Chapter 10 : Genome Plasticity of Influenza Viruses

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This chapter on genome plasticity of influenza viruses discusses the current knowledge of viral factors. Influenza viruses have caused devastating pandemics and epidemics in the past, and they continue to be a major health problem causing a huge economic burden worldwide. Thus, it is important to understand the characteristics of influenza viruses and to elucidate the extensive interplay between virus and host. Besides the eight structural proteins, influenza A virus encodes the three nonstructural proteins NS1, NEP, and PB1-F2. Influenza viruses pose a major problem for human health and thereby cause a substantial economic burden. The influenza pandemics which occurred in the past century share the fact that new subtypes of influenza A viruses were introduced into the human population. There are two classes of US Food and Drug Administration-approved drugs against influenza: inhibitors of the ion channel M2 and NA inhibitors. The first group comprises the adamantanes, rimantadine and amantadine, which act by inhibiting the viral ion channel M2 and thereby block the step of uncoating during virus entry. It becomes clear that circulating influenza viruses need to be closely monitored for resistance to the available drugs. Within the same host species genetic polymorphisms may occur and influence the ability of the virus to use the host proteins. For influenza viruses to survive, they need to be transmitted from host to host. The development of reverse genetics techniques has greatly advanced understanding of the virus and its replication cycle.

Citation: Stertz S, Palese P. 2012. Genome Plasticity of Influenza Viruses, p 162-177. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch10

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Influenza C virus
Tumor Necrosis Factor alpha
Influenza B virus
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Image of FIGURE 1

(A) Schematic representation of the influenza A virus particle. The virion possesses a membrane which is derived from the host cell plasma membrane and harbors the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA) as well as the ion channel M2. The inner side of the membrane is lined with the matrix protein M1. The viral ribonucleoprotein complexes (RNPs) consist of viral RNA which is encapsidated with the nucleoprotein NP and associated with the polymerase complex, which consists of the three subunits PB1, PB2, and PA. (B) Electron micrographs of influenza A virus particles. MDCK cells were infected with influenza A virus strain A/WSN/33 at a high multiplicity of infection. At 20 h postinfection, samples were fixed (2.5% glutaraldehyde in 0.1 M cacodylate buffer, followed by 2% osmium tetraoxide) and en bloc staining was performed (2% uranyl acetate). Samples were dehydrated and embedded in Epon 812 resin mixture. Ultrathin sections were stained with 2% uranyl acetate in 70% ethanol followed by Reynolds lead. Sections were examined with an H-7650 electron microscope (Hitachi) operated at 80 kV. A section of an MDCK cell from which progeny virions are budding is shown. The inset shows a higher magnification of one of the virions. In this cross section the eight RNP segments are visible as dot-like structures within the particle. These pictures were kindly provided by Yi-ying Chou, Mount Sinai School of Medicine, New York, NY. (C) Schematic representation of the influenza A virus replication cycle. Virions are taken up by endocytosis after binding of HA to sialic acid on surface proteins of the host cell plasma membrane. Upon acidification of the endosome, HA mediates fusion of the viral membrane with the endosomal membrane and the viral RNPs are released into the cytosol. The RNPs are transported to the nucleus, where transcription and replication occur. The late stages of the replication cycle take place at the budding sites at the plasma membrane, where the structural components of the virus form progeny virions.

Citation: Stertz S, Palese P. 2012. Genome Plasticity of Influenza Viruses, p 162-177. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch10
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Image of FIGURE 2

Antigenic drift of H1N1 viruses from 1918, 1943, 1986, and 2007. The HA trimeric complex is shown for virus strains A/Brevig Mission/1/1918, A/Weiss/43, A/Taiwan/1/1986, and A/Brisbane/59/2007 to illustrate the gradual accumulation of amino acid changes in the antigenic sites over the years. The structure of 1918 HA was obtained from the PDB server (ID: 2WRG), and the modeling for the other HA proteins was performed using the Swiss Model software. The left side shows the trimer from the side; the right side displays a zenithal view of the trimer. Blue corresponds to conserved amino acids, and red represents amino acids that differ from the 1918 HA. The antigenic sites are colored in light blue. Most neutralizing antibodies bind to the antigenic sites on the upper part of the trimeric complex. Thus, most amino acid changes occur at these sites. The structure modeling was kindly provided by Estanislao Nistal-Villan ( ).

Citation: Stertz S, Palese P. 2012. Genome Plasticity of Influenza Viruses, p 162-177. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch10
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Image of FIGURE 3

Influenza host-pathogen interaction map. Analysis of protein-protein interaction data for the host cell factors which were found to be required for influenza virus replication resulted in a highly significant ( < 0.001, permutation test) host-pathogen interaction map containing 4,266 interactions between 181 confirmed influenza virus-host cellular factors (green circles), 10 influenza virus-encoded proteins or complexes (red circles), and a further 184 cellular proteins (orange circles). Interaction data were elucidated based on binary protein interaction data derived from publicly available databases including BIND, HPRD, MINT, Reactome, Rual et al., and Stelzl et al. ( ) (BHMRRS; blue connections), curated protein complex data (CORUM; pink connections), the Hynet yeast two-hybrid database (aqua connections), and published viral-protein interaction data (yellow and green connections). Red circles indicate influenza nodes, green circles represent confirmed factors, and orange circles indicate unconfirmed influenza host proteins identified in the primary RNAi screen. Viral nodes are abbreviated as follows: HA, hemagglutinin; NS1, NS1 protein; M1, M1 matrix protein; NEP, NEP/NS2 protein; NP, NP protein; PB1 and PB2, the polymerase subunits PB1 and PB2; PB1-F2, PB1-F2 protein; vRNP, influenza virus ribonucleoprotein complex; virion, proteins incorporated into virions. Adapted from .

Citation: Stertz S, Palese P. 2012. Genome Plasticity of Influenza Viruses, p 162-177. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch10
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Image of FIGURE 4

1918 influenza mortality by age in the United States. The death rate during the 1918 influenza pandemic per 100,000 individuals is shown for different age groups. The resulting curve has a characteristic W shape, with the highest mortality in infants followed by elderly people. Children 5 to 14 years of age as well as adults 45 to 60 years of age displayed partial protection. Adapted from . doi:10.1128/9781555817213.ch10f04

Citation: Stertz S, Palese P. 2012. Genome Plasticity of Influenza Viruses, p 162-177. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch10
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Summary of virulence markers

Citation: Stertz S, Palese P. 2012. Genome Plasticity of Influenza Viruses, p 162-177. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch10

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