Sequence comparisons of A/AA/6/60 influenza viruses: mutations which may contribute to attenuation

Herlocher, M. Louise; Clavo, Anaira C.; Maassab, Hunein F.

doi:10.1016/0168-1702(96)01292-0

Cited by 43 publications

(20 citation statements)

References 53 publications

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“…The ferret is a natural host of both the A and B type human influenza virus, but many of the studies done with ferrets have focused on the strains of the type A influenza virus [25][26][27][28][29] .…”

Section: Strain Variationsmentioning

confidence: 99%

The Ferret: An Animal Model to Study Influenza Virus

Maher¹,

DeStefano²

2004

Lab Anim

224

190

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Section: Strain Variationsmentioning

confidence: 99%

The Ferret: An Animal Model to Study Influenza Virus

Maher¹,

DeStefano²

2004

Lab Anim

224

190

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“…It is claimed that the nature of the safety of cold-adapted influenza vaccines is based on a large number of point mutations distributed across the internal gene segments. However, only a small number of mapped mutations localized in the polymerase genes are responsible for the attenuation of cold-adapted virus strains that are unable to replicate at normal body temperature (21,22). In fact, the genetic stability of live coldadapted vaccine strains or other promising temperature-sensitive (ts) vaccine candidate strains are often questioned since viruses reisolated from vaccinated hosts reveal additional point mutations that might eventually function as "suppressor" mutations even causing enhanced replication properties and a possible loss of the ts phenotype of the revertant virus (22,39,47,48).…”

mentioning

confidence: 99%

Immunogenicity and Protection Efficacy of Replication-Deficient Influenza A Viruses with Altered NS1 Genes

Ferko

Stasakova

Romanova

et al. 2004

J Virol

106

100

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We explored the immunogenic properties of influenza A viruses with altered NS1 genes (NS1 mutant viruses). NS1 mutant viruses expressing NS1 proteins with an impaired RNA-binding function or insertion of a longer foreign sequence did not replicate in murine lungs but still were capable of inducing a Th1-type immune response resulting in significant titers of virus-specific serum and mucosal immunoglobulin G2 (IgG2) and IgA, but with lower titers of IgG1. In contrast, replicating viruses elicited high titers of serum and mucosal IgG1 but less serum IgA. Replication-deficient NS1 mutant viruses induced a rapid local release of proinflammatory cytokines such as interleukin-1␤ (IL-1␤) and IL-6. Moreover, these viruses also elicited markedly higher levels of IFN-␣/␤ in serum than the wild-type virus. Comparable numbers of virus-specific primary CD8؉ T cells were determined in all of the groups of immunized mice. The most rapid onset of the recall CD8؉ -T-cell response upon the wild-type virus challenge was detected in mice primed with NS1 mutant viruses eliciting high levels of cytokines. It is noteworthy that there was one NS1 mutant virus encoding NS1 protein with a deletion of 40 amino acids predominantly in the RNA-binding domain that induced the highest levels of IFN-␣/␤, IL-6 and IL-1␤ after infection. Mice that were immunized with this virus were completely protected from the challenge infection. These findings indicate that a targeted modification of the RNA-binding domain of the NS1 protein is a valuable technique to generate replication-deficient, but immunogenic influenza virus vaccines.Human influenza, caused by influenza A and B viruses, is a highly infectious acute respiratory disease spreading around the world in seasonal epidemics resulting in high morbidity and significant mortality. Influenza viruses have a segmented negative-strand RNA genome that encodes 10 or 11 proteins depending on the strain. The exchange of individual genome segments between different virus subtypes during a mixed infection (genetic reassortment) and the relatively rapid accumulation of point mutations in virus surface glycoproteins due to the high mutation rate of the RNA genome are the main reasons for antigenic "shift" and "drift" variations of emerging viruses escaping the preexisting immunity of the human population (53-55). Attempts to develop a vaccine inducing a longlasting protection against influenza have thus far been unsuccessful. In order to protect humans against circulating epidemic influenza virus strains, vaccine producers have to generate vaccines containing actualized influenza A (H1N1 and H3N2) and B virus components almost annually (19).The vaccination at present is accomplished with the commercially available chemically inactivated (killed) or live coldadapted (ca) attenuated influenza virus vaccines (10, 28, 36). The vaccine efficacy for both types of vaccines has been reported to be comparable in adults. However, live vaccines, apart from the easy and painless nasal administration induce not only the h...

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“…In order to further describe the effects of mutations in 101RKLKR105, mutant A/WSN/33 viruses generated by reverse genetic methods were tested in a mouse model to assess replication and possible attenuation compared to the original fully virulent A/WSN/33. We also explored additional M1 and M2 mutations including those identified during passage of influenza A viruses in the laboratory such as the temperature-sensitive strain A/WSN/33 ts51 or cold-adapted variant of strain A/Ann Arbor/ 6/60 (10).…”

mentioning

confidence: 99%

Attenuating Mutations of the Matrix Gene of Influenza A/WSN/33 Virus

Liu

2005

J Virol

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The matrix protein (M1) of influenza virus plays an essential role in viral replication. Our previous studies have shown that basic amino acids 101RKLKR105 of M1 are involved in RNP binding and nuclear localization. For the present work, the functions of 101RKLKR105 were studied by introducing mutations into the M gene of influenza virus A/WSN/33 by reverse genetic methods. Individual substitution, R101S or R105S, had a minimal effect on viral replication. In contrast, the double mutation R101S-R105S was synergistic and resulted in temperature sensitivity reflected by reduced viral replication at a restrictive temperature. To investigate the in vivo effect on infection, BALB/c mice were infected with either A/WSN/33 wild-type (Wt) or mutant viruses and assessed for signs of illness, viral replication in the lungs, and survival rates. The results from mouse studies indicated that the R101S-R105S double mutant virus was strongly attenuated, while single mutant viruses R101S and R105S were minimally attenuated compared to A/WSN33 Wt under the same conditions. In challenge studies, mice immunized by infection with R101S-R105S were fully protected from lethal challenge with A/WSN/33. The replication and attenuating properties of R101S-R105S suggest its potential in development of live influenza virus vaccines.

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Sequence comparisons of A/AA/6/60 influenza viruses: mutations which may contribute to attenuation

Cited by 43 publications

References 53 publications

The Ferret: An Animal Model to Study Influenza Virus

The Ferret: An Animal Model to Study Influenza Virus

Immunogenicity and Protection Efficacy of Replication-Deficient Influenza A Viruses with Altered NS1 Genes

Attenuating Mutations of the Matrix Gene of Influenza A/WSN/33 Virus

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