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Influenza virus protecting RNA : an effective prophylactic and therapeutic antiviral

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Dimmock, N. J., Rainsford, Edward W., Scott, P. D. (Paul D.) and Marriott, Anthony C.. (2008) Influenza virus protecting RNA : an effective prophylactic and therapeutic antiviral. Journal of Virology, Vol.82 (No.17). pp. 8570-8578. ISSN 0022-538X

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Official URL: http://dx.doi.org/10.1128/JVI.00743-08

Abstract

Another influenza pandemic is inevitable, and new measures to combat this and seasonal
influenza are urgently needed. Here we describe a new concept in antivirals based on a
defined, naturally occurring defective influenza RNA that has the potential to protect against
any influenza A virus in any animal host. This protecting RNA (244 RNA) is incorporated
into virions which although non-infectious, deliver the RNA to those cells of the respiratory
tract that are naturally targeted by infectious influenza virus. A small intranasal dose of this
244 protecting virus (120 ng) completely protected mice against a simultaneous lethal (10
LD50) challenge with influenza A/WSN (H1N1) virus. 244 virus also protected mice against
a strong challenge dose of all other subtypes tested (H2N2, H3N2, H3N8). This prophylactic
activity was maintained in the animal for at least 1 week prior to challenge. 244 virus was 10
to 100-fold more active than previously characterised influenza A defective viruses, and the
protecting activity was confirmed to reside in the 244 RNA molecule by recovering a
protecting virus entirely from cloned cDNA. There was clear therapeutic benefit when
protecting 244 virus was administered 24-48 h after lethal challenge, an effect which has not
been previously observed with any defective virus. Protecting virus reduced, but did not
abolish, replication of challenge virus in mouse lungs during both prophylactic and
therapeutic treatments. Protecting virus is a novel antiviral which has the potential to combat
influenza infections in humans, particularly when the infecting strain is not known, or is
resistant to antiviral drugs.

Item Type:

Journal Article

Subjects:

R Medicine > RM Therapeutics. Pharmacology

Divisions:

Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010)

Library of Congress Subject Headings (LCSH):

Influenza -- Treatment, Influenza A virus, Antiviral agents, RNA viruses

Journal or Publication Title:

Journal of Virology

Publisher:

American Society for Microbiology

ISSN:

0022-538X

Official Date:

September 2008

Dates:

Date	Event
September 2008	Published

Volume:

Vol.82

Number:

No.17

Number of Pages:

Page Range:

pp. 8570-8578

Identification Number:

10.1128/JVI.00743-08

Status:

Peer Reviewed

Access rights to Published version:

Restricted or Subscription Access

Funder:

Mercia Spinner

References:

