RNA silencing and HIV: A hypothesis for the etiology of the severe combined immunodeficiency induced by the virus

Abstract

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.

High Concentrations of Interleukin 15 in Breast Milk Are Associated with Protection against Postnatal HIV Transmission

“…Although these processes have been implicated in the pathogenesis of inflammatory bowel disease [14], they may also be beneficial by enhancing infant immune responses against HIV at the intestinal epithelium. Furthermore, it was recently suggested that HIV-intrinsic antisense anti–IL-15 micro-RNA is used by HIV to overcome IL-15–mediated immunity [15], further corroborating the protective role played by IL-15 against HIV.…”

Silencing Viral MicroRNA as a Novel Antiviral Therapy?

“…FMRP is an RNA-binding protein that is implicated in protein synthesis and miRNA processing. Thus HIV could use HAAmiRNA to deregulate the host miRNA mechanism to dispose the virus by depleting FMRP ( [56] and references therein.) Although the existence of these HAAmiRNAs has not been proven, it is tempting to speculate that, in accordance with other viruses, HIV encodes miRNAs allowing HIV to survive in the host.…”

MORT, a locus for apoptosis in the human immunodeficiency virus-type 1 antisense gene: implications for AIDS, Cancer, and Covid-19

“…Here we propose that a specific region of the Hap antisense gene located within the HIV-1 long terminal repeat (LTR) is contributing to the programmed cell death or apoptosis observed with HIV infection (Ludwig, et al, 2006;Ludwig, 2008). Hap RNA initiates in the repeat (R) region of the HIV-1 provirus and is transcribed in the reverse direction (antisense) to the other HIV genes, overlapping the beginning portion of TAR region DNA, the TATA box, the SP1 sites and NFKb sites controlling HIV-1 sense transcription, as well as 200 nucleotides of the 3' end of the nef gene ( Figure 1B) (Ludwig, et al, 2006;Ludwig, 2008). The introduction of this antisense gene into human cells induced programmed cell death or apoptosis, as classically defined (Kerr, et al, 1972;Clarke, et al, 1993;Schwartz and Osborne, 1993;Cohen, 1993).…”