Abstract
The emergence of highly pathogenic viruses and a high speed of infection spread put forward the problem of the development of novel antivirals and their delivery vehicles. In this study, we investigated the antiviral effect of the previously identified immunostimulatory 19-bp dsRNA (isRNA) with 3′-nucleotide overhangs, which stimulates interferon α synthesis when delivered using cationic liposomes consisting of 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride and lipid-helper dioleoylphosphatidylethanolamine and its PEGylated formulation P1500 in vitro and in vivo. In vitro data showed that isRNA/2X3-DOPE complexes protected L929 cells from encephalomyocarditis virus infection, while isRNA/P1500 complexes were not active, which correlates with their lower transfection activity in cell culture. Comparison of the interferon-inducing activity of isRNA in BALB/c, CBA and C57Bl/6 mice showed that PEGylated liposomes significantly enhance the interferon-inducing activity of isRNA in vivo. The antiviral efficacy of the isRNA in vivo was considerably affected by the delivery system. The cationic liposomes 2X3-DOPE did not enhance the antiviral properties of isRNA in vivo. Similar liposomes equipped with a PEGylated lipoconjugate provided a pronounced anti-influenza effect of the isRNA in vivo. Administration of isRNA to C57Bl/6 led to a decrease in virus titers in the lungs and a significant decrease in the severity of the infection. Administration of a similar formulation to BALB/c mice caused only a mild antiviral effect at the initial stages of the infection. The data show that isRNA in combination with the PEGylated delivery system can be considered an effective means of suppressing influenza A infection.
Highlights
The emergence of highly pathogenic viruses and the re-emergence of previously controlled infections, as well as drug resistance and the accelerated spread of infectious agents as a result of travel and transportation, make the development of new methods of combating viral diseases a top priority
We found that immunostimulatory 19-bp dsRNA (isRNA) in combination with PEG-containing cholesterol-based cationic liposomes stimulates the synthesis of IFN-α in mice and efficiently interferes with influenza infection
Type I IFNs play a central role in antiviral responses, causing the death of virus-infected cells and activating interferon stimulating genes (ISGs), making uninfected cells resistant to viral infection
Summary
The emergence of highly pathogenic viruses and the re-emergence of previously controlled infections, as well as drug resistance and the accelerated spread of infectious agents as a result of travel and transportation, make the development of new methods of combating viral diseases a top priority. Researchers are focused on immunotherapeutic drugs, eliminating the need to develop new specific drugs for each virus type or viral strand that directly affect the replication of the influenza virus. Activation of the innate immune system by appropriate immunotherapeutics occurs in the same way as during infection with the influenza virus and leads to the synthesis of a number of cytokines involved in the development of an antiviral response and the formation of an antiviral state that prevents the spread of infection between body cells [9]. Type I interferons (IFNs) play a central role in the development of the antiviral response, inducing resistance of uninfected cells to infection and determining the possibility of a successful outcome of the disease. The interferonogenic activity of dsRNA preparations has been intensively studied in order to create therapeutics for the treatment of viral diseases and to prevent the progression of tumors [12]
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