Influenza virus

Influenza epidemiology in humans

Fields Virology, 2nd ed, Fields & Knipe, eds, Raven Press, 1990, Fig.40-1

Influenza mortality from 1957 to 1979

Fields Virology, 2nd ed, Fields & Knipe, eds, Raven Press, 1990, Fig.40-11

Influenza virus structure

Structure of influenza virus. The diagram illustrates the main structural features of the virion. The surface of the particle contains three
kinds of spike proteins: the hemagglutinin (HA), neuraminidase (NA), and matrix (M2) protein embedded in a lipid bilayer derived from the
host cell and covers the matrix (M1) protein that surrounds the viral core. The ribonucleoprotein complex making up the core consists of
at least one of each of the eight single-stranded RNA segments associated with the nucleoprotein (NP) and the three polymerase
proteins (PB2, PB1, PA). RNA segments have base pairing between their 3 and 5 ends forming a panhandle. Their organization and the
role of NS2 in the virion remain unresolved. (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig.
47-2)

Influenza virus

Electron micrographs of influenza virus. AC: The structure of the internal components; (D) the external view. A substantial fraction (up to
50%) of influenza virions contain large helical internal components (A, B), which may contain individual ribonucleoprotein (RNP)
segments (C) linked together. The individual RNPs each contain a binding site for the viral polymerase, as seen by the immunogold
labeling of the end of the RNP segment (C). The external view of the virions (D) illustrates the pleomorphic appearance and the surface
spikes. Bar in all figures equals 50 nm. (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig. 47-2)

Influenza gene functions

From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Table 60-1.

Structure of the influenza hemagglutinin monomer

HA monomer. Sites A-E are immunodominant epitopes (From Fields Virology, 2nd ed, Fields & Knipe,
eds, Raven Press, 1990, Fig.40-4)

Structure of the influenza hemagglutinin trimer

HA trimer. (From Fields Virology, 2nd ed, Fields & Knipe, eds, Raven Press, 1990, Fig.39-6)

Influenza A hemagglutinin and neuraminidase subtypes

Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Table 47-1

Influenza A reservoir

Wild aquatic birds are the main reservoir of influenza A viruses. Virus transmission has been reported from weild waterfowl to poultry, sea
mammals, pigs, horses, and humans. Viruses are also transmitted between pigs and humans, and from poultry to humans. Equine
influenza viruses have recently been transmitted to dogs. (From Fields Vriology (2007) 5th edition, Knipe, DM & Howley, PM, eds, Wolters
Kluwer/Lippincott Williams & Wilkins, Philadelphia, Fig 48.1)

Influenza replication

Replication of influenza A virus. After binding (1) to sialic acid-containing receptors, influenza is endocytosed and fuses (2) with the vesicle
membrane. Unlike for most other RNA viruses, transcription (3) and replication (5) of the genome occur in the nucleus. Viral proteins are
synthesized (4), helical nucleocapsid segments form and associate (6) with the M1 protein-lined membranes containing M2 and the HA and NA
glycoproteins. The virus buds (7) from the plasma membrane with 11 nucleocapsid segments. (-), Negative sense; (+), positive sense; ER,
endoplasmic reticulum. (From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Figure 60-2.)

Influenza pathogenesis in humans

Six seronegative volunteers received 104.0 TCID50 of wild-type A/Bethesda/1015/68 virus intranasally on day 0. (From Fields Virology,
4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig. 47-10.)

Influenza pathogenesis

Pathogenesis of influenza A virus. The symptoms of influenza are caused by viral pathologic and immunopathologic effects, but the
infection may promote secondary bacterial infection. CNS, Central nervous system. (From Medical Microbiology, 5th ed., Murray,
Rosenthal & Pfaller, Mosby Inc., 2005, Figure 60-3.)

