Defective interfering viruses and their potential as antiviral agents

Defective interfering (DI) virus is simply defined as a spontaneously generated virus mutant from which a critical portion of the virus genome has been deleted. At least one essential gene of the virus is deleted, either in its entirety, or sufficiently to make it non‐functional. The resulting DI genome is then defective for replication in the absence of the product(s) of the deleted gene(s), and its replication requires the presence of the complete functional virus genome to provide the missing functions. In addition to being defective DI virus suppresses production of the helper virus in co‐infected cells, and this process of interference can readily be observed in cultured cells. In some cases, DI virus has been observed to attenuate disease in virus‐infected animals. In this article, we review the properties of DI virus, potential mechanisms of interference and progress in using DI virus (in particular that derived from influenza A virus) as a novel type of antiviral agent. Copyright © 2009 John Wiley & Sons, Ltd.

[1]  P. Magnus.  The in ovo production of incomplete virus by B/Lee and A/PR 8 influenza viruses , 1965 .

[2]  D. Garcin,et al.  Sendai virus defective-interfering genomes and the activation of interferon-beta. , 2006, Virology.

[3]  N. Dimmock,et al.  Approximately 150 nucleotides from the 5' end of an influenza A segment 1 defective virion RNA are needed for genome stability during passage of defective virus in infected cells. , 2000, Virology.

[4]  J. Holland,et al.  Properties of DI particle resistant mutants of vesicular stomatitis virus isolated from persistent infections and from undiluted passages , 1983, Cell.

[5]  L. A. Ball,et al.  The termini of VSV DI particle RNAs are sufficient to signal RNA encapsidation, replication, and budding to generate infectious particles , 1995, Virology.

[6]  N. Dimmock,et al.  Heterologous protection of mice from a lethal human H1N1 influenza A virus infection by H3N8 equine defective interfering virus: comparison of defective RNA sequences isolated from the DI inoculum and mouse lung. , 1998, Virology.

[7]  C. Rice,et al.  Alphavirus-based expression vectors: strategies and applications. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Schlesinger,et al.  Defective RNAs of Alphaviruses , 1986 .

[9]  S. Fields,et al.  Nucleotide sequences of influenza virus segments 1 and 3 reveal mosaic structure of a small viral RNA segment , 1982, Cell.

[10]  N. Dimmock,et al.  Intracellular stability of the interfering activity of a defective interfering influenza virus in the absence of virus multiplication. , 1987, Virology.

[11]  J. Holland,et al.  Vesicular stomatitis virus and its defective interfering particles exhibit in vitro transcriptional and replicative competition for purified L-NS polymerase molecules. , 1989, Virology.

[12]  C. White,et al.  The genomic sequence of defective interfering Semliki Forest virus (SFV) determines its ability to be replicated in mouse brain and to protect against a lethal SFV infection in vivo. , 1998, Virology.

[13]  Yukiko Muramoto,et al.  Hierarchy among Viral RNA (vRNA) Segments in Their Role in vRNA Incorporation into Influenza A Virions , 2006, Journal of Virology.

[14]  S. Kennedy,et al.  The generation and propagation of defective-interfering particles of Semliki Forest virus in different cell types. , 1978, Virology.

[15]  Yoshihiro Kawaoka,et al.  [Influenza virus receptors in the human airway]. , 2006, Uirusu.

[16]  Yoshihiro Kawaoka,et al.  Exploitation of Nucleic Acid Packaging Signals To Generate a Novel Influenza Virus-Based Vector Stably Expressing Two Foreign Genes , 2003, Journal of Virology.

[17]  S. Whelan,et al.  The 5′ Terminal Trailer Region of Vesicular Stomatitis Virus Contains a Position-Dependent cis-Acting Signal for Assembly of RNA into Infectious Particles , 1999, Journal of Virology.

[18]  D. Nayak,et al.  Defective-interfering (DI) RNAs of influenza viruses: origin, structure, expression, and interference. , 1985, Current topics in microbiology and immunology.

[19]  N. Dimmock,et al.  Protection of mice from lethal influenza: evidence that defective interfering virus modulates the immune response and not virus multiplication. , 1986, The Journal of general virology.

