RNA interference against viruses: strike and counterstrike

Abstract

RNA interference (RNAi) is a conserved sequence-specific, gene-silencing mechanism that is induced by double-stranded RNA. RNAi holds great promise as a novel nucleic acid-based therapeutic against a wide variety of diseases, including cancer, infectious diseases and genetic disorders. Antiviral RNAi strategies have received much attention and several compounds are currently being tested in clinical trials. Although induced RNAi is able to trigger profound and specific inhibition of virus replication, it is becoming clear that RNAi therapeutics are not as straightforward as we had initially hoped. Difficulties concerning toxicity and delivery to the right cells that earlier hampered the development of antisense-based therapeutics may also apply to RNAi. In addition, there are indications that viruses have evolved ways to escape from RNAi. Proper consideration of all of these issues will be necessary in the design of RNAi-based therapeutics for successful clinical intervention of human pathogenic viruses.

Inactivation of the type I interferon pathway reveals long double‐stranded RNA‐mediated RNA interference in mammalian cells

“…The failure to observe RNAi after virus infection of IFN‐deficient cells suggests several non‐mutually exclusive possibilities. Many viruses, including vertebrate ones, encode putative VSRs that might obscure RNAi effects on virus accumulation (Ding & Voinnet, 2007; Haasnoot et al , 2007; Wu et al , 2010). We did not detect an effect of RNAi on resistance to IAV ΔNS1 or EMCV ΔL, yet the role of other putative VSRs warrants further investigation.…”

“…Indeed, viRNA‐mediated RNAi constitutes the primary antiviral defence strategy of plants and invertebrates (Ding & Voinnet, 2007; Kemp & Imler, 2009; Swarts et al , 2014; tenOever, 2016). Consequently, plant and insect viruses have evolved virulence factors called viral suppressors of RNA silencing (VSRs) that block various steps of the antiviral RNAi mechanism (Haasnoot et al , 2007; Wu et al , 2010). Experimental appreciation of the effects of RNAi on virus accumulation therefore requires the use of VSR‐deficient viruses (Deleris et al , 2006; Wang et al , 2006a; Diaz‐Pendon et al , 2007; Maillard et al , 2013).…”

HIV-1 evolution: frustrating therapies, but disclosing molecular mechanisms

“…RNAi may also be a powerful method for intracellular immunization against HIV-1 ( Haasnoot et al 2007). We and others demonstrated long-term inhibition of virus replication in human T cells that stably express small-interfering RNAs (siRNAs) directed against the HIV-1 genome (Banerjea et al 2003;Boden et al 2003;Das et al 2004a;Lee et al 2005;ter Brake et al 2006ter Brake et al , 2008avon Eije et al 2008).…”

Diversity, evolution, and therapeutic applications of small RNAs in prokaryotic and eukaryotic immune systems

“…TD101 targets keratin 6a N171K mutant mRNA, in order to fight pachyonychia congenital (PC1), an autosomal dominant skin disease [109]. Additionally, drugs have been presented with the aim of fighting age-related macular edema, diabetic molecular edema, hepatitis C virus, glaucoma, optic atrophy, amyloidosis, cytomegalovirus, human immunodeficiency virus, human papillomavirus, and many different forms of cancer [13,61,82,109,123]. For example, ALN-VSP02 aims to treat solid liver tumors, EZN-2968 aims to treat lymphoma, advanced solid tumors, and liver metastases, and the FANG vaccine aims to treat ovarian cancer, colon cancer, and other solid tumors.…”