Date Published: January 25, 2019
Publisher: Public Library of Science
Author(s): Shira Modai, Luba Farberov, Eytan Herzig, Ofer Isakov, Amnon Hizi, Noam Shomron, Klaus Roemer.
HIV-1 is the causative agent of AIDS (Autoimmune Deficiency Syndrome). HIV-1 infection results in systemic CD4+ T cell depletion, thereby impairing cell-mediated immunity. MicroRNAs are short (~22 nucleotides long), endogenous single-stranded RNA molecules that regulate gene expression by binding to the 3′ untranslated regions (3′ UTR) of mRNA transcripts. The relation between HIV-1 infection and human miRNA expression profile has been previously investigated, and studies have shown that the virus can alter miRNA expression and vice versa. Here, we broaden the understanding of the HIV-1 infection process, and show that miRNA-186, 210 and 222 are up-regulated following HIV-1 infection of human Sup-T1 cells. As a result, the host miRNA target genes: Dicer1 (Double-Stranded RNA-Specific Endoribonuclease), HRB (HIV-1 Rev-binding protein) and HIV-EP2 (Human Immunodeficiency Virus Type I Enhancer Binding Protein 2), are down-regulated. Moreover, testing the miRNA-gene anti- correlation on the Jurkat and the HeLa-MAGI cell lines demonstrated the ability of the miRNAs to down-regulate viral expression as well. To conclude, we found that human miR-186, 210 and 222 directly regulate the human genes Dicer1, HRB and HIV-EP2, thus may be filling key roles during HIV-1 replication and miRNA biogenesis. This finding may contribute to the development of new therapeutic strategies.
Infection with the human immunodeficiency virus type 1 (HIV-1) results in systemic CD4 T cell depletion that impairs cell-mediated immunity; this leads to numerous opportunistic infections and cancers. Therefore, the overall medical condition caused by HIV-1 infections is called Acquired Immunodeficiency Syndrome (AIDS). Rates of both infection and death relating to HIV-1 have been declining, due to lifelong treatment by a cocktail of 3–4 medications. Nonetheless, about 36.7 million people are currently living with HIV-1 and approximately 1 million die from it annually (UNAIDS Data, 2017). Since 1981, when the first cases of HIV-1 infections were reported, detection, control, and the eventual elimination of the viral HIV-1 infection and AIDS have become worldwide goals. Achieving these goals has proven to be highly challenging, as HIV-1 has become increasingly resistant to therapy, by evading the immune response, as well as by altering cellular immune function and protecting infected cells from apoptosis[1–3]. The combination of Anti-retroviral Therapy (cART), which is used to suppress HIV-1 to undetectable levels in patients’ plasma, is a major medical success. Nevertheless, HIV-1 is far from being completely eliminated, and the development of novel means to completely suppress viral replication is of high importance.
TargetRank (http://genes.mit.edu/targetrank/) and TargetScan 5.1 (http://www.targetscan.org/) were used to predict target genes of the examined miRNAs. The miRBase (http://www.mirbase.org/) and UCSC genome browser (https://genome.ucsc.edu/) were used to obtain sequences of the miRNAs and their predicted 3’UTR target genes, as well as for in silico PCR prior to ordering primers. RNAfold webserver (http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi) was used to predict secondary structures and the amount of free energy released when the 3’UTR of the target genes are spontaneously folded.
HIV-1 infection has been shown to promote the expression of various small RNA molecules that originate from both viral and human genomes, and that may affect the virus and host organism[2,32–35]. The involvement of these small RNA molecules in the pathogenesis of HIV-1 infection may be important for viral detection, as well as for gaining new insights regarding the infection process. In this work, we explored the expression profile of one type of small RNA–miRNA–during HIV-1 infection.