A ts+ ca− (non-temperature-sensitive, non-cold-adapted) revertant of the A/Leningrad/134/47/57 ca strain influenza virus [A/Leningrad/134/47/ts+18/1957(H2N2)], obtained in our previous study, lost phenotypic manifestation of ts mutations by the PB2, NP and NS genes, although, according to sequencing data, it acquired only two true reversions of a mutation in the PB2 and PB1 genes. Direct sequencing showed the appearance of 27 additional mutations (13 coding) in the genes encoding the PB2, PB1, PA, NP, M and NS proteins of the revertant, along with the above-mentioned two true reversions. We conjecture that some of these mutations suppressed phenotypic manifestation of ts mutations in the NS and NP genes.
AlboC.,
ValenciaA.,
PortelaA.1995; Identification of an RNA binding region within the N-terminal third of the influenza A virus nucleoprotein. J Virol 69:3799–3806
BuonagurioD. A.,
O'NeillR. E.,
ShutyakL.,
D'ArcoG. A.,
BechertT. M.,
KazachkovY.,
WangH. P.,
DeStefanoJ.,
CoelinghK. L.other authors2006; Genetic and phenotypic stability of cold-adapted influenza viruses in a trivalent vaccine administered to children in a day care setting. Virology 347:296–306[CrossRef]
ChaT. A.,
ZhaoJ.,
LaneE.,
MurrayM. A.,
StecD. S.1997; Determination of the genome composition of influenza virus reassortants using multiplex reverse transcription-polymerase chain reaction followed by fluorescent single-strand conformation polymorphism analysis. Anal Biochem 252:24–32[CrossRef]
FalconA. M.,
FortesP.,
MarionR. M.,
BelosoA.,
OrtinJ.1999; Interaction of influenza virus NS1 protein and the human homologue of Staufen in vivo and in vitro
. Nucleic Acids Res 27:2241–2247[CrossRef]
GhendonY.1998; Cold-adapted, live influenza vaccines developed in Russia. In Textbook of Influenza pp 391–399 Edited by
NicholsonK. G.,
WebsterR. G.,
HayA. J.
Oxford: Blackwell Science;
GhendonY. Z.,
KlimovA. I.,
AlexandrovaG. I.,
PolezhaevF. I.1981; Analysis of genome composition and reactogenicity of recombinants of cold-adapted and virulent virus strains. J Gen Virol 53:215–224[CrossRef]
GhendonY. Z.,
MarkushinS. G.,
LisovskayaK.,
PennC. R.,
MahyB. W. J.1982; Extragenic suppression of a ts phenotype during recombination between ts mutants of two fowl plague virus strains with a ts mutation in gene 1
. J Gen Virol 62:239–248[CrossRef]
KiselevaI.,
SuQ.,
TonerT. J.,
SzymkowiakC.,
KwanW. S.,
RudenkoL.,
ShawA. R.,
YouilR.2004; Cell-based assay for the determination of temperature sensitive and cold adapted phenotypes of influenza viruses. J Virol Methods 116:71–78[CrossRef]
KlimovA. I.,
CoxN. J.1995; PCR restriction analysis of genome composition and stability of cold-adapted reassortant live influenza vaccines. J Virol Methods 52:41–49[CrossRef]
KlimovA. I.,
CoxN. J.,
YotovW. V.,
RochaE.,
AlexandrovaG. I.,
KendalA. P.1992; Sequence changes in the live attenuated, cold-adapted variants of influenza A/Leningrad/134/57 (H2N2) virus. Virology 186:795–797[CrossRef]
KlimovA. I.,
EgorovA. Y.,
GushinaM. I.,
MedvedevaT. E.,
GambleW. C.,
RudenkoL. G.,
AlexandrovaG. I.,
CoxN. J.1995; Genetic stability of cold-adapted A/Leningrad/134/47/57 (H2N2) influenza virus: sequence analysis of live cold-adapted reassortant vaccine strains before and after replication in children. J Gen Virol 76:1521–1525[CrossRef]
KlimovA. I.,
KiselevaI. V.,
AlexandrovaG. I.,
CoxN. J.2001; Genes coding for polymerase proteins are essential for attenuation of the cold-adapted A/Leningrad/134/47/57 (H2N2) influenza virus. In Options for the Control of Influenza IV , Int Congr Servol 1219 pp 955–959 Edited by
OsterhausA.,
CoxN.,
HampsonA.
Amsterdam: Elsevier;
LambR. A.,
KrugR. M.2001; Orthomyxoviridae : the viruses and their replication. In Fields Virology, 4th edn. pp 1487–1531 Edited by
KnippeD. M.,
HowleyP. M.
Philadelphia: Lippincott Williams & Wilkins;
MarionR. M.,
AragonT.,
BelosoA.,
NietoA.,
OrtinJ.1997; The N-terminal half of the influenza virus NS1 protein is sufficient for nuclear retention of mRNA and enhancement of viral mRNA translation. Nucleic Acids Res 25:4271–4277[CrossRef]
MarkushinS. G.,
AkopovaI. I.,
KoptyajevaI. B.,
TsfasmanT. M.,
GhendonY. Z.2006; Molecular mechanisms of reversion to the ts+phenotype of cold-adapted influenza A strains – attenuation donors for the influenza reassortant live attenuated vaccines. Vopr Virusol 51:17–22 (in Russian
NevedomskaiaG. N.,
MedvedevaT. E.,
ZhikharevaI. V.,
KlimovA. I.,
AleksandrovaG. I.1992; The evaluation of the degree of attenuation of cold-adapted influenza A virus strains in CBA-strain mouse and Syrian hamster models. Vopr Virusol 37:37–40 (in Russian
QianX. Y.,
Alonso-CaplenF.,
KrugR. M.1994; Two functional domains of the influenza virus NS1 protein are required for regulation of nuclear export of mRNA. J Virol 68:2433–2441
QuinlivanM.,
ZamarinD.,
Garcia-SastreA.,
CullinaneA.,
ChambersT.,
PaleseP.2005; Attenuation of equine influenza viruses through truncations of the NS1 protein. J Virol 79:8431–8439[CrossRef]
ScholtissekC.,
SpringS. B.1982; Extragenic suppression of temperature-sensitive mutations in RNA segment 8 by replacement of different RNA segments with those of other influenza A virus prototype strains. Virology 118:28–34[CrossRef]
StasakovaJ.,
FerkoB.,
KittelC.,
SereinigS.,
RomanovaJ.,
KatingerH.,
EgorovA.2005; Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1 β and 18. J Gen Virol 86:185–195[CrossRef]
TreanorJ. J.,
BujaR.,
MurphyB. R.1991; Intragenic suppression of a deletion mutation of the nonstructural gene of an influenza A virus. J Virol 65:4204–4210
TreanorJ. J.,
PerkinsM.,
BattagliaR.,
MurphyB. R.1994; Evaluation of the genetic stability of the temperature-sensitive PB2 gene mutation of the influenza A/Ann Arbor/6/60 cold-adapted vaccine virus. J Virol 68:7684–7688