Influenza reassortment in an intermediate host

Natural demonstration of reassortment of influenza variants in an intermediate host, with subsequent interspecies transmission. A 1980
H7N7 emergent virus with high mortality for seals is consistent with reassortment between two concurrently circulating avian viruses. The
virus caused a conjunctivitis in humans handling the seals, and could be experimentally transmitted (assymptomatically) to other species.
(From Fields Virology, 2nd ed, Fields & Knipe, eds, Raven Press, 1990, Fig.40-8)

Influenza reassortment in humans

Genetic reassortment between human H1N1 and H3N3 viruses. Reassortamt viruses (R1 and R2) containing mixed gene constellations
were isolated from humans during 1978 and 1979 but not since. (From Fields Virology, 2nd ed, Fields & Knipe, eds, Raven Press, 1990,
Fig.40-9)

Antigenic drift

Antigenic drift of H3N2 viruses between 1968 and 1997 as demonstrated by their cross-reactivity in hemagglutination-inhibition tests. (From
Fields Virology, 4th ed, Fields & Knipe, eds, Raven Press, 1990,Table 47-3.)

Influenza A evolution: antigenic shift

Postulated evolution of the influenza A viruses currently circulating in humans. Seroarcheology suggests that H2N2 and H3N8 influenza
viruses circulated in humans in 1889 and 1900, respectively. Phylogenetic evidence suggests that an influenza virus possessing eight gene
segments from avian influenza reservoirs was transmitted to humans and pigs before 1918 and replaced the 1900 strain. This virus was
probably carried from North America to Europe by American troops and caused the catastrophic Spanish influenza pandemic of 1918. In
1957 the Asian pandemic virus acquired three genes (PB1, HA, and NA) from the avian influenza gene pool in wild ducks by genetic
reassortment and kept five other genes from the circulating human strain. After the Asian strain appeared, the H1N1 strains disappeared
from humans. In 1968 the Hong Kong pandemic virus acquired two genes (PB1 and HA) from the duck reservoir by reassortment and kept
six genes from the virus circulating in humans. After the appearance of the Hong Kong strain, the H2N2 Asian strains were no longer
detectable in humans. In 1977 the Russian H1N1 influenza virus that had circulated in humans in 1950 reappeared and spread in children
and young adults. This virus probably escaped from a laboratory and has continued to cocirculate with the H3N2 influenza viruses in the
human population. (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig. 47-1.)

Diagnosis, treatment, vaccination

Diagnosis
Culture, hemadsorbtion, viral antigen detection

Treatment
Amantidine and rimantidine target M2
Zanamivir and oseltamivir target neuraminidase

Vaccination
Formalin fixed wild type virus approved for parenterally
administered vaccination.
Trivalent: two current A strains and one current B strain.

Live attenuated vaccine now available (Flumist)

Temperature sensitive recombinant bearing relevant HA and NA
genes.

Must anticipate shift and drift in order to identify appropriate

vaccine strain.

Recombinant live attenuated vaccine

Production of live attenuated viruses by genetic reassortment between two influenza A viruses by transfer of genes from an attenuated donor
virus to a virulent wild-type virus. The attenuated reassortant live vaccine virus contains the genes that code for the hemagglutinin and
neuraminidase from the virulent wild-type virus and the genes that confer attenuation from the attenuated donor virus. (From Fields Vriology
(2007) 5th edition, Knipe, DM & Howley, PM, eds, Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, Fig 48.11)

Summary: influenza

Structure
Negative sense segmented ssRNA genome, helical nucleocapsid,
enveloped

Pathogenesis

respiratory transmission
replication in nucleus; budding
no spread (usually)
innate and antibody response important; antigenic shift and drift
local symptoms from cell killing; systemic symptoms from immune
response; exaggerated disease in young and elderly; viral and bacterial
pneumonia complications

Diagnosis
culture, hemadsorbtion, viral antigen detection

Treatment/prevention
amantidine and rimantidine target matrix; zanamivir and oseltamivir
target NA
killed and live vaccines need constant updating