Extensive antigenic variability and a capricious epidemiology are characteristics of influenza A and B viruses of man. The haemagglutinin (HA) undergoes frequent and progressive antigenic drift as a result of selection, under immunological pressure, of viruses possessing alterations in the amino acid sequences at specific sites in the molecule. Here we present evidence for an additional selection mechanism for antigenic variants of influenza virus that depends on differing host cell tropisms of virus subpopulations. These studies were initiated after earlier observations of the occurrence of a marked degree of antigenic variation during passage of laboratory strains of influenza virus in eggs and cell cultures (J.C.J., in preparation). We have now shown that cultivation of influenza B viruses in eggs selects subpopulations which are antigenically distinct from virus from the same source grown in mammalian cell cultures. As antigenic characterization of influenza virus strains for epidemiological purposes and for the preparation of influenza vaccines conventionally relies on the cultivation of virus in eggs, our findings may have important practical implications for vaccine design and efficacy.

Adolescent↗

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Three-dimensional structure of a complex of antibody with influenza virus neuraminidase.

The structure of a complex between influenza virus neuraminidase and an antibody displays features inconsistent with the inflexible 'lock and key' model of antigen-antibody binding. The structure of the antigen changes on binding, and that of the antibody may also change; the interaction therefore has some of the character of a handshake.

Amino Acid Sequence↗

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Influenza: an emerging disease.

Because all known influenza A subtypes exist in the aquatic bird reservoir, influenza is not an eradicable disease; prevention and control are the only realistic goals. If people, pigs, and aquatic birds are the principal variables associated with interspecies transfer of influenza virus and the emergence of new human pandemic strains, influenza surveillance in these species is indicated. Live-bird markets housing a wide variety of avian species together (chickens, ducks, geese, pigeon, turkeys, pheasants, guinea fowl), occasionally with pigs, for sale directly to the public provide outstanding conditions for genetic mixing and spreading of influenza viruses; therefore, these birds should be monitored for influenza viruses. Moreover, if pigs are the mixing vessel for influenza viruses, surveillance in this population may also provide an early warning system for humans.

Disease Outbreaks↗

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[Differences in receptor specificity between the influenza A viruses isolated from the duck, chicken, and human].

The affinity of the duck, chicken, and human influenza viruses to the host cell sialosides was determined, and considerable distinctions between duck and chicken viruses were found. Duck viruses bind to a wide range of sialosides, including the short-stem gangliosides. Most of the chicken viruses, like human ones, lose the ability to bind these gangliosides, which strictly correlates with the appearance of carbohydrate at position 158-160. The affinity of the chicken viruses to sialoglycoconjugates of chicken intestine as well as chicken, monkey, and human respiratory epithelial cells exceeds that of the duck viruses. The human influenza viruses have high affinity to the same cells but do not bind at all to the duck epithelial cell. This testifies to the absence of 6'-sialylgalactose residues from the duck cells, in contrast to chicken and monkey cells. The alteration of the receptor specificity of chicken viruses in comparison with duck ones results in the similarity of the patterns of accessible cells for chicken and human influenza viruses. This may be the cause of the appearance of the line of H9N2 viruses from Hong Kong live bird markets with receptor specificity similar to that of H3N2 human viruses, and of the ability of H5N1 and H9N2 chicken influenza viruses to infect humans.

Animals↗

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Assessment of retrovirus-expressed nucleoprotein as a vaccine against lethal influenza virus infections of chickens.

Hemagglutinin-based influenza vaccines stimulate protection in chickens that is limited to the serotype of the expressed hemagglutinin. To evaluate whether a more highly conserved influenza virus protein might stimulate a broader protective response, the influenza virus nucleoprotein (NP) was introduced into a retroviral vector (mRCAS/NP). NP is an internal influenza virus protein that has been shown to stimulate cytotoxic T-cell responses in influenza-virus-infected mice. Cells infected with mRCAS/NP expressed approximately 10% of the level of NP observed in influenza-virus-infected chicken embryo fibroblasts. Immunocompetent chicks were vaccinated intramuscularly with approximately 1 x 10(5) NP-expressing units of mRCAS/NP. Four weeks later, chicks were bled and challenged with a highly pathogenic avian influenza virus (A/Chicken/Victoria/1/85). The NP-expressing vector stimulated an influenza-virus-specific response, as indicated by the presence of antibody to NP, but failed to protect against the lethal challenge.

Animals↗

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[Evolution of avian influenza viruses H5N1 (1997-2004) in southern and south-eastern Asia].

Highly pathogenic avian influenza viruses of the H5N1 subtype are widespread and have become endemic in poultry in southern and southeastern Asia. An unprecedented epizootic was caused by these viruses in 8 countries in the winter of 2003 to 2004. This fact along with more frequent human cases of the infection with unusually high mortality rates in Vietnam and Thailand raises concern that these H5N1 events may lead to a new influenza A virus pandemic. This review summarizes the results of studies dealing with the ecology and evolution of avian influenza H5N1 viruses in southern and southeastern Asia since 1997. The pathogenesis of the infection in human beings and laboratory animals and possible determinants of the high pathogenicity of H5N1 viruses in mammals are considered. A scheme for designing modified H5N1 vaccines using the latest advances in reverse genetics of influenza viruses is given.

Animals↗

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Influenza virus surveillance in waterfowl in Pennsylvania after the H5N2 avian outbreak.

