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Gene Therapy for HIV and Chronic Infections pp 51–69Cite as

U1 interference (U1i) for Antiviral Approaches

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Part of the book series: Advances in Experimental Medicine and Biology ((ASGCT,volume 848))

Abstract

U1 snRNP (U1 small nuclear ribonucleoprotein) is an essential component of the splicing machinery. U1 snRNP also plays an additional role in 3′-end mRNA processing when it binds close to polyadenylation sites (PAS). Cotranscriptionally, U1 snRNP binding close to putative PAS prevents premature cleavage and polyadenylation and consequently safeguards pre-mRNA transcripts and defines promoter directionality. At the 3′-end of mRNAs, U1 snRNP binding to putative PAS may regulate mRNA length or inhibit polyadenylation and, therefore, gene expression. U1 interference (U1i) is a technique to inhibit gene expression based on the property of U1 snRNP to inhibit polyadenylation. It requires the expression of a modified U1 snRNP, which interacts with a target gene upstream of its PAS and inhibits target gene expression. U1i has been used to inhibit the expression of reporter or endogenous genes both in tissue culture and in animal models. In addition, U1i combination with RNA interference (RNAi), another RNA-based gene silencing technology, results in a synergistic increased inhibition. This is of special interest for antiviral therapy, where strong inhibitions may be required to decrease the expression of replicative viral RNAs and impact the replication cycle. Furthermore, the combination of U1i and RNAi-based inhibitors should prevent the appearance of viral variants resistant to the treatment and allows the dose of inhibitors to be decreased and a functional inhibition to be obtained with fewer off target effects. In fact, U1i has been used to inhibit the expression of HIV-1 and HBV, whose viral genomes express mRNAs that must be polyadenylated by the nuclear polyadenylation machinery. In the case of HBV, antiviral U1i has been combined with RNAi to demonstrate a strong inhibition of expression from HBV sequences in vivo. This shows that, although several aspects of U1i technology remain to be addressed, U1i and U1i combined with RNAi have great potential as antivirals.

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Authors and Affiliations

  1. Department of Gene Therapy and Hepatology, Center for Applied Medical Research, Pio XII 55, Pamplona, Navarra, 31008, Spain

    Lorea Blázquez & Puri Fortes Ph.D.

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  1. Lorea Blázquez
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  2. Puri Fortes Ph.D.
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Correspondence to Puri Fortes Ph.D. .

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Editors and Affiliations

  1. University of Amsterdam, Amsterdam, The Netherlands

    Ben Berkhout

  2. The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Hildegund C.J. Ertl

  3. University of the Witwatersrand, Johannesburg, South Africa

    Marc S. Weinberg

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© 2015 American Society of Gene and Cell Therapy

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Blázquez, L., Fortes, P. (2015). U1 interference (U1i) for Antiviral Approaches. In: Berkhout, B., Ertl, H., Weinberg, M. (eds) Gene Therapy for HIV and Chronic Infections. Advances in Experimental Medicine and Biology(), vol 848. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2432-5_3

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