1. Aronsson, F., B. Robertson, H. G. Ljunggren, and K. Kristensson. 2003. Invasion
and persistence of the neuroadapted influenza virus A/NWS/33 in the mouse olfactory
system. Viral Immunology 16:415-423.
2. Belshe, R. B., K. L. Nichol, S. B. Black, H. Shinefield, J. Cordova, R. Walker, C.
Hessel, I. Cho, and P. M. Mendelman. 2004. Safety, efficacy, and effectiveness of
live attenuated, cold-adapted influenza vaccine in an indicated population aged 5-49
years. Clinical Infectious Diseases 39:920-927.
3. Cane, C., and N. J. Dimmock. 1990. Intracellular stability of the gene encoding
influenza virus haemagglutinin. Virology 175:385-390.
4. Cane, C., L. McLain, and N. J. Dimmock. 1987. Intracellular stability of the
interfering activity of a defective interfering influenza virus in the absence of virus
multiplication. Virology 159:259-264.
5. Cox, N. J., and K. Subbarao. 2000. Global epidemiology of influenza: past and
present. Annual Review of Medicine 51:407-421.
6. Cox, N. J., and K. Subbarao. 1999. Influenza. The Lancet 354:1277-1282.
7. Dimmock, N. J. 1996. Antiviral activity of defective interfering influenza virus in
vivo, p. 421-445. In S. Myint and D. Taylor-Robinson (ed.), Viral and Other Infections
of the Respiratory Tract. Chapman and Hall, London.
8. Dimmock, N. J., and A. C. Marriott. 2006. In vivo antiviral activity: defective
interfering virus protects better against virulent influenza A virus than avirulent virus.
J. Gen. Virol. 87:In press.
9. Doherty, P. C., D. J. Topham, and R. A. Tripp. 1996. Establishment and persistence
of virus-specific CD4+ and CD8+ T cell memory. Immunological Reviews 150:23-44.
10. Duhaut, S. D., and N. J. Dimmock. 2003. Defective influenza A virus generated
entirely from plasmids: its RNA is expressed in infected mouse lung and modulates
disease. Journal of Virological Methods 108:75-82.
11. Duhaut, S. D., and N. J. Dimmock. 1998. Heterologous protection against a lethal
human H1N1 influenza virus infection of mice by a H3N8 equine defective interfering
virus: comparison of defective RNA sequences isolated from the DI inoculum and
mouse lung. Virology 248:241-253.
12. Eichelberger, M. C., M. Wang, W. Allan, R. G. Webster, and P. C. Doherty. 1991.
Influenza virus RNA in the lung and lymphoid tissue of immunologically intact and
CD4-depleted mice. Journal of General Virology 72:1695-1698.
13. Hayden, F. G. 2006. Antiviral resistance in influenza viruses - implications for
management and pandemic response. New England Journal of Medicine 354:785-788.
14. Holland, J. J. 1990. Generation and replication of defective viral genomes, p. 77-99.
In B. N. Fields and D. M. Knipe (ed.), Virology, 2nd ed. Raven Press, New York.
15. Huang, A. S., and D. Baltimore. 1970. Defective viral particles and viral disease
processes. Nature (London) 226:325-327.
16. Jennings, P. A., J. T. Finch, G. Winter, and J. S. Robertson. 1983. Does the higher
order of the influenza virus ribonucleoprotein guide sequence rearrangements in
influenza viral RNA. Cell 34:619-627.
17. Karber, G. 1968. p. 118. In A. J. Rhodes and C. E. van Rooyen (ed.), Textbook of
Virology, 5th ed. Williams and Wilkins Co., Baltimore.
18. Lamb, R. A., and R. M. Krug. 1996. Orthomyxoviridae: the viruses and their
replication, p. 1353-1395. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.),
Fields Virology, 3rd ed, vol. 1. Lippincott-Raven Publishers, Philadelphia.
19. Le, Q. L., M. Kiso, K. Someya, Y. Sakai, N. D. Nguyen, K. L. H. Nguyen, N. D.
Pham, H. H. Ngyen, S. Yamada, Y. Muramoto, T. Horimoto, A. Takada, H. Goto,
T. Suzuki, Y. Suzuki, and Y. Kawaoka. 2005. Isolation of drug-resistant H5N1 virus.
Nature (London) 437:1108.
20. Mann, A., A. C. Marriott, S. Balasingam, R. Lambkin, J. S. Oxford, and N. J.
Dimmock. 2006. Interfering vaccine (defective interfering influenza A virus) protects
ferrets from influenza, and allows them to develop solid immunity to reinfection.
Vaccine 24:4290-4296.
21. Mayor, S. 2006. Review says oseltamivir and zanamivir should be kept for epidemics
of flu. British Medical Journal 332:196.
22. Neumann, G., T. Watanabe, H. Ito, S. Watanabe, H. Goto, P. Gao, M. Hughes, D.
R. Perez, R. Donis, G. Hobom, and Y. Kawaoka. 1999. Generation of influenza A
viruses entirely from cloned DNAs. Proceedings of the National Academy of Sciences
of the United States of America 96:9345-9350.
23. Noble, S., and N. J. Dimmock. 1994. Defective interfering type A equine influenza
virus (H3N8) protects mice from morbidity and mortality caused by homologous and
heterologous subtypes of type A influenza virus. Journal of General Virology
75:3485-3491.
24. Noble, S., L. McLain, and N. J. Dimmock. 2004. Interfering vaccine: a novel
antiviral that converts a potentially virulent infection into one that is subclinical and
immunizing. Vaccine 22:3018-3025.
25. Noda, T., H. Sagara, A. Yen, A. Takada, H. Kida, R. H. Cheng, and Y. Kawaoka.
2006. Architecture of ribonucleoprotein complexes in influenza A virus particles.
Nature (London) 439:490-492.
26. Park, C. H., K. Matsuda, Y. Sunden, A. Ninomiya, A. Takada, H. Ito, T. Kimura,
K. Ochiai, and T. Umemura. 2003. Persistence of viral RNA segments in the central
nervous system of mice after recovery from acute influenza A virus infection.
Veterinary Microbiology 97:259-268.
27. Russell, C. J., and R. G. Webster. 2005. The genesis of a pandemic influenza virus.
Cell 123:368-371.
28. Sekellick, M. J., and P. I. Marcus. 1982. Interferon induction by viruses. VIII
Vesicular stomatitis virus: [+/-] DI-011 particles induce interferon in the absence of
standard virions. Virology 117:280-285.
29. Shinya, K., M. Ebina, S. Yamada, M. Ono, N. Kasai, and Y. Kawaoka. 2006.
Influenza virus receptors in the human airway. Nature (London) 440:435-436.
30. Simon, A. E., M. J. Roossinck, and Z. Havelda. 2004. Plant virus satellite and
defective interfering RNAs: new paradigms for a new century. Annual Review of
Phytopathology 42:415-437.
31. Strahle, L., D. Garcin, and D. Kolakofsky. 2006. Sendai defective-interfering
genomes and the activation of interferon-beta. Virology 351:101-111.
32. Subbarao, K., H. Chen, D. Swayne, L. Mingay, E. Fodor, G. Brownlee, X. Xu, X.
Lu, J. Katz, N. Cox, and Y. Matsuoka. 2003. Evaluation of a genetically modified
reassortant H5N1 influenza A virus vaccine candidate by plasmid-based reverse
genetics. Virology 305:192-200.
33. Sweet, C., and H. Smith. 1980. Pathogenicity of influenza virus. Microbiological
Reviews 44:303-330.
34. Taubenberger, J. K., A. H. Reid, R. M. Lourens, R. Wang, G. Jin, and T. G.
Fanning. 2005. Characterization of the 1918 influenza virus polymerase genes.
Nature (London) 437:889-893.
35. Wang, M., and R. G. Webster. 1990. Lack of persistence of influenza virus genetic
information in ducks. Archives of Virology 111:263-267.
36. Wang, X.-H., R. Aliyari, W.-X. Li, H.-W. Li, K. Kim, R. Carthew, P. Atkinson,
and S.-W. Ding. 2006. RNA interference directs innate immunity against viruses in
adult Drosophila. Science 312:452-454.
37. Webster, R. G., W. J. Bean, O. T. Gorman, T. M. Chambers, and Y. Kawaoka.
1992. Evolution and ecology of influenza A viruses. Microbiological Reviews 56:152-
179.