During the latter stages of the lethal H5N2 influenza eradication program in domestic poultry in Pennsylvania in 1983-84, surveillance of waterfowl was done to determine if these birds harbored influenza viruses that might subsequently appear in poultry. From late June to November 1984, 182 hemagglutinating viruses were isolated from 2043 wild birds, primarily ducks, in the same geographical area as the earlier lethal H5N2 avian influenza outbreak. The virus isolates from waterfowl included paramyxoviruses (PMV-1, -4, and -6) and influenza viruses of 13 antigenic combinations. There was only one H5N2 isolate from a duck. Although this virus was antigenically related to the lethal H5N2 virus, genetic and antigenic analysis indicated that it could be discriminated from the virulent family of H5N2 viruses, and it did not originate from chickens. Many of the influenza viruses obtained from wild ducks were capable of replicating in chickens after experimental inoculation but did not cause disease. These studies show that many influenza A virus strains circulating in waterfowl in the vicinity of domestic poultry in Pennsylvania did not originate from domestic poultry. These influenza viruses from wild ducks were capable of infecting poultry; however, transmission of these viruses to poultry apparently was avoided by good husbandry and control measures.

Animal Population Groups↗

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Emergence of amantadine-resistant H5N2 avian influenza virus during a simulated layer flock treatment program.

An experiment was designed to simulate field conditions in which preventive treatment is not initiated until after some chickens in a flock are infected with avian influenza (AI). Twelve hens began to receive amantadine hydrochloride on the day they were inoculated (day 0) with highly pathogenic AI virus, A/chicken/Pa/1370/83. These hens remained clinically normal through 8 days postinoculation (PI), but five died after day 9; mean death time (MDT) was 18 days. Three of 12 hens given amantadine beginning 1 day PI died (MDT 5.4 days), seven of 12 hens given amantadine beginning 3 days PI died (MDT 3.7 days), and all 12 inoculated hens not given amantadine died (MDT 4.9 days). The delayed mortality in the day 0 treatment group was likely due not to the original inoculum but to the emergence of a drug-resistant virus population. Virus isolated from a dead hen from that group was resistant to the actions of amantadine in both in ovo and in vivo tests. The lack of late mortality due to the drug-resistant virus in the day 1 and day 3 treatment groups, which were in close contact with the day 0 treatment group, was attributed to their becoming infected before treatment with the drug and to the development of protective immunity.

Amantadine↗

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Host range of A/Chicken/Pennsylvania/83 (H5N2) influenza virus.

The highly pathogenic A/Chicken/Penn./1370/83 (H5N2) avian influenza virus, which caused 80% mortality in chickens in Pennsylvania, produced only mild transient illness in experimentally infected pheasants, little or no clinical signs in ring-billed gulls and pigs, and no clinical signs in pekin ducks. Virus could be recovered from only the upper respiratory tract of gulls and pigs for 1-2 days. Infection in ducks resulted in intestinal replication of virus in only 1 out of 12 ducks. By contrast, pheasants shed virus in feces (10(4.7) EID50) for at least 15 days. These studies reinforce wildlife surveillance findings indicating that gulls and ducks are unlikely to have transmitted virus between chicken farms during the 1983 outbreak. Although experimental data suggest that wild gallinaceous birds such as pheasants are potentially capable of virus transmission, there has been no evidence of this from wildlife surveillance in Pennsylvania. Experimental infection of chickens with H5N2 virus isolated from wild ducks one year before the Pennsylvania outbreak or a gull virus (H5N1) isolated in the quarantine area in 1983 resulted in asymptomatic infections and virus replication occurring only in the upper respiratory tract. These studies suggest that if the first H5N2 virus infecting chickens in Pennsylvania originated from waterbirds, changes in host specificity and pathogenicity for chickens and other gallinaceous birds probably occurred during emergence of the Chicken/Penn./83 virus. It is recommended that attention be given in the future to the isolation of domestic poultry from contact with wild aquatic birds.

Animals↗

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Wildlife surveillance associated with an outbreak of lethal H5N2 avian influenza in domestic poultry.

Wildlife surveillance was conducted for influenza viruses in conjunction with the 1983-84 lethal H5N2 avian influenza epizootic in domestic poultry in Pennsylvania, New Jersey, Maryland, and Virginia. Virus-isolation attempts made on cloacal and tracheal swabs from 4,466 birds and small rodents within the quarantined areas and 1,511 waterfowl in nearby Maryland yielded only a single H5N2 isolate from a pen-raised chukar in Pennsylvania. Antibodies against hemagglutinin type 5 and/or neuraminidase type 2 were found in 33% of the aquatic birds tested; however, this finding could not be used to confirm previous H5N2 avian influenza virus activity because of the possibility of prior infections with multiple influenza subtypes. The low prevalence of lethal H5N2 avian influenza virus in wild birds and small rodents strongly indicated that these animals were not responsible for dissemination of the disease among poultry farms during the outbreak.

Animals↗

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Standardization of inactivated H5N2 influenza vaccine and efficacy against lethal A/Chicken/Pennsylvania/1370/83 infection.

The hemagglutinin concentration of beta-propiolactone-inactivated influenza vaccine containing A/Duck/N.Y./189/82 (H5N2) virus was measured by single-radial-immunodiffusion (SRD) test. After administration of vaccine to chickens in Freund's complete adjuvant, vaccine efficacy was assessed by challenge with lethal A/Chicken/Penn./1370/83 (H5N2) virus. SRD potency values correlated with post-vaccination antibody levels and protection against infection.

Animals↗