Temperature Sensitive Mutations in Influenza A Viral Ribonucleoprotein Complex Responsible for the Attenuation of the Live Attenuated Influenza Vaccine

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2018 Oct 18

PMID 30326610

Citations 23

Authors

Luis Martinez-Sobrido

Olve Peersen

Aitor Nogales

Affiliations

Soon will be listed here.

Abstract

Live attenuated influenza vaccines (LAIV) have prevented morbidity and mortality associated with influenza viral infections for many years and represent the best therapeutic option to protect against influenza viral infections in humans. However, the development of LAIV has traditionally relied on empirical methods, such as the adaptation of viruses to replicate at low temperatures. These approaches require an extensive investment of time and resources before identifying potential vaccine candidates that can be safely implemented as LAIV to protect humans. In addition, the mechanism of attenuation of these vaccines is poorly understood in some cases. Importantly, LAIV are more efficacious than inactivated vaccines because their ability to mount efficient innate and adaptive humoral and cellular immune responses. Therefore, the design of potential LAIV based on known properties of viral proteins appears to be a highly appropriate option for the treatment of influenza viral infections. For that, the viral RNA synthesis machinery has been a research focus to identify key amino acid substitutions that can lead to viral attenuation and their use in safe, immunogenic, and protective LAIV. In this review, we discuss the potential to manipulate the influenza viral RNA-dependent RNA polymerase (RdRp) complex to generate attenuated forms of the virus that can be used as LAIV for the treatment of influenza viral infections, one of the current and most effective prophylactic options for the control of influenza in humans.

Citing Articles

Are we serologically prepared against an avian influenza pandemic and could seasonal flu vaccines help us?.

Sanz-Munoz I, Sanchez-Martinez J, Rodriguez-Crespo C, Concha-Santos C, Hernandez M, Rojo-Rello S mBio. 2025; 16(2):e0372124.

PMID: 39745389 PMC: 11796349. DOI: 10.1128/mbio.03721-24.

Interferon signaling in the nasal epithelium distinguishes among lethal and common cold coronaviruses and mediates viral clearance.

Otter C, Renner D, Fausto A, Tan L, Cohen N, Weiss S Proc Natl Acad Sci U S A. 2024; 121(21):e2402540121.

PMID: 38758698 PMC: 11127059. DOI: 10.1073/pnas.2402540121.

Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1.

Khalil A, Nogales A, Martinez-Sobrido L, Mostafa A Front Cell Infect Microbiol. 2024; 14:1357866.

PMID: 38375361 PMC: 10875036. DOI: 10.3389/fcimb.2024.1357866.

Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance.

Otter C, Renner D, Fausto A, Tan L, Cohen N, Weiss S bioRxiv. 2024; .

PMID: 38187597 PMC: 10769301. DOI: 10.1101/2023.12.18.571720.

Nucleoprotein as a Promising Antigen for Broadly Protective Influenza Vaccines.

Rak A, Isakova-Sivak I, Rudenko L Vaccines (Basel). 2023; 11(12).

PMID: 38140152 PMC: 10747533. DOI: 10.3390/vaccines11121747.

References

Maassab H, Bryant M . The development of live attenuated cold-adapted influenza virus vaccine for humans. Rev Med Virol. 1999; 9(4):237-44. DOI: 10.1002/(sici)1099-1654(199910/12)9:4<237::aid-rmv252>3.0.co;2-g. View

Naffakh N, van der Werf S . Comparative analysis of the ability of the polymerase complexes of influenza viruses type A, B and C to assemble into functional RNPs that allow expression and replication of heterotypic model RNA templates in vivo. Virology. 1999; 265(2):342-53. DOI: 10.1006/viro.1999.0059. View

Gubareva L, Kaiser L, Hayden F . Influenza virus neuraminidase inhibitors. Lancet. 2000; 355(9206):827-35. DOI: 10.1016/S0140-6736(99)11433-8. View

Osterhaus A, Rimmelzwaan G, Martina B, Bestebroer T, Fouchier R . Influenza B virus in seals. Science. 2000; 288(5468):1051-3. DOI: 10.1126/science.288.5468.1051. View

Ali A, Avalos R, Ponimaskin E, Nayak D . Influenza virus assembly: effect of influenza virus glycoproteins on the membrane association of M1 protein. J Virol. 2000; 74(18):8709-19. PMC: 116382. DOI: 10.1128/jvi.74.18.8709-8719.2000. View

