Design of modified U1i molecules against HIV-1 RNA

Knoepfel, Stefanie A; Abad, Amaya; Abad, Xabi; Fortes, Puri; Berkhout, Ben

doi:10.1016/j.antiviral.2012.03.010

Cited by 11 publications

(14 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore drugs that influence splicing factors/RNA splicing may have some desirable consequences on HIV gene expression. To date, several studies have presented mixed results targeting a U1 snRNP-based polyadenylation/splicing related inhibition approach to HIV therapy [70,71]. Thus more work is clearly needed in this area.…”

Section: Introductionmentioning

confidence: 99%

Putting an ‘End’ to HIV mRNAs: capping and polyadenylation as potential therapeutic targets

Wilusz

2013

AIDS Res Ther

View full text Add to dashboard Cite

Like most cellular mRNAs, the 5′ end of HIV mRNAs is capped and the 3′ end matured by the process of polyadenylation. There are, however, several rather unique and interesting aspects of these post-transcriptional processes on HIV transcripts. Capping of the highly structured 5′ end of HIV mRNAs is influenced by the viral TAT protein and a population of HIV mRNAs contains a trimethyl-G cap reminiscent of U snRNAs involved in splicing. HIV polyadenylation involves active repression of a promoter-proximal polyadenylation signal, auxiliary upstream regulatory elements and moonlighting polyadenylation factors that have additional impacts on HIV biology outside of the constraints of classical mRNA 3’ end formation. This review describes these post-transcriptional novelties of HIV gene expression as well as their implications in viral biology and as possible targets for therapeutic intervention.

show abstract

Section: Introductionmentioning

confidence: 99%

Putting an ‘End’ to HIV mRNAs: capping and polyadenylation as potential therapeutic targets

Wilusz

2013

AIDS Res Ther

View full text Add to dashboard Cite

show abstract

“…The lack of effect could be due to the fact that cells were transduced at a low multiplicity of infection (MOI) and therefore only integrated a single copy of the U1in gene. Indeed, the ratio between exogenous and endogenous U1 snRNAs was much lower in stably versus transiently transfected cells [ 37 ]. These results suggest that, while a single copy of a potent antiviral shRNA cassette is suffi cient, a single copy of the U1i gene is insuffi cient to prevent the spread of HIV-1 [ 52 ].…”

Section: Hiv-1mentioning

confidence: 95%

“…In an independent study, 14 new anti-HIV-1 U1i molecules were extensively tested in various in vitro models and in lentivirus-transduced CD4 + T cells to study the impact of U1in on HIV-1 replication [ 37 ]. U1i molecules were designed according to previously proposed rules [ 24 , 25 ] and were 100 % complementary to at least 70 % of all HIV-1 sequences deposited in Los Alamos database ( http://www.hiv.…”

Section: Hiv-1mentioning

confidence: 99%

U1 interference (U1i) for Antiviral Approaches

Blázquez

Fortes

2015

Advances in Experimental Medicine and Biology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Therefore, HIV-1 products have been the preferred targets for antiviral RNAs. Figure 4 depicts the major antiviral RNA categories, but others approaches have been tried [90,91].…”

Section: Antiviral Rnasmentioning

confidence: 99%