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Chapter 42 : Influenza Virus

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Abstract:

Homologous recombination between corresponding RNA segments of different influenza viruses has not been observed, in contrast to the high frequency of recombination observed among the genomes of positive-sense RNA viruses, like polioviruses, and retroviruses. The virulence and host range of influenza viruses relate to the surface glycoproteins, as well as to other viral proteins. Zoonotic influenza virus infections are also spread by these routes through direct and indirect exposures and perhaps rarely by gastrointestinal infection. Influenza virus RNA is readily detected on fomites, and virus retains infectiousness longer on hard, nonporous surfaces, in low humidity, and at cooler temperatures, but the importance of transmission via fomites is unclear. Pathogenicity and cell tropism of influenza viruses relate in part to the hemagglutinin (HA) cleavability by particular host cell enzymes. Serine proteases, presumably derived from host epithelial cells, cleave the HA precursor molecule into HA1 and HA2 to render human influenza viruses infectious. Currently, use of inactivated influenza vaccine is the most important measure for reducing influenza virus-related morbidity and mortality. Drug recipients may experience subclinical infection, which usually confers protection against infection by the same strain. As antiviral chemoprophylaxis does not interfere with the immune response to inactivated vaccine, they can be administered concurrently. However, concurrent use of any anti-influenza antiviral drug might interfere with the immunogenicity of live attenuated influenza virus vaccines (LAIV).

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42

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Influenza A virus Subtype H5N1
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Figures

Image of FIGURE 1
FIGURE 1

Circulation of human influenza A, B, and C viruses. Solid lines indicate that strains have been isolated and characterized. Three different influenza A virus HA subtypes (H1, H2, and H3) and two NA subtypes (N1 and N2) were identified in humans during the 20th century. The RNA genome of the extinct pandemic 1918 virus has been sequenced from RNA fragments in formalin-fixed and frozen tissue samples from 1918 victims following RT-PCR ( ). The virus was then reconstructed in the laboratory by reverse genetics (solid square) ( ).

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 2
FIGURE 2

(A) Schematic diagram of an influenza A virus. HA, NA, and M2 are transmembrane proteins anchored in the lipid membrane of the virus. Inside the lipid membrane is a layer of the M1 protein. The RNP core consists of the different RNA segments which are covered by NP molecules. In addition, they carry an RNA-dependent RNA polymerase complex (P proteins). The RNA segments possess a panhandle-fork-corkscrew structure which appears to be stabilized by base pairing between the 3′ and 5′ ends of the RNAs. NEP is also part of the viral core structure. (B) Schematic depiction of influenza virus HA. Antigenic changes cluster into five highly variable regions (A to E) surrounding the receptor-binding pocket. The latter is too small to allow ingress of antibody and remains conserved. See Color Plate 25 depicting the interaction of neutralizing antibody with HA. (Panel B courtesy of Robert Webster, St. Jude Children’s Hospital, Memphis, TN.)

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 3
FIGURE 3

(A) Genetic map of influenza A/PR/8/34 (H1N1) virus. Purified RNAs were separated on a polyacrylamide gel; assignment of genes coding for one or two viral proteins is indicated. (B) Plasmid-only rescue of infectious influenza virus. Twelve plasmids are introduced into mammalian cells: four plasmids lead to expression of the viral proteins required for viral RNA replication (PA, PB1, PB2, and NP), and eight plasmids express precise copies of the eight viral RNA segments (PA, PB1, PB2, HA, NP, NA, M, and NS). The resulting viral RNAs are replicated and transcribed by the reconstituted influenza virus RNA-dependent RNA polymerase. Recombinant infectious influenza virus is generated 48 to 72 h after transfection of cells ( ). Recently, several improvements of the plasmid-only rescue for influenza A viruses have been introduced ( ). Also, reverse-genetics systems for influenza B and C viruses have been successfully developed ( ).

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 4
FIGURE 4

Reassortment of influenza A viruses leading to a new pandemic strain. Coinfection of the same cell with a human H2N2 (thin lines) virus and an animal (avian) strain with an H3 HA (thick lines) results in reassortment. The H3N2 virus responsible for the pandemic in 1968 is postulated to derive its PB1 and H3 genes (thick lines) from the animal strain and its remaining six RNAs, including the N2 gene, from the H2N2 parent (thin lines) ( ).

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 5
FIGURE 5

Replication of influenza virus. For a description of different replication steps, see the text.

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 6
FIGURE 6

Transcription and replication of influenza virus RNAs. (A) The 3′-terminal 15 nt and the 5′-terminal 22 nt of an NS gene (vRNA) are shown. The 3′-terminal 12 nt and the 5′-terminal 13 nt are highly conserved among influenza virus RNAs. The six U’s at the 5′ end are part of the polyadenylation signal. Transcription leads to a polyadenylated mRNA which is primed by short capped RNA molecules derived from nascent cellular transcripts and terminates at the stretch of six U’s near the 5′ end of the incoming vRNA. Full-length cRNAs are copied from vRNAs and are then used as templates for the generation of new vRNA molecules. All RNAs are shown as linear molecules. (B) The vRNA is represented here by a panhandle-fork structure. The 3′ and 5′ ends are postulated to base pair, but it is not known which RNA structure (panhandle-fork-corkscrew) is the predominant one in vivo.

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 7
FIGURE 7

Influenza activity in the United States, 1995 to 2007, based on isolates reported to the Influenza Branch, CDC. Influenza activity has occurred each year during this interpandemic period, often with mixtures of influenza A subtypes and/or B viruses. (Figure kindly provided by Lynnette Brammer and Joe Bresee, Influenza Division, CDC.)

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 8
FIGURE 8

Pneumonia and influenza (P%I) deaths presented as a percentage of total deaths in the United States, 2002 to 2007. Total deaths and those attributed to pneumonia and influenza deaths are reported weekly from 122 cities in the United States to the CDC. Excess mortality above the epidemic threshold has been seen particularly in association with influenza A (H3N2) subtype activity. (Figure kindly provided by Lynnette Brammer and Joe Bresee, Influenza Division, CDC.)

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 9
FIGURE 9

Photomicrographs of lung tissue from patients with primary influenza A viral pneumonia. Histologic sections were stained with hematoxylin and eosin and were viewed at an original magnification of approximately ×125. (A) Intra-alveolar hemorrhage with erythrocytes and exudate filling alveoli; (B) extensive hyaline membrane formation; (C) early regenerative phase with a metaplastic epithelium. (Figure kindly provided by Phillip Feldman, Department of Pathology, University of Virginia.)

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Image of FIGURE 10
FIGURE 10

Sequential chest radiographs from a 30-year-old nonimmunocompromised female with acute influenza A virus pneumonia. (A) Her symptoms began 1 day before first radiograph, which shows right middle and bilateral lower lobe infiltrates. Her respiratory status deteriorated rapidly and she required mechanical ventilation but survived. (B) The second radiograph, taken approximately 24 h after admission, shows diffuse infiltrates.

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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Tables

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TABLE 1

Influenza A virus RNA segments and proteins

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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TABLE 2

Recent examples of human illness due to infection by avian influenza viruses

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
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TABLE 3

Influenza A virus pandemics and other important influenza events during the past century

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
Generic image for table
TABLE 4

Target groups for influenza immunization

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
Generic image for table
TABLE 5

Comparison of seasonal inactivated vaccines and LAIV

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42
Generic image for table
TABLE 6

Suggested dose regimens for antiviral administration in seasonal influenza

Citation: Hayden F, Palese P. 2009. Influenza Virus, p 943-976. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch42

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