Perez D, Donis R . Functional analysis of PA binding by influenza a virus PB1: effects on polymerase activity and viral infectivity. J Virol. 2001; 75(17):8127-36. PMC: 115057. DOI: 10.1128/jvi.75.17.8127-8136.2001. View

Youngner J, Whitaker-Dowling P, Chambers T, Rushlow K, Sebring R . Derivation and characterization of a live attenuated equine influenza vaccine virus. Am J Vet Res. 2001; 62(8):1290-4. DOI: 10.2460/ajvr.2001.62.1290. View

Chambers T, Holland R, Tudor L, Townsend H, Cook A, Bogdan J . A new modified live equine influenza virus vaccine: phenotypic stability, restricted spread and efficacy against heterologous virus challenge. Equine Vet J. 2002; 33(7):630-6. DOI: 10.2746/042516401776249291. View

Lee M, Bishop K, Medcalf L, Elton D, Digard P, Tiley L . Definition of the minimal viral components required for the initiation of unprimed RNA synthesis by influenza virus RNA polymerase. Nucleic Acids Res. 2002; 30(2):429-38. PMC: 99831. DOI: 10.1093/nar/30.2.429. View

10.

Thompson W, Shay D, Weintraub E, Brammer L, Cox N, Anderson L . Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003; 289(2):179-86. DOI: 10.1001/jama.289.2.179. View

11.

Jin H, Lu B, Zhou H, Ma C, Zhao J, Yang C . Multiple amino acid residues confer temperature sensitivity to human influenza virus vaccine strains (FluMist) derived from cold-adapted A/Ann Arbor/6/60. Virology. 2003; 306(1):18-24. DOI: 10.1016/s0042-6822(02)00035-1. View

12.

Jin H, Zhou H, Lu B, Kemble G . Imparting temperature sensitivity and attenuation in ferrets to A/Puerto Rico/8/34 influenza virus by transferring the genetic signature for temperature sensitivity from cold-adapted A/Ann Arbor/6/60. J Virol. 2003; 78(2):995-8. PMC: 368857. DOI: 10.1128/jvi.78.2.995-998.2004. View

13.

Poole E, Elton D, Medcalf L, Digard P . Functional domains of the influenza A virus PB2 protein: identification of NP- and PB1-binding sites. Virology. 2004; 321(1):120-33. DOI: 10.1016/j.virol.2003.12.022. View

14.

Falcon A, Marion R, Zurcher T, Gomez P, Portela A, Nieto A . Defective RNA replication and late gene expression in temperature-sensitive influenza viruses expressing deleted forms of the NS1 protein. J Virol. 2004; 78(8):3880-8. PMC: 374278. DOI: 10.1128/jvi.78.8.3880-3888.2004. View

15.

Xu X, Lindstrom S, Shaw M, Smith C, Hall H, Mungall B . Reassortment and evolution of current human influenza A and B viruses. Virus Res. 2004; 103(1-2):55-60. DOI: 10.1016/j.virusres.2004.02.013. View

16.

Liu T, Ye Z . Introduction of a temperature-sensitive phenotype into influenza A/WSN/33 virus by altering the basic amino acid domain of influenza virus matrix protein. J Virol. 2004; 78(18):9585-91. PMC: 514994. DOI: 10.1128/JVI.78.18.9585-9591.2004. View

17.

McCullers J, Saito T, Iverson A . Multiple genotypes of influenza B virus circulated between 1979 and 2003. J Virol. 2004; 78(23):12817-28. PMC: 525012. DOI: 10.1128/JVI.78.23.12817-12828.2004. View

18.

Nayak D, Hui E, Barman S . Assembly and budding of influenza virus. Virus Res. 2004; 106(2):147-65. PMC: 7172797. DOI: 10.1016/j.virusres.2004.08.012. View

19.

Hoffmann E, Mahmood K, Chen Z, Yang C, Spaete J, Greenberg H . Multiple gene segments control the temperature sensitivity and attenuation phenotypes of ca B/Ann Arbor/1/66. J Virol. 2005; 79(17):11014-21. PMC: 1193632. DOI: 10.1128/JVI.79.17.11014-11021.2005. View

20.

Schmitt A, Lamb R . Influenza virus assembly and budding at the viral budozone. Adv Virus Res. 2005; 64:383-416. DOI: 10.1016/S0065-3527(05)64012-2. View