Elsevier

Vaccine

Volume 25, Issue 16, 20 April 2007, Pages 3175-3178
Vaccine

Nucleic acid-based antiviral drugs against seasonal and avian influenza viruses

https://doi.org/10.1016/j.vaccine.2007.01.051Get rights and content

Abstract

Influenza viruses are etiological agents of deadly flu that continue to pose global health threats, and have caused global pandemics that killed millions of people worldwide. The availability of neuraminidase inhibitors and attenuated vaccines improves our ability to defend against influenza, but their benefits can be significantly limited by drug-resistance and virus mutations. Nucleic acid-based drugs may represent a promising class of antiviral agents that could play a role in the prevention and treatment of influenza. Efficacy studies in animals have shown that ds RNA, such as poly ICLC can provide effective and broad-spectrum prophylaxis against lethal challenges against various strains of influenza A virus. Furthermore, similar level of antiviral protection in mice can be provided by using short fragments of oligonucleotides that induce antiviral immunity. Finally, influenza virus expression can also be specifically inhibited or suppressed using antisense oligonucleotides that bind to viral mRNA encoding key viral proteins. The versatility and potency of nucleic acid-based drugs make them potential drug candidates for used in seasonal or pandemic influenza situations.

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

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