNA-induced silencing complex (RISC) (3, 4). Although two Dicer enzymes Dcr1 and Dcr2 have been found in fruit flies and are responsible for the generation of miRNAs and siRNAs, respectively, there exists only one single Dicer in humans, which produces both miRNAs and siRNAs (3). Dcr2 is known to associate with a dsRNA-binding protein (dsRBP) termed R2D2, which binds to siRNA and facilitates its passage from Dcr2 to RISC (5, 6).A new family of dsRBPs, which includes Loquacious in Drosophila as well as TRBP and PACT in humans, has been shown recently to interact with Dicer and be required for its function in RNAi (7-12). Unlike its counterparts in Drosophila that have only one dsRBP partner, human Dicer appears to associate with two closely related dsRBPs, TRBP and PACT (10 -12). TRBP was originally identified and characterized by its high affinity for TAR, a hairpin RNA encoded by human immunodeficiency virus type 1 (13). PACT was initially cloned as a cellular protein activator of PKR kinase (14, 15). Although both PACT and TRBP bind to PKR and have three similar dsRNA-binding domains (dsRBDs), TRBP exerts an inhibitory effect on PKR (16 -20).Although both TRBP and PACT interact with and support the function of human Dicer in RNAi (10 -12), it is not understood whether their binding with Dicer is simultaneous or mutually exclusive. TRBP and PACT are closely related, and both are capable of homodimerization (21,22). In addition, they share two binding partners, [16][17][...

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Section: Discussionmentioning

confidence: 99%

Human TRBP and PACT Directly Interact with Each Other and Associate with Dicer to Facilitate the Production of Small Interfering RNA

Kok

Ching

et al. 2007

Journal of Biological Chemistry

214

219

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“…15 However, astrocytes undergo a restricted infection that leads to little or no virus production, and several blocks to viral replication have been described in the literature. 16,17 Whether HIV-1 transcription of viruses that reside in the central nervous system (CNS) is regulated differently within astrocytes and contributes to their restricted infection remains unknown. Regardless, HIV-1 infection of astrocytes results in their dysfunction and subsequent loss of neuronal support.…”

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confidence: 99%

Reduced Basal Transcriptional Activity of Central Nervous System-Derived HIV Type 1 Long Terminal Repeats

Gray

Cowley

Crespan

et al. 2013

AIDS Research and Human Retroviruses

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New evidence indicates that astrocytes of the central nervous system (CNS) are extensively infected with human immunodeficiency virus type 1 (HIV-1) in vivo. Although no new virus is produced, this nonproductive or restricted infection contributes to the pathogenesis of HIV-associated dementia (HAD) and compromises virus eradication strategies. The HIV-1 long terminal repeat (LTR) plays a critical role in regulating virus production from infected cells. Here, we determined whether LTRs derived from CNS and non-CNS compartments are genetically and functionally distinct and contribute to the restricted nature of astrocyte infection. CNS-and/or non-CNS-derived LTRs (n = 82) were cloned from primary HIV-1 viruses isolated from autopsy tissues of seven patients who died with HAD. Phylogenetic analysis showed interpatient and intrapatient clustering of LTR nucleotide sequences. Functional analysis showed reduced basal transcriptional activity of CNS-derived LTRs in both astrocytes and T cells compared to that of non-CNS-derived LTRs. However, LTRs were heterogeneous in their responsiveness to activation by Tat. Therefore, using a relatively large, independent panel of primary HIV-1 LTRs derived from clinically well-characterized subjects, we show that LTRs segregate CNS-from non-CNSderived tissues both genetically and functionally. The reduced basal transcriptional activity of LTRs derived from the CNS may contribute to the restricted HIV-1 infection of astrocytes and latent infection within the CNS. These findings have significance for understanding the molecular basis of HIV-1 persistence within cellular reservoirs of the CNS that need to be considered for strategies aimed at eradicating HIV-1.

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“…Ong and co-workers demonstrated that HIV-1 replicates poorly in astrocytes because of high PKR levels, which inhibit translation of viral proteins. Viral replication, however, can be rescued by the expression of TRBP protein [103]. In addition, the Gatignol group confirmed the Ong's data using siRNA against TRBP in the context of HIV replication, obtaining up to fivefold viral production.…”

Section: Rnai and Hiv-1 Pathogenesismentioning

confidence: 78%

“…The relevance of TRBP protein on HIV replication found support on the Ong et al and Christensen et al's studies [103,104]. Ong and co-workers demonstrated that HIV-1 replicates poorly in astrocytes because of high PKR levels, which inhibit translation of viral proteins.…”

Section: Rnai and Hiv-1 Pathogenesismentioning

confidence: 87%

RNA interference and HIV‐1 infection

Kanzaki

Ornelas

Argañaraz

2007

Reviews in Medical Virology

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Life-prolonging antiretroviral therapy remarkably reduces viral load, but it does not eradicate the virus. An important obstacle preventing virus clearance is the presence of latent virion reservoirs in the host. However, new promising antiviral approaches are emerging, and a number of host cell factors involved in the disease progression and control of HIV-1 replication have been recently discovered. For instance, the RNA interference (RNAi) mechanism, besides many functions conserved throughout evolution, works as a defence mechanism against noxious transcripts which may provide a new tool to block viral replication. The recent definition of basic RNAi mechanisms, as well as the discovery of micro RNAs (microRNAs) encoded by the host cell genome and by HIV-1, also suggest that RNAi may be involved in the control of HIV replication.

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Low TRBP Levels Support an Innate Human Immunodeficiency Virus Type 1 Resistance in Astrocytes by Enhancing the PKR Antiviral Response

Cited by 76 publications

References 62 publications

Human TRBP and PACT Directly Interact with Each Other and Associate with Dicer to Facilitate the Production of Small Interfering RNA

Human TRBP and PACT Directly Interact with Each Other and Associate with Dicer to Facilitate the Production of Small Interfering RNA

Reduced Basal Transcriptional Activity of Central Nervous System-Derived HIV Type 1 Long Terminal Repeats

RNA interference and HIV‐1 infection

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