Influenza viruses that require 10 genomic segments as antiviral therapeutics

English version

Autoři: Alfred T. Harding ^aff001; Griffin D. Haas ^aff001; Benjamin S. Chambers ^aff001; Nicholas S. Heaton ^aff001
Působiště autorů: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States of America ^aff001
Vyšlo v časopise: Influenza viruses that require 10 genomic segments as antiviral therapeutics. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008098
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008098

Souhrn

Influenza A viruses (IAVs) encode their genome across eight, negative sense RNA segments. During viral assembly, the failure to package all eight segments, or packaging a mutated segment, renders the resulting virion incompletely infectious. It is known that the accumulation of these defective particles can limit viral disease by interfering with the spread of fully infectious particles. In order to harness this phenomenon therapeutically, we defined which viral packaging signals were amenable to duplication and developed a viral genetic platform which produced replication competent IAVs that require up to two additional artificial genome segments for full infectivity. The modified and artificial genome segments propagated by this approach are capable of acting as “decoy” segments that, when packaged by coinfecting wild-type viruses, lead to the production of non-infectious viral particles. Although IAVs which require 10 genomic segments for full infectivity are able to replicate themselves and spread in vivo, their genomic modifications render them avirulent in mice. Administration of these viruses, both prophylactically and therapeutically, was able to rescue animals from a lethal influenza virus challenge. Together, our results show that replicating IAVs designed to propagate and spread defective genomic segments represent a potent anti-influenza biological therapy that can target the conserved process of particle assembly to limit viral disease.

Klíčová slova:

Genetic interference – Genomic signal processing – Influenza A virus – Influenza viruses – Mammalian genomics – Viral genomics – Viral replication – Virions

Zdroje

1. WHO. Influenza (Seasonal): The World Health Organization 2018 [updated January 2018November 13th 2018]. Available from: http://www.who.int/mediacentre/factsheets/fs211/en/

2. Iuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet. 2018;391(10127):1285–300. Epub 2017/12/19. doi: 10.1016/S0140-6736(17)33293-2 29248255; PubMed Central PMCID: PMC5935243.

3. Putri W, Muscatello DJ, Stockwell MS, Newall AT. Economic burden of seasonal influenza in the United States. Vaccine. 2018;36(27):3960–6. Epub 2018/05/29. doi: 10.1016/j.vaccine.2018.05.057 29801998.

4. Hussain M, Galvin HD, Haw TY, Nutsford AN, Husain M. Drug resistance in influenza A virus: the epidemiology and management. Infect Drug Resist. 2017;10:121–34. Epub 2017/05/02. doi: 10.2147/IDR.S105473 28458567; PubMed Central PMCID: PMC5404498.

5. Dong G, Peng C, Luo J, Wang C, Han L, Wu B, et al. Adamantane-resistant influenza a viruses in the world (1902–2013): frequency and distribution of M2 gene mutations. PLoS One. 2015;10(3):e0119115. Epub 2015/03/15. doi: 10.1371/journal.pone.0119115 25768797; PubMed Central PMCID: PMC4358984.

6. Bright RA, Medina MJ, Xu XY, Perez-Oronoz G, Wallis TR, Davis XHM, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet. 2005;366(9492):1175–81. doi: 10.1016/S0140-6736(05)67338-2 WOS:000232311300027. 16198766

7. Garten R, Blanton L, Elal AIA, Alabi N, Barnes J, Biggerstaff M, et al. Update: Influenza Activity in the United States During the 2017–18 Season and Composition of the 2018–19 Influenza Vaccine. MMWR Morb Mortal Wkly Rep. 2018;67(22):634–42. Epub 2018/06/08. doi: 10.15585/mmwr.mm6722a4 PubMed Central PMCID: PMC5991814. 29879098

8. Moscona A. Neuraminidase Inhibitors for Influenza. New England Journal of Medicine. 2005;353(13):1363–73. doi: 10.1056/NEJMra050740 16192481

9. Bloom JD, Gong LI, Baltimore D. Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance. Science. 2010;328(5983):1272–5. doi: 10.1126/science.1187816 WOS:000278318600033. 20522774

10. Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother. 2008;52(9):3284–92. doi: 10.1128/AAC.00555-08 WOS:000258667300039. 18625765

11. Monto AS, McKimm-Breschkin JL, Macken C, Hampson AW, Hay A, Klimov A, et al. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother. 2006;50(7):2395–402. doi: 10.1128/AAC.01339-05 WOS:000238721200016. 16801417

12. Barik S. New treatments for influenza. BMC Med. 2012;10:104. Epub 2012/09/15. doi: 10.1186/1741-7015-10-104 22973873; PubMed Central PMCID: PMC3523090.

