Nucleic acid-based antiviral drugs against seasonal and avian influenza viruses
Introduction
The global crisis posed by the emergence of the avian H5N1 influenza virus provides testament to the challenges of defending against a deadly virus that is unpredictable and ever changing. As the human death toll from the bird flu outbreaks continues to increase, the world is moving close to a potential influenza pandemic. With a reported case fatality rate over 50% [1], an influenza pandemic by a highly transmissible strain of avian H5N1 influenza virus that could potentially kill millions of people worldwide.
Influenza viruses undergo constant genetic changes. These antigenic changes in part enable them to develop resistance to antiviral drugs and vaccines. To circumvent these challenges, there are compelling reasons to develop prophylactic and therapeutic strategies that are broad-spectrum and that protect against seasonal or avian influenza viruses. Of particular importance are antiviral agents that can elicit long lasting protective innate immune responses, and that are not directed against specific range of viruses, and thus are less susceptible to emergence of drug-resistance.
Rapid advances in viral genomics, gene function and rational drug design have led to the development of nucleic acid-based antiviral agents that could be used in antiviral prevention and treatment. These antiviral agents are versatile in their mode of action in that they can be designed to elicit broad-spectrum antiviral immunity, interfere with viral replication, suppress viral gene expression or cleave viral mRNAs.
The ability of some nucleic acid-based drugs to elicit broad-spectrum antiviral immunity is of particular importance in the prevention and treatment of influenza infection. The enhancement of innate, cellular immunity and antiviral resistance may offer the potential of protection against a number of seasonal and avian strains of influenza viruses, regardless of genetic mutations, reassortments, recombinations, zoonotic origin or drug-resistance. Nucleic acid-based drugs currently in development that can stimulate the host's immune responses against viral infections include CpG containing oligonucleotides [2] and ds RNA, such as poly ICLC [3]. These drugs are Toll-like receptor (TLR) agonists, and are in various stages of clinical development.
Poly ICLC is a synthetic double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with poly-l-lysine and carboxymethyl cellulose (LC). It is shown to be a potent immunomodulating agent. As a ds RNA, it is Toll-like receptor-3 agonist, and has diverse immunological actions. It is a potent inducer of interferon-α, -β and -γ [4]. It activates natural killer cells and macrophages. The antiviral efficacy of poly ICLC is evaluated in this report against seasonal and avian influenza strains, to determine whether poly ICLC could have a potential role to play against influenza.
In addition, a virus specific therapeutic approach involving the use of antisense oligonucleotides to suppress viral gene expression is also evaluated in this report. This strategy provides a highly selective and sequence-specific way to block viral replication by targeting expression of key viral proteins at the molecular level. In this study, the feasibility of using an antisense oligonucleotide with a sequence that is complementary to influenza mRNA encoding the heamagglutinin protein was evaluated for the post exposure treatment of influenza A/PR/8/34 infection in mice.
Furthermore, this report also highlights the use of a liposome drug delivery system for nucleic acid-based antiviral drugs. When encapsulated in or complexed with liposomes, nucleic acids are protected against nuclease degradation in vivo. The use of liposomes also provide specific targeting of nucleic acids to intracellular sites of infection, or to professional antigen-presenting cells of the immune system. The delivery of nucleic acids to sites of infection, without adversely affecting normal cells and organs, will decrease drug toxicity and/or enhance antiviral activity [5].
Section snippets
Materials and methods
Poly ICLC, and antisense oligonucleotides used in this study were supplied by Oncovir Inc (Washington, DC) and Oligos Etc Inc. (Wilsonville, OR), respectively. Method of preparation and lipid compositions of liposome-encapsulated poly ICLC has been previously described [5].
