Abstract
The nature of the interaction between replicating HIV-1 and the cellular RNAi pathway has been controversial, but it is clear that it can be complex and multifaceted. It has been proposed that the interaction is bi-directional, whereby cellular silencing pathways can restrict HIV-1 replication, and in turn, HIV-1 can suppress silencing pathways. Overall suppression of RNAi has been suggested to occur via direct binding and inhibition of Dicer by the HIV-1 Tat protein or through sequestration of TRBP, a Dicer co-factor, by the structured TAR element of HIV-1 transcripts. The role of Tat as an inhibitor of Dicer has been questioned and our results support and extend the conclusion that Tat does not inhibit RNAi that is mediated by either exogenous or endogenous miRNAs. Similarly, we find no suppression of silencing pathways in cells with replicating virus, suggesting that viral products such as the TAR RNA elements also do not reduce the efficacy of cellular RNA silencing. However, knockdown of Dicer does allow increased viral replication and this occurs at a post-transcriptional level. These results support the idea that although individual miRNAs can act to restrict HIV-1 replication, the virus does not counter these effects through a global suppression of RNAi synthesis or processing.
Highlights
RNA interference (RNAi) is an evolutionarily conserved mechanism of sequence dependent gene regulation that can have a role in host cell defense against intracellular pathogens and transposons
RNAi can be essential for antiviral defense in plants and lower eukaryotes; in higher eukaryotes, innate immune mechanisms such as those mediated through interferons and Toll-like receptor pathways are prominent, leading to questions regarding the antiviral role of RNAi in these organisms
In order to understand the role of RNAi in cellular defense mechanisms against HIV-1, we first tried to confirm findings indicating that the viral Tat protein acts as a suppressor of RNA silencing (SRS)
Summary
RNA interference (RNAi) is an evolutionarily conserved mechanism of sequence dependent gene regulation that can have a role in host cell defense against intracellular pathogens and transposons. The global suppression of RNAi by virally encoded proteins is a common countermeasure to host antiviral mechanisms mediated by RNA silencing [6], and similar suppression mechanisms have been proposed for several mammalian viruses [7,8]. It has been suggested that binding of the cellular protein TRBP to the structured TAR elements present in HIV-1 transcripts competitively inhibits the activity of TRBP as a co-factor for Dicer, leading to a downregulation of miRNA processing pathways [12,13]. The notion that HIV-1 has evolved gene products that are able to globally suppress RNAi in order to promote its own replication has remained controversial and evidence has been presented that Tat acts only in its well-characterized role as a transcriptional activator, and does not suppress RNA silencing [14]
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