13. Mullard A. FDA approves first new flu drug in 20 years. Nat Rev Drug Discov. 2018;17(12):853. Epub 2018/11/30. doi: 10.1038/nrd.2018.219 30482963.

14. Dimmock NJ, Easton AJ. Defective interfering influenza virus RNAs: time to reevaluate their clinical potential as broad-spectrum antivirals? J Virol. 2014;88(10):5217–27. Epub 2014/02/28. doi: 10.1128/JVI.03193-13 24574404; PubMed Central PMCID: PMC4019098.

15. Sun Y, Jain D, Koziol-White CJ, Genoyer E, Gilbert M, Tapia K, et al. Immunostimulatory Defective Viral Genomes from Respiratory Syncytial Virus Promote a Strong Innate Antiviral Response during Infection in Mice and Humans. PLoS pathogens. 2015;11(9):e1005122. Epub 2015/09/04. doi: 10.1371/journal.ppat.1005122 26336095; PubMed Central PMCID: PMC4559413.

16. Yount JS, Kraus TA, Horvath CM, Moran TM, Lopez CB. A novel role for viral-defective interfering particles in enhancing dendritic cell maturation. Journal of immunology (Baltimore, Md: 1950). 2006;177(7):4503–13. Epub 2006/09/20. doi: 10.4049/jimmunol.177.7.4503 16982887.

17. Li D, Lott WB, Lowry K, Jones A, Thu HM, Aaskov J. Defective interfering viral particles in acute dengue infections. PLoS One. 2011;6(4):e19447. Epub 2011/05/12. doi: 10.1371/journal.pone.0019447 21559384; PubMed Central PMCID: PMC3084866.

18. Davis AR, Hiti AL, Nayak DP. Influenza defective interfering viral RNA is formed by internal deletion of genomic RNA. Proc Natl Acad Sci U S A. 1980;77(1):215–9. Epub 1980/01/01. doi: 10.1073/pnas.77.1.215 6928614; PubMed Central PMCID: PMC348239.

19. Eisfeld AJ, Neumann G, Kawaoka Y. At the centre: influenza A virus ribonucleoproteins. Nat Rev Microbiol. 2015;13(1):28–41. Epub 2014/11/25. doi: 10.1038/nrmicro3367 25417656; PubMed Central PMCID: PMC5619696.

20. Saira K, Lin X, DePasse JV, Halpin R, Twaddle A, Stockwell T, et al. Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus. J Virol. 2013;87(14):8064–74. Epub 2013/05/17. doi: 10.1128/JVI.00240-13 23678180; PubMed Central PMCID: PMC3700204.

21. Brooke CB. Population Diversity and Collective Interactions during Influenza Virus Infection. J Virol. 2017;91(22). Epub 2017/09/01. doi: 10.1128/JVI.01164-17 28855247; PubMed Central PMCID: PMC5660503.

22. Diefenbacher M, Sun J, Brooke CB. The parts are greater than the whole: the role of semi-infectious particles in influenza A virus biology. Curr Opin Virol. 2018;33:42–6. Epub 2018/07/28. doi: 10.1016/j.coviro.2018.07.002 30053722.

23. Laske T, Heldt FS, Hoffmann H, Frensing T, Reichl U. Modeling the intracellular replication of influenza A virus in the presence of defective interfering RNAs. Virus Research. 2016;213:90–9. doi: 10.1016/j.virusres.2015.11.016 26592173

24. Duhaut SD, McCauley JW. Defective RNAs inhibit the assembly of influenza virus genome segments in a segment-specific manner. Virology. 1996;216(2):326–37. Epub 1996/02/15. doi: 10.1006/viro.1996.0068 8607262.