[20]  H. Ly,et al.  Mutational Analyses of Packaging Signals in Influenza Virus PA, PB1, and PB2 Genomic RNA Segments , 2007, Journal of Virology.

[21]  Xuemin Zhang,et al.  A host dicer is required for defective viral RNA production and recombinant virus vector RNA instability for a positive sense RNA virus , 2008, Proceedings of the National Academy of Sciences.

[22]  D. Nayak,et al.  Structure of Defective-Interfering RNAs of Influenza Viruses and Their Role in Interference , 1989 .

[23]  N. Dimmock,et al.  Protection of three strains of mice against lethal influenza in vivo by defective interfering virus. , 1993, Virus research.

[24]  P. I. Marcus,et al.  Interferon induction by viruses. XIX. Vesicular stomatitis virus--New Jersey: high multiplicity passages generate interferon-inducing, defective-interfering particles. , 1989, Virology.

[25]  N. Dimmock.  Antiviral Activity of Defective Interfering Influenza Virus in vivo , 1996 .

[26]  A. J. Bourne,et al.  Sialic acid receptor detection in the human respiratory tract: evidence for widespread distribution of potential binding sites for human and avian influenza viruses , 2007, Respiratory research.

[27]  T. Deng,et al.  A Single Amino Acid Mutation in the PA Subunit of the Influenza Virus RNA Polymerase Promotes the Generation of Defective Interfering RNAs , 2003, Journal of Virology.

[28]  N. Dimmock,et al.  Interfering vaccine: a novel antiviral that converts a potentially virulent infection into one that is subclinical and immunizing. , 2004, Vaccine.

[29]  R. Lamb,et al.  Orthomyxoviridae: The Viruses and Their Replication. , 1996 .

[30]  Yoshihiro Kawaoka,et al.  Avian flu: Influenza virus receptors in the human airway , 2006, Nature.

[31]  T. Kirkwood,et al.  Defective interfering particles and virus evolution. , 1993, Trends in microbiology.

[32]  N. Dimmock,et al.  Protection of mice from lethal influenza by defective interfering virus: T cell responses. , 1992, The Journal of general virology.

[33]  S. Finke,et al.  Virus Promoters Determine Interference by Defective RNAs: Selective Amplification of Mini-RNA Vectors and Rescue from cDNA by a 3′ Copy-Back Ambisense Rabies Virus , 1999, Journal of Virology.

[34]  N. Dimmock,et al.  Defective interfering type A equine influenza virus (H3N8) protects mice from morbidity and mortality caused by homologous and heterologous subtypes of influenza A virus. , 1994, The Journal of general virology.

[35]  N. Dimmock,et al.  One defective interfering particle per cell prevents influenza virus-mediated cytopathology: an efficient assay system. , 1988, Journal of General Virology.

[36]  Ron A M Fouchier,et al.  Immunopathology and Infectious Disease Human and Avian Influenza Viruses Target Different Cells in the Lower Respiratory Tract of Humans and Other Mammals , 2010 .

[37]  Y. Guan,et al.  Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract , 2007, Nature Medicine.

[38]  T. Noda,et al.  Architecture of ribonucleoprotein complexes in influenza A virus particles , 2006, Nature.

[39]  Yuying Liang,et al.  cis-Acting Packaging Signals in the Influenza Virus PB1, PB2, and PA Genomic RNA Segments , 2005, Journal of Virology.

[40]  G. Wertz,et al.  Cells that express all five proteins of vesicular stomatitis virus from cloned cDNAs support replication, assembly, and budding of defective interfering particles. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Nayak,et al.  Defective interfering influenza viruses and host cells: establishment and maintenance of persistent influenza virus infection in MDBK and HeLa cells , 1980, Journal of virology.

[42]  N. Dimmock,et al.  Defective influenza A virus generated entirely from plasmids: its RNA is expressed in infected mouse lung and modulates disease. , 2003, Journal of virological methods.

[43]  A. Huang,et al.  Cyclic production of vesicular stomatitis virus caused by defective interfering particles. , 1974, The Journal of infectious diseases.

[44]  L. Prevec,et al.  Homotypic and Heterotypic Interference by Defective Particles of Vesicular Stomatitis Virus , 1970, Nature.

