Abstract
There is little doubt among the experts that sooner or later we will face a pandemic avian H5N1 influenza outbreak. Human deaths may reach the millions. While most believe that this zoonotic infection will arise in Asia, recent experience with the “swine flu” in Mexico suggests that the virus can make the jump from birds to humans anywhere the two species interact. Reconstruction of the influenza virus responsible for the 1918 pandemic of “Spanish flu” indicates that an avian influenza A virus made the transition from birds to humans more-or-less intact as a result of mutational events in the avian virus genome. The other two influenza pandemics, the Asian (1957) and the Hong Kong (1968) arose as a result of genetic reassortment between avian and human influenza virus strains, presumably in vivo.
The influenza viruses are very prone to mutations. This phenomenon is attributable to the error-prone RNA polymerase enzyme encoded by the viral RNA, and because the negative-stranded RNA genome is segmented into at least 8 RNA segments coding for 10 viral proteins. These fragments can be exchanged, one for another, in cells or tissues infected with different influenza viruses, thereby giving rise to new recombinant viruses with expanded host tropisms. The virus is enveloped and possesses a surface-expressed virus-encoded neuraminidase used for virion attachment to susceptible cells. Unlike virtually all other RNA viruses, influenza replicates in cell nuclei. These oddities provide research scientists with a number of different molecular and biochemical “targets” for drugs and medicinal intervention. The central thesis of this book and collection of essays is that antiviral drug therapies represent our first (and best) line of defense against an emergent avian influenza-origin human pathogen. Even under the best case scenarios, production, distribution, and administration of a vaccine would take 8 to 12 months. During this interval the virus would be spread throughout the world and many millions of people would die. Our very recent experiences with the so-called Mexican swine flu outbreak and its rapid spread to the United States, Canada and Europe illustrate the rapidity of spread and the public health risks involved. For this reason alone, this book is very timely in its appearance and very neatly summarizes a number of different approaches to interventional drug therapies.
In this book, Editor Paul Torrence has drawn together a set of experts on influenza and has charged each of them with providing the reader with a concise overview of the antiviral drugs and their presumed targets and modes of action. In the over 50 years since discovery, the molecular mode(s) of action of the type I interferons (predominately alpha subgroup) have been elucidated; standard interferon inducers such as poly I:C are reviewed as are the interferon-inducing effects of CpGs, a new class of adjuvant-like immunostimulatory molecules. The interferons are generated very early in infection and serve as a cytokine signaling link between innate and adaptive immunity. Interferon alpha in particular has broad spectrum antiviral effects and has been shown to boost innate immune responses and other tissue/organ defenses. This cytokine is approved for human use in hepatitis C patients and should be useful as an effective low cost antiviral drug.
The most elegant of the anti-virals are those that use molecular biology approaches such as interfering RNA (iRNA) as inhibitors of viral RNA transcription, other nucleic acid inhibitors and various peptide inhibitors that block virion envelope host envelope fusional events. Included also under this general approach are fucoidan, a sulfated polysaccharide, and various glycopeptides that inhibit adhesion of the virus to carbohydrate residues on the surfaces of cells. For the intracellular inhibitors, issues of delivery, stability and dosing represent formidable obstacles to overcome.
Neuraminidase inhibitors (cyclopentane and pyrrolidine derivatives) such as Tamiflu, permivir and zanamivir are reviewed, particularly since some of these are approved for use in humans. As well, ribavirin and viramidine (inhibitors of virus encoded IMP dehydrogenase) are also discussed. As the authors indicate, widespread and/or indiscriminate use of these classes of influenza inhibitors has given rise to viral variants that are resistant, making these the viral equivalent of antibiotic-resistant bacterial pathogens. One method devised to combat drug resistance is to employ several drugs with slightly different modes of action; this approach appears to be successful in halting (or at least dramatically reducing) the incidence of escape mutant resistant influenza virus strains. In the absence of an effective vaccine, stockpiling some of these drugs for emergency use seems prudent.
This collection of essays and reviews is reader-friendly and concisely addresses both the potential and problematic approaches to anti-viral therapies. The authors and editor make a very convincing case for these drugs as a first-line of defense against the coming Influenza A pandemic. The illustrations, particularly those provided by Dr. Shigeta in Chapter 4 (Broadly effective anti-respiratory virus agents) are first-rate and graphically illustrate the target sites in viral proteins for the anti-virals. This book is an excellent addition to the field of virology and appears to be mandatory reading for those whose research interest includes the enveloped RNA viruses.