25. Odagiri T, Tashiro M. Segment-specific noncoding sequences of the influenza virus genome RNA are involved in the specific competition between defective interfering RNA and its progenitor RNA segment at the virion assembly step. J Virol. 1997;71(3):2138–45. Epub 1997/03/01. 9032347; PubMed Central PMCID: PMC191316.

26. Lamb RA, Choppin PW. The Gene Structure and Replication of Influenza Virus. Annual Review of Biochemistry. 1983;52(1):467–506. doi: 10.1146/annurev.bi.52.070183.002343 6351727

27. Huang AS, Palma EL. Chapter 4—Defective Interfering Particles As Antiviral Agents. In: Pollard M, editor. Perspectives in Virology. 9: Elsevier; 1975. p. 77–90.

28. Noble S, McLain L, Dimmock NJ. Interfering vaccine: a novel antiviral that converts a potentially virulent infection into one that is subclinical and immunizing. Vaccine. 2004;22(23–24):3018–25. Epub 2004/08/07. doi: 10.1016/j.vaccine.2004.02.013 15297051.

29. Dimmock NJ, Rainsford EW, Scott PD, Marriott AC. Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral. J Virol. 2008;82(17):8570–8. Epub 2008/06/27. doi: 10.1128/JVI.00743-08 18579602; PubMed Central PMCID: PMC2519629.

30. Dimmock NJ, Dove BK, Scott PD, Meng B, Taylor I, Cheung L, et al. Cloned defective interfering influenza virus protects ferrets from pandemic 2009 influenza A virus and allows protective immunity to be established. PLoS One. 2012;7(12):e49394. Epub 2012/12/20. doi: 10.1371/journal.pone.0049394 23251341; PubMed Central PMCID: PMC3521014.

31. Smith CM, Scott PD, O'Callaghan C, Easton AJ, Dimmock NJ. A Defective Interfering Influenza RNA Inhibits Infectious Influenza Virus Replication in Human Respiratory Tract Cells: A Potential New Human Antiviral. Viruses. 2016;8(8). Epub 2016/08/25. doi: 10.3390/v8080237 27556481; PubMed Central PMCID: PMC4997599.

32. von Magnus P. Incomplete Forms of Influenza Virus. In: Smith KM, Lauffer MA, editors. Advances in Virus Research. 2: Academic Press; 1954. p. 59–79. doi: 10.1016/s0065-3527(08)60529-1 13228257

33. Holland JJ. Generation and replication of defective viral genomes. In: Fields BN, Knipe DM, editors. Fields Virology. 2 ed. New York, NY: Raven Press; 1990. p. 77–99.

34. Gao Q, Lowen AC, Wang TT, Palese P. A nine-segment influenza a virus carrying subtype H1 and H3 hemagglutinins. J Virol. 2010;84(16):8062–71. doi: 10.1128/JVI.00722-10 20519387; PubMed Central PMCID: PMC2916553.

35. Muramoto Y, Takada A, Fujii K, Noda T, Iwatsuki-Horimoto K, Watanabe S, et al. Hierarchy among viral RNA (vRNA) segments in their role in vRNA incorporation into influenza A virions. J Virol. 2006;80(5):2318–25. Epub 2006/02/14. doi: 10.1128/JVI.80.5.2318-2325.2006 16474138; PubMed Central PMCID: PMC1395381.

36. Gao Q, Chou Y-Y, Doğanay S, Vafabakhsh R, Ha T, Palese P. The Influenza A Virus PB2, PA, NP, and M Segments Play a Pivotal Role during Genome Packaging. Journal of Virology. 2012;86(13):7043. doi: 10.1128/JVI.00662-12 22532680

37. Shapiro GI, Gurney T Jr., Krug RM. Influenza virus gene expression: control mechanisms at early and late times of infection and nuclear-cytoplasmic transport of virus-specific RNAs. J Virol. 1987;61(3):764–73. Epub 1987/03/01. 3806797; PubMed Central PMCID: PMC254018.

38. Hatada E, Hasegawa M, Mukaigawa J, Shimizu K, Fukuda R. Control of influenza virus gene expression: quantitative analysis of each viral RNA species in infected cells. J Biochem. 1989;105(4):537–46. Epub 1989/04/01. doi: 10.1093/oxfordjournals.jbchem.a122702 2760014.

