Protection against lethal influenza virus challenge by RNA interference<i>in vivo</i>

Tompkins, S. Mark; Lo, Chia-Yun; Tumpey, Terrence M.; Epstein, Suzanne L.

doi:10.1073/pnas.0402630101

Cited by 358 publications

(304 citation statements)

References 35 publications

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“…With further optimization of transfection carriers and siRNAs and the use of multiple doses, siRNAs may prove to be potent inhibitors of influenza virus infection in humans. Consistent with this view, in an independent study by Tompkins et al (41) using the same siRNAs, multidoses and multiroutes of administration significantly promoted the survival of mice after lethal challenge. It is notable that similar and complementary results were obtained in these two independent studies, using different carriers, doses, strains of mice, and virus strains.…”

Section: Discussionsupporting

confidence: 64%

Inhibition of influenza virus production in virus-infected mice by RNA interference

Filip

Bai

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

420

345

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Influenza A virus infection is a major source of morbidity and mortality worldwide. Because the effectiveness of existing vaccines and antiviral drugs is limited, development of new treatment modalities is needed. Here, we show that short interfering RNAs (siRNAs) specific for conserved regions of influenza virus genes can prevent and treat influenza virus infection in mice. Virus production in lungs of infected mice is reduced by siRNAs given either before or after initiating virus infection, by using slow i.v. administration of small volumes containing siRNAs in complexes with a polycation carrier. Similar effects also are observed when mice are given DNA vectors i.v. or intranasally, from which siRNA precursors can be transcribed. Development of delivery systems that may be compatible with human use demonstrates the potential utility of siRNAs for prophylaxis and therapy of influenza virus infections in humans.

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Section: Discussionsupporting

confidence: 64%

Inhibition of influenza virus production in virus-infected mice by RNA interference

Filip

Bai

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

420

345

View full text Add to dashboard Cite

show abstract

“…[40][41][42][43] In contrast, the therapeutic efficacy was greatly reduced if siRNAs/ shRNAs were given a few days after viral challenge. The failure to treat more established viral infections was probably due to the low in vivo transduction rate of siRNAs and plasmid-based shRNAs.…”

Section: Discussionmentioning

confidence: 95%

Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA

Chen

et al. 2006

Gene Ther

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RNA interference (RNAi) was reported to block hepatitis B virus (HBV) gene expression and replication in vitro and in vivo. However, it remains a technical challenge for RNAibased therapy to achieve long-term and complete inhibition effects in chronic HBV infection, which presumably requires more extensive and uniform transduction of the whole infected hepatocytes. To increase the in vivo transfection efficiency in liver, we used a double-stranded adenoassociated virus 8-pseudotyped vector (dsAAV2/8) to deliver shRNA. HBV transgenic mice were used as an animal model to evaluate the inhibition effects of the RNAi-based gene therapy. A single administration of dsAAV2/8 vector, carrying HBV-specific shRNA, effectively suppressed the steady level of HBV protein, mRNA and replicative DNA in liver of HBV transgenic mice, leading to up to 2-3 log 10 decrease in HBV load in the circulation. Significant HBV suppression sustained for at least 120 days after vector administration. The therapeutic effect of shRNA was target sequence dependent and did not involve activation of interferon. These results underscore the potential for developing RNAi-based therapy by dsAAV2/8 vector to treat HBV chronic infection, and possibly other persistent liver infections as well.

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“…The RNAi pathway converts double-stranded RNA into siRNAs, which trigger the degradation of an mRNA with complementary sequence (31). Importantly, the RNAi pathway acts as a defense against RNA viruses in plants and some animals, leading to great reductions or complete elimination (32,33). Further, introduction of RNAi pathway proteins from Saccharomyces castellii into the naturally RNAi-null S. cerevisiae resulted in greatly decreased levels of persistently infecting L-A totivirus (26).…”

Section: Significancementioning

confidence: 99%

Tilting the balance between RNA interference and replication eradicatesLeishmaniaRNA virus 1 and mitigates the inflammatory response

Brettmann

Shaik

Zangger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Many Leishmania (Viannia) parasites harbor the double-stranded RNA virus Leishmania RNA virus 1 (LRV1), which has been associated with increased disease severity in animal models and humans and with drug treatment failures in humans. Remarkably, LRV1 survives in the presence of an active RNAi pathway, which in many organisms controls RNA viruses. We found significant levels (0.4 to 2.5%) of small RNAs derived from LRV1 in both Leishmania braziliensis and Leishmania guyanensis, mapping across both strands and with properties consistent with Dicer-mediated cleavage of the dsRNA genome. LRV1 lacks cis-or trans-acting RNAi inhibitory activities, suggesting that virus retention must be maintained by a balance between RNAi activity and LRV1 replication. To tilt this balance toward elimination, we targeted LRV1 using long-hairpin/stem-loop constructs similar to those effective against chromosomal genes. LRV1 was completely eliminated, at high efficiency, accompanied by a massive overproduction of LRV1-specific siRNAs, representing as much as 87% of the total. For both L. braziliensis and L. guyanensis, RNAi-derived LRV1-negative lines were no longer able to induce a Tolllike receptor 3-dependent hyperinflammatory cytokine response in infected macrophages. We demonstrate in vitro a role for LRV1 in virulence of L. braziliensis, the Leishmania species responsible for the vast majority of mucocutaneous leishmaniasis cases. These findings establish a targeted method for elimination of LRV1, and potentially of other Leishmania viruses, which will facilitate mechanistic dissection of the role of LRV1-mediated virulence. Moreover, our data establish a third paradigm for RNAi-viral relationships in evolution: one of balance rather than elimination.dsRNA virus | protozoan parasite | endosymbiont | trypanosomatid protozoa | microbial pathogenesis

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Protection against lethal influenza virus challenge by RNA interferencein vivo

Cited by 358 publications

References 35 publications

Inhibition of influenza virus production in virus-infected mice by RNA interference

Inhibition of influenza virus production in virus-infected mice by RNA interference

Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA

Tilting the balance between RNA interference and replication eradicatesLeishmaniaRNA virus 1 and mitigates the inflammatory response

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