The basic virology, clinical syndromes, epidemiology, and approved antiviral drugs for influenza virus infections are presented in Table 1 . Efforts have intensified in recent years to understand the pathogenesis of the various forms of influenza virus infection and to develop new treatments (Beigel and Bray, 2008). To develop effective antiviral therapies for this wide range of diseases, it is essential to have laboratory animal models that replicate the major features of illness in humans and provide selective, sensitive and reproducible results. Selecting the appropriate laboratory animal infection is very important in the drug development process. Some animals, such as pigs and ferrets, are naturally susceptible to infection by influenza viruses, but some of the other species that have been used for influenza studies are not. For the latter, the virus requires adaptation before it can replicate in the animal and/or cause disease (e.g., human seasonal influenza viruses in mice, rats). Once influenza viruses infect an animal, the virus may cause nonlethal disease or lethal disease. The type of disease that is induced can be manipulated by the investigator and is dependent on a variety of factors including virus strain, amount of virus in the inoculum, route of inoculation, time allowed for the disease to develop and the animal's immune status.
Table 1 Influenza A virus infections: the basics.
Classification and structure Influenza viruses are spherical or pleomorphic, single-stranded, negative-sense RNA viruses belonging to the family Orthomyxoviridae. Influenza A and B viruses contain eight separate ribonucleoprotein (RNP) segments, while influenza C virus contains seven, each of which encodes 1 or 2 proteins. The internal antigens (M1 and NP proteins) are the type-specific antigens used to determine if a particular virus is A, B or C, while the external hemagglutinin (HA) and neuraminidase (NA) are the subtype- and strain-specific antigens.



Infection cycle Influenza virus binds to receptors on the surface of the host cell via the HA protein. It is internalized into endosomes, after which pH-dependent fusion and uncoating release the viral RNPs into the cytoplasm, where they are transported into the nucleus for replication. Viral messenger RNAs are exported out of the nucleus for protein synthesis, and some of the resulting proteins are transported back into the nucleus to assist in replication and RNP assembly. New RNPs assemble with other virus proteins at the M1 matrix to form virions, which bud from the plasma membrane.



Epidemiology Influenza A viruses cause chronic, asymptomatic infection in the gastrointestinal tracts of wild birds, but are also able to infect and cause disease in a variety of mammals. Such avian viruses cause a range of illness in humans, ranging from conjunctivitis through the fulminant illness caused by the recently emerged H5N1 virus. On rare occasions, an influenza A virus is introduced into human populations and spreads rapidly to cause a global pandemic. This can occur either when an avian virus with a novel HA protein adapts to human-to-human transmission, or when an avian virus undergoes genomic reassortment during co-infection of an influenza virus-infected mammal such as a pig. As a pandemic virus circulates, it undergoes progressive antigenic drift in its HA and NA proteins, permitting to re-infect the same populations in regular outbreaks of “seasonal” influenza.



Clinical syndromes Symptoms of seasonal influenza typically include high fever, chills, headache, sore throat, dry cough, myalgia, anorexia, and malaise. Complications include primary viral pneumonia, secondary bacterial pneumonia, or combined bacterial and viral pneumonia. Severe infections caused by the recently emerged avian influenza A H5N1 virus are characterized by rapid development of diffuse interstitial pneumonia, viremia and shock leading to death.



Vaccines Inactivated vaccines (Fluzone®, Fluvirin™) obtained from infected chicken embryos are most commonly used. Attenuated vaccines include FluMist®.



Approved therapeutics Approved therapeutics for seasonal influenza A virus infections include the neuraminidase inhibitors oseltamivir phosphate (Tamiflu®) and zanamivir (Relenza®) and the M2 ion channel blockers amantadine (Symmetrel®) and rimantadine (Flumadine®).