39. Kummer S, Flottmann M, Schwanhausser B, Sieben C, Veit M, Selbach M, et al. Alteration of protein levels during influenza virus H1N1 infection in host cells: a proteomic survey of host and virus reveals differential dynamics. PLoS One. 2014;9(4):e94257. Epub 2014/04/11. doi: 10.1371/journal.pone.0094257 24718678; PubMed Central PMCID: PMC3981805.

40. Gao Q, Palese P. Rewiring the RNAs of influenza virus to prevent reassortment. Proc Natl Acad Sci U S A. 2009;106(37):15891–6. Epub 2009/10/07. doi: 10.1073/pnas.0908897106 19805230; PubMed Central PMCID: PMC2747214.

41. Noda T, Sagara H, Yen A, Takada A, Kida H, Cheng RH, et al. Architecture of ribonucleoprotein complexes in influenza A virus particles. Nature. 2006;439(7075):490–2. Epub 2006/01/27. doi: 10.1038/nature04378 16437116.

42. Harding AT, Heaton BE, Dumm RE, Heaton NS. Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs. Mbio. 2017;8(3). ARTN e00669-17 doi: 10.1128/mBio.00669-17 WOS:000404733300050. 28588131

43. Heaton NS, Leyva-Grado VH, Tan GS, Eggink D, Hai R, Palese P. In vivo bioluminescent imaging of influenza a virus infection and characterization of novel cross-protective monoclonal antibodies. J Virol. 2013;87(15):8272–81. doi: 10.1128/JVI.00969-13 23698304; PubMed Central PMCID: PMC3719835.

44. Reuther P, Gopfert K, Dudek AH, Heiner M, Herold S, Schwemmle M. Generation of a variety of stable Influenza A reporter viruses by genetic engineering of the NS gene segment. Sci Rep. 2015;5:11346. Epub 2015/06/13. doi: 10.1038/srep11346 26068081; PubMed Central PMCID: PMC4464305.

45. Fiege JK, Langlois RA. Investigating influenza A virus infection: tools to track infection and limit tropism. J Virol. 2015;89(12):6167–70. doi: 10.1128/JVI.00462-15 25855737; PubMed Central PMCID: PMC4474293.

46. Li J, Arevalo MT, Zeng M. Engineering influenza viral vectors. Bioengineered. 2013;4(1):9–14. Epub 2012/08/28. doi: 10.4161/bioe.21950 22922205; PubMed Central PMCID: PMC3566024.

47. Chou YY, Vafabakhsh R, Doganay S, Gao QS, Ha T, Palese P. One influenza virus particle packages eight unique viral RNAs as shown by FISH analysis. P Natl Acad Sci USA. 2012;109(23):9101–6. doi: 10.1073/pnas.1206069109 WOS:000304991100066. 22547828

48. Nakatsu S, Sagara H, Sakai-Tagawa Y, Sugaya N, Noda T, Kawaoka Y. Complete and Incomplete Genome Packaging of Influenza A and B Viruses. Mbio. 2016;7(5). ARTN e01248-16 doi: 10.1128/mBio.01248-16 WOS:000390132900051. 27601575

49. Brooke CB. Biological activities of 'noninfectious' influenza A virus particles. Future Virol. 2014;9(1):41–51. doi: 10.2217/fvl.13.118 WOS:000335009100009. 25067941

50. Marshall N, Priyamvada L, Ende Z, Steel J, Lowen AC. Influenza Virus Reassortment Occurs with High Frequency in the Absence of Segment Mismatch. Plos Pathog. 2013;9(6). ARTN e1003421 doi: 10.1371/journal.ppat.1003421 WOS:000321206600030. 23785286

51. Jacobs NT, Onuoha NO, Anita A, Anita R, Steel J, Lowen AC. Incomplete influenza A virus genomes are abundant but readily complemented during spatially structured viral spread. bioRxiv. 2019. Epub 1/23/19. https://doi.org/10.1101/529065.

52. Perez JT, Garcia-Sastre A, Manicassamy B. Insertion of a GFP reporter gene in influenza virus. Curr Protoc Microbiol. 2013;Chapter 15:Unit 15G 4. Epub 2013/05/21. doi: 10.1002/9780471729259.mc15g04s29 23686828; PubMed Central PMCID: PMC3878617.