[45]  A. Osterhaus,et al.  Evidence for specific packaging of the influenza A virus genome from conditionally defective virus particles lacking a polymerase gene. , 2006, Vaccine.

[46]  L. A. Ball,et al.  Infectious defective interfering particles of VSV from transcripts of a cDNA clone , 1992, Cell.

[47]  John J. Holland,et al.  Vesicular stomatitis virus defective interfering particles can contain extensive genomic sequence rearrangements and base substitutions , 1984, Cell.

[48]  Giovanni Cardone,et al.  Influenza virus pleiomorphy characterized by cryoelectron tomography , 2006, Proceedings of the National Academy of Sciences.

[49]  N. Dimmock,et al.  Defective segment 1 RNAs that interfere with production of infectious influenza A virus require at least 150 nucleotides of 5' sequence: evidence from a plasmid-driven system. , 2002, The Journal of general virology.

[50]  J Perrault,et al.  Origin and replication of defective interfering particles. , 1981, Current topics in microbiology and immunology.

[51]  Tokiko Watanabe,et al.  Generation of influenza A viruses entirely from cloned cDNAs. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  J. Holland,et al.  Effects of Defective Interfering Viruses on Virus Replication and Pathogenesis In Vitro and In Vivo , 1991, Advances in Virus Research.

[53]  W. Barclay,et al.  A Reverse Genetics Approach for Recovery of Recombinant Influenza B Viruses Entirely from cDNA , 2002, Journal of Virology.

[54]  J. Holland,et al.  Continuing coevolution of virus and defective interfering particles and of viral genome sequences during undiluted passages: virus mutants exhibiting nearly complete resistance to formerly dominant defective interfering particles , 1987, Journal of virology.

[55]  A. Barrett,et al.  Defective interfering viruses and infections of animals. , 1986, Current topics in microbiology and immunology.

[56]  J. Finch,et al.  Does the higher order structure of the influenza virus ribonucleoprotein guide sequence rearrangements in influenza viral RNA? , 1983, Cell.

[57]  N. Dimmock,et al.  Characterization of putative defective interfering (DI) A/WSN RNAs isolated from the lungs of mice protected from an otherwise lethal respiratory infection with influenza virus A/WSN (H1N1): a subset of the inoculum DI RNAs. , 1995, Virology.

[58]  J. McCauley,et al.  Defective RNAs inhibit the assembly of influenza virus genome segments in a segment-specific manner. , 1996, Virology.

[59]  Rahul Raman,et al.  Transmission and Pathogenesis of Swine-Origin 2009 A(H1N1) Influenza Viruses in Ferrets and Mice , 2009, Science.

[60]  J. Oxford,et al.  Interfering vaccine (defective interfering influenza A virus) protects ferrets from influenza, and allows them to develop solid immunity to reinfection. , 2006, Vaccine.

[61]  D. Baltimore,et al.  Defective Viral Particles and Viral Disease Processes , 1970, Nature.

[62]  P. Magnus.  Incomplete Forms of Influenza Virus , 1954 .

[63]  G. Wertz,et al.  Replication and amplification of defective interfering particle RNAs of vesicular stomatitis virus in cells expressing viral proteins from vectors containing cloned cDNAs , 1990, Journal of virology.

[64]  S. Schlesinger,et al.  Defective interfering particles of Sindbis virus do not interfere with the homologous virus obtained from persistently infected BHK cells but do interfere with Semliki Forest virus , 1981, Journal of virology.

[65]  S. Whelan,et al.  Defective Interfering Particles of Vesicular Stomatitis Virus: Functions of the Genomic Termini☆ , 1997 .

[66]  N. Dimmock,et al.  The receptor preference of influenza viruses , 2010, Influenza and other respiratory viruses.

[67]  M. E. Reichmann,et al.  The size and the cistronic origin of defective vesicular stomatitis virus particle RNAs in relation to homotypic and heterotypic interference. , 1976, Journal of molecular biology.

[68]  N. Dimmock,et al.  In vivo antiviral activity: defective interfering virus protects better against virulent Influenza A virus than avirulent virus. , 2006, The Journal of general virology.

[69]  N. Dimmock,et al.  Influenza Virus Protecting RNA: an Effective Prophylactic and Therapeutic Antiviral , 2008, Journal of Virology.