Broad-spectrum protection against influenza infection using nucleic acid-based drugs
Mounting evidences in animal studies suggest synthetic ds RNA, such as poly ICLC can elicit effective and protective antiviral immune responses to influenza infection. This antiviral immune responses induced by these drugs have been shown to confer complete protection in mice against multiple challenge doses of influenza A viruses, including influenza A/PR/8/34 (H1N1) and A/Aichi (H3N2) strains [3]. When encapsulated in liposomes, poly ICLC given intranasally to mice can elicit complete
Conclusion
With both seasonal and avian influenza virus developing increased resistance to both antiviral drugs [9] and vaccines [10], there are compelling reasons to develop novel antiviral approaches that are broad-spectrum and independent of the genetic make up of the influenza viruses. The development of such approaches not only will decrease the likelihood of resistance, but may also offer protection against new variants of influenza viruses of zoonotic origin.
The significant difference between avian
References (11)
Mechanisms and applications of immune stimulatory CpG oligodeoxynucleotides
Biochim Biophys Acta
(1999)- et al.
Liposome-mediated immunotherapy against respiratory influenza virus infection using double stranded RNA poly ICLC
Vaccine
(1999) - et al.
Prophylaxis of acute respiratory virus infection using nucleic acid-based drugs
Vaccine
(2005) - World Health Organization....
- et al.
Prophylactic and therapeutic efficacies of poly(IC.LC) against respiratory influenza A virus infection in mice
Antimicrob Agents Chemother
(1995)
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2017, Antiviral ResearchCitation Excerpt :Hiltonol® also activates natural killer cells and macrophages. The antiviral efficacy of Hiltonol® was previously evaluated against avian influenza virus and Hiltonol® appeared to provide effective and broad-spectrum prophylaxis against avian influenza virus (Wong et al., 2007). For our in vivo studies, we recommend to administer the safe dose of Hiltonol® at 2.5 mg/kg/day.
Antiviral effects of liposome-encapsulated PolyICLC against Dengue virus in a mouse model
2016, Biochemical and Biophysical Research CommunicationsDelivery of oligonucleotides with lipid nanoparticles
2015, Advanced Drug Delivery ReviewsCitation Excerpt :The use of antisense ONs as an antiviral agent was first demonstrated in 1978 by Zamecnik and Stephenson when they observed that a 13-mer ON could block Rous sarcoma virus replication [120]. Since then, ON-based agents have been widely tested as anti-viral agents in different viral diseases in vitro or in vivo, such as Hepatitis B [121,122], human papillomavirus [123,124], human immunodeficiency virus [71,125–129], and influenza virus [130–134]. Antisense ONs are usually developed based on some defined viral elements including structural, translational, and assembly elements.
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2015, Advanced Drug Delivery ReviewsCitation Excerpt :Poly ICLC elicits an antiviral immune response via activation of the Toll-like receptor-3 which induces the production of IFN-α, -β and -γ [240–242], that in turn leads to the stimulation of both the innate and adaptive immune responses, including the activation of natural killer cells. Development efforts are currently focused on the production of a nasal spray that can deliver effective doses of poly ICLC directly to the respiratory tract [240–242]. In 2009 Nanotherapeutics was awarded a $30.9 million National Institute of Allergy and Infectious Diseases (NIAID) 5 year contract to develop an inhaled formulation of the injectable antiviral drug, cidofovir for post-exposure prophylaxis and treatment of smallpox virus (Variola major).
Oligonucleotides designed to inhibit TLR9 block Herpes simplex virus type 1 infection at multiple steps
2014, Antiviral ResearchCitation Excerpt :They also have high inhibitory potential, can be selected against almost any target, and exhibit limited toxicity or immunogenicity (Hagedorn et al., 2013; Mescalchin and Restle, 2011). Studies have indicated antisense oligonucleotides may function as antiviral agents for viruses including HIV and HBV (Galderisi et al., 1999; Mescalchin and Restle, 2011), HCV (Janssen et al., 2013) and Influenza (Wong et al., 2010, 2007). Vitravene, an antisense drug used for the treatment of CMV retinitis in AIDs patients, consists of a phosphorothioate oligonucleotide designed to inhibit human CMV replication (Galderisi et al., 1999).