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: It is of particular interest that human miR-146 has been shown to functionally interact with human mRNA 3'UTR sites for IRAK1 and thereby downregulate protein expression. Expression of primary miR-146 transcripts is regulated by NF-kB sites, sites that are also important enhancer elements for expression of HIV-1 RNA transcripts [14,77,79]. IRAK1 is involved in the signalling cascade induced by activation of Toll-like receptors (TLRs) that are important in innate immunity. Experimental evidence that miR-146a/b may function as a novel negative regulator has been recently shown . If HIV uses a microRNA mechanism like miR-146a to interact with IRAK1 mRNAs, which are expressed in macrophages and dendritic cells, it may provide yet another means for early viral impact on the host innate immunity pathways.