Influenza viruses have a multipartite, negative-sense, single-stranded RNA genome and a lipid envelope. They are divided into 3 genera, A, B and C within the family Orthomyxoviridae
, based on the antigenic properties of the viral nucleoprotein. Influenza B and C viruses principally infect humans, usually causing mild illness in children, and undergo only gradual antigenic variation (Wright and Webster, 2001
). By contrast, the influenza A viruses are maintained in a vast natural reservoir in wild waterfowl and shorebirds, from which they emerge to cause disease in domestic poultry, horses, pigs and humans. Their ability to infect the human respiratory tract and the periodic emergence of antigenically novel agents through genomic reassortment enable the influenza A viruses to cause periodic worldwide epidemics with high morbidity and mortality (“pandemic influenza”).
Individual isolates of influenza A virus are classified by subtype, based on the antigenic identity of two glycoproteins embedded in the virion’s lipid envelope, the hemagglutinin (HA) and the neuraminidase (NA) (). Studies of avian viruses have identified 16 antigenically distinct variants of HA and 9 of NA, leading to the existence of a large number of viral subtypes with different HA/NA pairs. Protective immunity resulting from previous infection or vaccination is based principally on neutralizing antibodies against HA, and to a lesser extent on antibodies to NA (Hayden and Palese, 2002
Figure 1 The influenza A virus replication cycle. The virion core contains 8 RNA genome segments encapsidated by nucleoprotein (RNPs) and embedded together with associated polymerase (P) molecules in a matrix of M1 proteins. After binding to sialic acid-galactose (more ...)
The emergence of new pandemic subtypes of influenza A virus occurs through two pathways. The first is for an avian virus to infect and cause disease in a human (“avian influenza”) and evolve during the course of illness to become transmissible from person to person. The second is made possible by the multipartite genome, which permits a circulating seasonal agent to acquire new HA and NA genes through reassortment (“antigenic shift”), when a cell is co-infected by a seasonal virus and either an avian virus or one that has adapted to a mammalian host, such as pigs. Novel viruses emerged several times during the 20th century. In 1918, an avian H1N1 virus acquired the capacity for efficient respiratory transmission, resulting in a catastrophic pandemic. As the H1N1 virus continued to circulate, the progressive accumulation of mutations in the H1 and N1 genes then permitted antigenically “drifted” variants to return and reinfect the same populations, causing recurrent outbreaks of illness (“seasonal influenza”). In 1957, a new reassortant virus appeared in which the two surface glycoproteins of H1N1 were replaced by avian H2 and N2. A second reassortment event produced H3N2 influenza in 1968, after which the H2N2 virus soon ceased to circulate.
As each new virus emerged and spread around the world, influenza morbidity and mortality increased markedly, then declined as the human population acquired some degree of immunity and the agent underwent progressive antigenic drift (Wright and Webster, 2001
). A seasonal variant of the H1N1 virus reappeared in 1977, apparently through an accidental laboratory release, and it continues to circulate along with the H3N2 virus, both in humans and in pigs. Because an influenza A virus with a novel HA has not entered the human population since 1968, the emergence of a new pandemic strain is likely. Such a virus might obtain its HA from an agent such as the avian/swine reassortant H2N3 that has been detected in the USA (Ma et al., 2008
), or from any of several purely avian strains that have infected humans during the past decade (see below).
At present, the most concerning scenario would be the pandemic spread of the highly virulent avian H5N1 virus that first appeared in Hong Kong in 1997, causing lethal primary viral pneumonia in 6 of 18 confirmed human infections (Chan et al., 2002
; To et al., 2001
; Yuen et al., 1998
). Although cases ceased once all local poultry had been destroyed, the virus continued to spread and reassort among wild birds, and since 2003 it has re-emerged as the cause of poultry outbreaks and sporadic cases of severe human illness in several southeast Asian countries (Beigel et al., 2005
; Li et al., 2004
), and has been carried by migratory birds and the transport of domestic poultry to Indonesia and across Asia to Africa and Europe. As of December 17th, 2007, a total of 340 confirmed human cases had been reported in 13 countries, with 209 deaths (Shinya et al., 2005
; WHO, 2007
). Fortunately, only a few instances of person-to-person transmission have been documented.
Vaccines are the principal defense against influenza, but because it takes time to produce an antigenically appropriate and immunogenic product and deliver it to entire populations, antiviral drugs will be a principal countermeasure to reduce the impact of a new pandemic (Monto, 2006
; Moscona, 2005a
). The current armamentarium of licensed anti-influenza medications consists of 4 drugs: two adamantanes, amantadine and rimantadine (), and two NA inhibitors, the oral drug oseltamivir (Tamiflu®) and the inhaled medication zanamivir (Relenza®) (). Because their licensure was obtained based on studies in healthy adults with uncomplicated seasonal influenza, little is known about how these drugs should be used to treat severe disease. In particular, only anecdotal information is available on the treatment of fulminant H5N1 virus infections with oseltamivir. Therapy of severe influenza is made even more challenging by the rapid emergence of drug-resistant viruses, especially during treatment with the adamantanes, and by the lack of an approved parenteral medication that can be administered to patients incapable of swallowing or inhaling a drug. The only other licensed drug with anti-influenza activity, ribavirin (Virazole®), has been used to only a very limited extent to treat severe infections (see below) ().
Licensed antivirals that block the influenza A M2 ion channel: amantadine (A); rimantadine (B). (Courtesy of Pieter Leyssen).
The structure of N-acetylneuraminic (sialic) acid (A) and antiviral drugs that compete with it for the active site of the influenza A or B neuraminidase: oseltamivir (B); zanamivir (C); peramivir (D). (Courtesy of Pieter Leyssen.)
Nucleoside analogues that interfere with influenza virus RNA polymerase function: ribavirin (A); viramidine (B); T-705 (C). (Courtesy of Pieter Leyssen.)