RNA silencing and HIV: a hypothesis for the etiology of the severe combined immunodeficiency induced by the virus.
Bottom Line: Duplex or double-stranded RNA of several hundred nucleotides in length is a key initiating element of RNA interference (RNAi) in several species.MicroRNAs (miRNAs) interact in a sequence-specific manner with target messenger RNAs (mRNAs) to induce either cleavage of the message or impede translation.Other potential human mRNA targets include interleukin-15 (IL-15) mRNA, the fragile x mental retardation protein (FMRP) mRNA, and the IL-1 receptor-associated kinase 1 (IRAK1) mRNA, amongst others.
A novel intrinsic HIV-1 antisense gene was previously described with RNA initiating from the region of an HIV-1 antisense initiator promoter element (HIVaINR). The antisense RNA is exactly complementary to HIV-1 sense RNA and capable of forming approximately 400 base-pair (bp) duplex RNA in the region of the long terminal repeat (LTR) spanning the beginning portion of TAR in the repeat (R) region and extending through the U3 region. Duplex or double-stranded RNA of several hundred nucleotides in length is a key initiating element of RNA interference (RNAi) in several species. This HIVaINR antisense RNA is also capable of forming multiple stem-loop or hairpin-like secondary structures by M-fold analysis, with at least one that perfectly fits the criteria for a microRNA (miRNA) precursor. MicroRNAs (miRNAs) interact in a sequence-specific manner with target messenger RNAs (mRNAs) to induce either cleavage of the message or impede translation. Human mRNA targets of the predicted HIVaINR antisense RNA (HAA) microRNAs include mRNA for the human interleukin-2 receptor gamma chain (IL-2RG), also called the common gamma (gammac) receptor chain, because it is an integral part of 6 receptors mediating interleukin signalling (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R and IL-21R). Other potential human mRNA targets include interleukin-15 (IL-15) mRNA, the fragile x mental retardation protein (FMRP) mRNA, and the IL-1 receptor-associated kinase 1 (IRAK1) mRNA, amongst others. Thus the proposed intrinsic HIVaINR antisense RNA microRNAs (HAAmiRNAs) of the human immunodeficiency virus form complementary targets with mRNAs of a key human gene in adaptive immunity, the IL-2Rgammac, in which genetic defects are known to cause an X-linked severe combined immunodeficiency syndrome (X-SCID), as well as mRNAs of genes important in innate immunity. A new model of intrinsic RNA silencing induced by the HIVaINR antisense RNA in the absence of Tat is proposed, with elements suggestive of both small interfering RNA (siRNA) and miRNA.
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Mentions: HIVaINR antisense RNA forms extensive intrinsic duplex structure by M-fold analysis and DINAMelt server (see Figure 1 and additional file 1). Nineteen separate HIVaINR antisense RNA duplex structures with dG of -99.2 to -94.9 could form by the enhanced Mfold program (additional file 1) [31-33]. The plasticity of structure demonstrated is remarkable, but still does not represent all the potential influences on 3-dimensional RNA structure; the effect of protein binding or pseudoknot formation is not considered. miRNAs are generated from long primary transcripts containing hairpin or stem-loop structures (pri-miRNAs) that are first processed in the nucleus by the RNase III enzyme Drosha in partnership with the dsRNA binding protein, DGCR8 or DiGeorge syndrome critical region gene 8 [34-36]. The prototypic metazoan pri-miRNA consists of a stem of ~32–33 base-pairs (bp) with a terminal loop and flanking single-stranded RNA at the base of the stem-loop, although in plants, the stem-loop might be much longer [7,37]. Cleavage by the Drosha-DGCR8 complex converts the pri-miRNA into small stem-loop structures called precursor miRNAs (pre-miRNAs). This is then further processed by another RNase III enzyme (Dicer)/dsRNA binding protein duo into mature miRNAs. In an elegant paper by Ritchie, et al., they addressed what parameters might distinguish precursor miRNAs (pre-miRNAs) from other duplex structures of similar size and free energy . In a cellular world in which long RNA duplexes are frequent, the RNAse III enzymes of the microRNA pathways, Drosha and Dicer, must be able to distinguish the appropriate RNA stem-loops that signal a primary or precursor miRNA for cleaving into the mature 21- to 25- nucleotide (nt) long, single-stranded miRNA [38,39]. Some reports suggest that a larger apical loop size, as well as flanking single-stranded RNA extensions at the base of the primary miRNA hairpin is important for Drosha function[40,41]. A recent study found the terminal loop was not essential, but the cleavage site for Drosha was determined by the distance (~11 bp) from the base of the hairpin stem and single-stranded RNA junction .