Effective inhibition of hepatitis E virus replication in A549 cells and piglets by RNA interference (RNAi) targeting RNA-dependent RNA polymerase

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Abstract

RNA interference (RNAi) is a natural mechanism for suppressing or silencing expression of aberrant or foreign genes. It is a powerful antiviral strategy that has been widely employed to protect hosts from viral infection. Hepatitis E (HE) is an acute fulminant hepatitis in adults that has particularly high mortality in pregnant women. At this point in time, there is no vaccine or antiviral treatment that is effective against the infectious agent, HEV. The nonstructural polyprotein region possesses an RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of the viral RNA genome. RdRp is therefore regarded as one of the most attractive candidates for RNA interference (RNAi). In the present study, the high efficiency and specificity of siRNA were evaluated by Real-Time quantitative PCR and Western blot assays. Protective effects against HEV infection were achieved in A549 cells and in piglets. In piglets treated with a shRNA-RdRp-1 expression plasmid prior to HEV inoculation, HEV antigens were significantly reduced in the liver, spleen, and kidneys, and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were clearly decreased. These results suggested that RNAi is a potentially effective antiviral strategy against HEV replication and infection.

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T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice.

J. Yao, Hee Kim, Kyung Bok Lee … (2008)

Evaluation of the therapeutic potential of RNAi for HIV infection has been hampered by the challenges of siRNA delivery and lack of suitable animal models. Using a delivery method for T cells, we show that siRNA treatment can dramatically suppress HIV infection. A CD7-specific single-chain antibody was conjugated to oligo-9-arginine peptide (scFvCD7-9R) for T cell-specific siRNA delivery in NOD/SCIDIL2rgamma-/- mice reconstituted with human lymphocytes (Hu-PBL) or CD34+ hematopoietic stem cells (Hu-HSC). In HIV-infected Hu-PBL mice, treatment with anti-CCR5 (viral coreceptor) and antiviral siRNAs complexed to scFvCD7-9R controlled viral replication and prevented the disease-associated CD4 T cell loss. This treatment also suppressed endogenous virus and restored CD4 T cell counts in mice reconstituted with HIV+ peripheral blood mononuclear cells. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naive T cells in Hu-HSC mice and effectively suppress viremia in infected mice. Thus, siRNA therapy for HIV infection appears to be feasible in a preclinical animal model.

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Short interfering RNA confers intracellular antiviral immunity in human cells.

Raul Andino, Leonid Gitlin, Sveta Karelsky (2002)

Gene silencing mediated by double-stranded RNA (dsRNA) is a sequence-specific, highly conserved mechanism in eukaryotes. In plants, it serves as an antiviral defence mechanism. Animal cells also possess this machinery but its specific function is unclear. Here we demonstrate that dsRNA can effectively protect human cells against infection by a rapidly replicating and highly cytolytic RNA virus. Pre-treatment of human and mouse cells with double-stranded, short interfering RNAs (siRNAs) to the poliovirus genome markedly reduces the titre of virus progeny and promotes clearance of the virus from most of the infected cells. The antiviral effect is sequence-specific and is not attributable to either classical antisense mechanisms or to interferon and the interferon response effectors protein kinase R (PKR) and RNaseL. Protection is the result of direct targeting of the viral genome by siRNA, as sequence analysis of escape virus (resistant to siRNAs) reveals one nucleotide substitution in the middle of the targeted sequence. Thus, siRNAs elicit specific intracellular antiviral resistance that may provide a therapeutic strategy against human viruses.

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Safety and efficacy of a recombinant hepatitis E vaccine.

Marc Fourneau, Khin Saw Aye Myint, Sanjaya Shrestha … (2007)

Hepatitis E virus (HEV) is an important cause of viral hepatitis. We evaluated the safety and efficacy of an HEV recombinant protein (rHEV) vaccine in a phase 2, randomized, double-blind, placebo-controlled trial. In Nepal, we studied 2000 healthy adults susceptible to HEV infection who were randomly assigned to receive three doses of either the rHEV vaccine or placebo at months 0, 1, and 6. Active (including hospital) surveillance was used to identify acute hepatitis and adverse events. The primary end point was the development of hepatitis E after three vaccine doses. A total of 1794 subjects (898 in the vaccine group and 896 in the placebo group) received three vaccine doses; the total vaccinated cohort was followed for a median of 804 days. After three vaccine doses, hepatitis E developed in 69 subjects, of whom 66 were in the placebo group. The vaccine efficacy was 95.5% (95% confidence interval [CI], 85.6 to 98.6). In an intention-to-treat analysis that included all 87 subjects in whom hepatitis E developed after the first vaccine dose, 9 subjects were in the vaccine group, with a vaccine efficacy of 88.5% (95% CI, 77.1 to 94.2). Among subjects in a subgroup randomly selected for analysis of injection-site findings and general symptoms (reactogenicity subgroup) during the 8-day period after the administration of any dose, the proportion of subjects with adverse events was similar in the two study groups, except that injection-site pain was increased in the vaccine group (P=0.03). In a high-risk population, the rHEV vaccine was effective in the prevention of hepatitis E. (ClinicalTrials.gov number, NCT00287469 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.

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Author and article information

Contributors

Fen Huang

Xiuguo Hua

Shixing Yang

Congli Yuan

Wen Zhang

Journal

Journal ID (nlm-ta): Antiviral Res

Journal ID (iso-abbrev): Antiviral Res

Title: Antiviral Research

Publisher: Elsevier B.V.

ISSN (Print): 0166-3542

ISSN (Electronic): 1872-9096

Publication date PMC-release: 1 July 2009

Publication date (Print): September 2009

Publication date (Electronic): 1 July 2009

Volume: 83

Issue: 3

Pages: 274-281

Affiliations

Zoonosis Laboratory, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, PR China

Author notes

[* ]Corresponding author. Tel.: +86 21 34206149; fax: +86 21 34206263. hxg@ 123456sjtu.edu.cn

Article

Publisher ID: S0166-3542(09)00377-5

DOI: 10.1016/j.antiviral.2009.06.008

PMC ID: 7114333

PubMed ID: 19576249

SO-VID: 501575e8-3b58-4270-8bbb-62676fbacdc8

License:

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