Temperature-sensitive mutants of influenza virus XVI. Transfer of the two ts lesions present in the Udorn/72-ts- 1 A2 donor virus to the Victoria/3/75 wild-type virus

Murphy, Brian R.; Wood, Frank T.; Massicot, Judith G.; Chanock, Robert M.

doi:10.1016/0042-6822(78)90281-7

Cited by 30 publications

(18 citation statements)

References 9 publications

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“…These include the recombination of current, wild-type influenza viruses with strains of low virulence for man, such as A/PR8 or A/Okuda/57 (2,15), and the preparation of temperaturesensitive or cold-adapted virus mutants (10,17). The ts lesion or ca property produced in these latter virus strains can be transferred by recombination to influenza virus strains bearing current haemagg]utinin (HA) and neuraminidase (NA) antigens (22,28). Reduced replication of ts and ca viruses compared to that of their wild-type parent strains in hamster lung tissue has been used to evaluate these viruses, and the possession of the ts property by influenza viruses has been associated with a loss of virulence of these viruses for man (17), and m a y therefore serve as a useful marker of attenuation.…”

Section: Discussionmentioning

confidence: 99%

“…One approach to this problem has been based on the rationale that temperaturesensitive (ts) strains of influenza virus, although able to multiply as well as wildtype parent strains at the lower temperatures found in the nasal passages of man, would be restricted in their replication at the higher temperature present in the lung (15). Thus, one group of workers have produced viruses with ts lesions, and the ts lesions transferred by recombination to current wild-type antigenic variants of type A influenza viruses (22,25,26). Other recombinant viruses have been prepared in a similar way, from a cold-adapted (ca) parent virus (10,12,28).…”

Section: Introductionmentioning

confidence: 98%

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Growth of influenza A viruses in hamsters

Abou-Donia

Jennings

Potter

1980

Archives of Virology

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The growth characteristics of four temperature-sensitive or cold-adapted recombinant influenza viruses and eight recombinant influenza viruses derived in other ways, together with the wild-type, parent viruses of these strains, were tested in hamster lungs and turbinates and in embryonated eggs at different temperatures for their replicative ability. The results showed that although the temperature-sensitive and cold-adapted recombinant viruses replicated to considerably lower titres than their wild-type parent virus strains in hamster lung and at 37 degrees C in embryonated eggs, no similar pattern of growth was observed for the group of A/PR 8 and A/Okuda recombinant influenza viruses studied in these systems. The hamster model is not therefore generally applicable as a marker for attenuated influenza virus vaccine strains.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Growth of influenza A viruses in hamsters

Abou-Donia

Jennings

Potter

1980

Archives of Virology

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“…This virus was m a d e b y m a t i n g two ts viruses, one t h a t possessed a ts m u t a t i o n on the P 3 gene and the other a ts m u t a t i o n on the P1 gene (3). To evaluate the ability of this donor virus to a t t e n u a t e new wild t y p e viruses, it was m a t e d with the influenza A/Victoria/3/75 ( H 3 N 2 ) wild t y p e virus, and six ts recombinant viruses bearing the Vic/75 hemagglutinin were isolated (4). Five of the Vic/75-ts-lA2 recombinants t h a t had a 37°C shutoff t e m p e r a t u r e and the two ts lesions of their Udorrt/72-ts-lA2 parent replicated to low titer or not at all in the hamster's lungs and were 100-fold restricted in the nasal t u r b i n a t e s like their ts parental virus (4).…”

Section: Introductionmentioning

confidence: 99%

“…To evaluate the ability of this donor virus to a t t e n u a t e new wild t y p e viruses, it was m a t e d with the influenza A/Victoria/3/75 ( H 3 N 2 ) wild t y p e virus, and six ts recombinant viruses bearing the Vic/75 hemagglutinin were isolated (4). Five of the Vic/75-ts-lA2 recombinants t h a t had a 37°C shutoff t e m p e r a t u r e and the two ts lesions of their Udorrt/72-ts-lA2 parent replicated to low titer or not at all in the hamster's lungs and were 100-fold restricted in the nasal t u r b i n a t e s like their ts parental virus (4). Since the parental and double-lesion recombinant t s -l A 2 viruses exhibited a similar restriction of replication in vitro at 37 ° C and in vivo, it appeared likely t h a t the two t s -l A 2 ts lesions would effect a similar level of a t t e n u a t i o n following transfer into other antigenic variants of influenza A virus.…”

Section: Introductionmentioning

confidence: 99%

Temperature-sensitive mutants of influenza A virus. Transfer of the twots-1 A 2ts lesions present in the Udorn/72-ts-1 A 2 donor virus to the influenza A/Alaska/6/77 (H 3 N 2) wild type virus

Murphy

Wood

Massicot

et al. 1980

Archives of Virology

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The Udorn/72-ts-1A2 temperature-sensitive influenza A virus has a 37 degrees C shutoff temperature and a ts mutation on the genes coding for the P1 and P3 proteins. This ts donor virus was produced with the expectation that the transfer of its two ts genes would regularly and predictably attenuate each new variant of influenza A virus. It had previously been mated with the A/Victoria/75 (H3N2) virus and five Vic/75-ts-1A2 rcombinants were isolated that had both ts-1A2 ts genes and in vitro and in vivo genetic and biological properties similar to their Udorn/72-ts-1A2 parent. The present study was designed to determine if the acquisition of the two ts-1A2 ts genes would also confer a specific level of attenuation on the influenza A/Alaska/6/77 (H3N2) wild type virus. Fifteen recombinant Alaska/77-ts-1A2 viruses were isolated and characterized genetically for the number and location of ts mutations. These clones were also studied for their level of replication and genetic stability in hamsters. Four recombinants possessed both of the ts-1A2 mutations and had a 37 degrees C shutoff temperature for plaque formation. Two recombinants possessed only a ts P1 gene and had either a 38 degrees C or 39 degrees C shutoff temperature. The remaining nine clones had the ts P3 gene and a shutoff temperature of 37 degrees C, 38 degrees C or 39 degrees C. Each of the four 37 degrees C shutoff temperature recombinants that possessed both ts P1 and P3 genes were restricted at least 10,000-fold in replication in the hamster's lung and approximately 100-fold in the nasal turbinates compared to the level of replication of wild type virus in these sites. All isolates from these animals retained the ts phenotype. The level of replication in vivo of the ts P1 and P3 segregants was related to their shutoff temperature of plaque formation in vitro, e.g. the 38 degrees C ts P3 segregant was less restricted in replication in the lungs than a 37 degrees C ts P3 segregant. All isolates from animals infected with the ts P3 segregants were ts, whereas a low level of genetic instability was detected for one of the ts P1 segregants. Since ten independent ts-1A2 recombinants (one Udorn/72, 5 Victoria/75 and 4 Alaska/77) with both ts-1A2 mutations exhibited the same genetic and biologic properties, it is likely that these ts P1 and P3 genes were the prime determinants of attenuation and could effect a similar level of attenuation in other influenza A viruses within the H3N2 subtype.

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“…Studiesofts reassortant viruses derived from A/Udorn/72-ts-lA2 donor virus previously demonstrated that the ts genes of the donor virus are responsible for attenuation in humans (6) and that the shutoff temperatures of plaque formation in vitro is related to the level of the viral replication in the lungs of hamsters (5). The function of the ts property in attenuation of the A/Ann Arbor/6/60 donor virus is still obscure, however, since the ca reassortants bearing different shutoff temperatures do not show a significant variation in their level of attenuation for humans (9).…”

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confidence: 99%