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: While folding free energy and stem length were not sufficient to discrimate miRNA precursors from other long RNA duplexes, it was determined by computational analysis that nonprecursor duplexes differed from real miRNA precursors in having increased lengths and numbers of bulges and internal loops and larger apical loop size . These secondary structure characteristics were utilized in developing a miRNA prediction algorithm, with comparisons done using the RNAforester tool [42,43]. When the HIVaINR antisense RNA sequence from nt 168–253  was submitted to this structure-based miRNA analysis tool for analysis, it received a perfect score (100) consistent with this sequence being a microRNA precursor (Ritchie et al, ) . Further comparison with the M-fold duplexes demonstrated that even with the 390 nucleotide HIVaINR antisense RNA  subjected to enhanced M-fold, some of the structures could potentially be processed (first by Drosha, then Dicer) into this final pre-miRNA (see additional file 1, structure with folding energy dG = -96.7). This was important, inasmuch as the HIVaINR antisense RNA stem-loop also contained 25 bases that could in turn form yet another duplex or target with several human mRNAs. Two of the many mRNAs targeted included mRNA of the human gene, interleukin-2 receptor gamma chain (IL-2Rγc), a gene in which defects are responsible for X-linked severe combined immuno-deficiency (X-SCID), as well as the human interleukin-15 mRNA, discussed below (diagrammed in Figure 2A, B, E).