Editing Defective interfering particle

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[[File:RF00496.jpg|thumbnail|Predicted secondary structure of the [[Coronavirus SL-III cis-acting replication element]], a genomic structure required for BCoV DI RNA replication<ref name=BovineCorona>{{cite journal | vauthors = Raman S, Bouma P, Williams GD, Brian DA | title = Stem-loop III in the 5' untranslated region is a cis-acting element in bovine coronavirus defective interfering RNA replication | journal = Journal of Virology | volume = 77 | issue = 12 | pages = 6720–6730 | date = June 2003 | pmid = 12767992 | pmc = 156170 | doi = 10.1128/JVI.77.12.6720-6730.2003 }}</ref>]]
'''Defective interfering particles''' ('''DIPs'''), also known as '''defective interfering viruses''', are spontaneously generated [[virus]] mutants in which a critical portion of the particle's genome has been lost due to defective replication or [[non-homologous recombination]].<ref>{{cite journal | vauthors = White KA, Morris TJ | title = Nonhomologous RNA recombination in tombusviruses: generation and evolution of defective interfering RNAs by stepwise deletions | journal = Journal of Virology | volume = 68 | issue = 1 | pages = 14–24 | date = January 1994 | pmid = 8254723 | pmc = 236259 | doi = 10.1128/JVI.68.1.14-24.1994 }}</ref><ref name=AntiviralDIPs>{{cite journal | vauthors = Marriott AC, Dimmock NJ | title = Defective interfering viruses and their potential as antiviral agents | journal = Reviews in Medical Virology | volume = 20 | issue = 1 | pages = 51–62 | date = January 2010 | pmid = 20041441 | doi = 10.1002/rmv.641 | s2cid = 26359078 }}</ref> The mechanism of their formation is presumed to be as a result of template-switching during replication of the viral genome, although non-replicative mechanisms involving direct ligation of genomic RNA fragments have also been proposed.<ref name="Pathak"/><ref>{{cite journal | vauthors = Gmyl AP, Belousov EV, Maslova SV, Khitrina EV, Chetverin AB, Agol VI | title = Nonreplicative RNA recombination in poliovirus | journal = Journal of Virology | volume = 73 | issue = 11 | pages = 8958–8965 | date = November 1999 | pmid = 10516001 | pmc = 112927 | doi = 10.1128/JVI.73.11.8958-8965.1999 }}</ref> DIPs are derived from and associated with their parent virus, and particles are classed as DIPs if they are rendered non-infectious due to at least one essential gene of the virus being lost or severely damaged as a result of the defection.<ref name=Pathak>{{cite journal | vauthors = Pathak KB, Nagy PD | title = Defective Interfering RNAs: Foes of Viruses and Friends of Virologists | journal = Viruses | volume = 1 | issue = 3 | pages = 895–919 | date = December 2009 | pmid = 21994575 | pmc = 3185524 | doi = 10.3390/v1030895 | doi-access = free }}</ref> A DIP can usually still penetrate host cells, but requires another fully functional virus particle (the 'helper' virus) to [[coinfection|co-infect]] a cell with it, in order to provide the lost factors.<ref name=Makino>{{cite journal | vauthors = Makino S, Shieh CK, Soe LH, Baker SC, Lai MM | title = Primary structure and translation of a defective interfering RNA of murine coronavirus | journal = Virology | volume = 166 | issue = 2 | pages = 550–560 | date = October 1988 | pmid = 2845661 | pmc = 7131284 | doi = 10.1016/0042-6822(88)90526-0 | author-link4 = Susan Baker (virologist) }}</ref><ref name=Textbook>{{cite book | veditors = Palmer SR, Soulsby L, Torgerson P, Brown DW |title=Oxford Textbook of Zoonoses: Biology, Clinical Practice, and Public Health Control |date=2011 |publisher=OUP Oxford |isbn=978-0-19-857002-8 |pages=399–400 |doi=10.1093/med/9780198570028.001.0001 }}</ref>

DIPs were first [[Von Magnus phenomenon|observed]] as early as the 1950s by Von Magnus and Schlesinger, both working with influenza viruses.<ref>{{cite journal | vauthors = Gard S, Von Magnus P, Svedmyr A, Birch-Andersen A | title = Studies on the sedimentation of influenza virus | journal = Archiv für die Gesamte Virusforschung | volume = 4 | issue = 5 | pages = 591–611 | date = October 1952 | pmid = 14953289 | doi = 10.1007/BF01242026 | s2cid = 21838623 }}</ref> However, direct evidence for DIPs was only found in the 1960s by Hackett who noticed presence of ‘stumpy’ particles of vesicular stomatitis virus in electron micrographs<ref>{{cite journal | vauthors = Hackett AJ | title = A possible morphologic basis for the autointerference phenomenon in vesicular stomatitis virus | journal = Virology | volume = 24 | issue = 1 | pages = 51–59 | date = September 1964 | pmid = 14208902 | doi = 10.1016/0042-6822(64)90147-3 }}</ref> and the formalization of DIPs terminology was in 1970 by Huang and Baltimore.<ref name="Huang"/> DIPs can occur within nearly every class of both DNA and RNA viruses both in clinical and laboratory settings including [[poliovirus]], [[SARS coronavirus]], [[Measles virus|measles]], [[alphavirus]]es, [[Human respiratory syncytial virus|respiratory syncytial virus]] and [[Influenza|influenza virus]].<ref name="ReferenceA">{{cite journal | vauthors = Sun Y, Jain D, Koziol-White CJ, Genoyer E, Gilbert M, Tapia K, Panettieri RA, Hodinka RL, López CB | display-authors = 6 | title = Immunostimulatory Defective Viral Genomes from Respiratory Syncytial Virus Promote a Strong Innate Antiviral Response during Infection in Mice and Humans | journal = PLOS Pathogens | volume = 11 | issue = 9 | pages = e1005122 | date = September 2015 | pmid = 26336095 | pmc = 4559413 | doi = 10.1371/journal.ppat.1005122 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dimmock NJ, Dove BK, Scott PD, Meng B, Taylor I, Cheung L, Hallis B, Marriott AC, Carroll MW, Easton AJ | display-authors = 6 | title = Cloned defective interfering influenza virus protects ferrets from pandemic 2009 influenza A virus and allows protective immunity to be established | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e49394 | date = 2012 | pmid = 23251341 | pmc = 3521014 | doi = 10.1371/journal.pone.0049394 | doi-access = free | bibcode = 2012PLoSO...749394D }}</ref><ref>{{cite journal | vauthors = Saira K, Lin X, DePasse JV, Halpin R, Twaddle A, Stockwell T, Angus B, Cozzi-Lepri A, Delfino M, Dugan V, Dwyer DE, Freiberg M, Horban A, Losso M, Lynfield R, Wentworth DN, Holmes EC, Davey R, Wentworth DE, Ghedin E | display-authors = 6 | title = Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus | journal = Journal of Virology | volume = 87 | issue = 14 | pages = 8064–8074 | date = July 2013 | pmid = 23678180 | pmc = 3700204 | doi = 10.1128/JVI.00240-13 | author22 = INSIGHT FLU003 Study Group | author21 = INSIGHT FLU002 Study Group }}</ref><ref>{{cite journal | vauthors = Petterson E, Guo TC, Evensen Ø, Mikalsen AB | title = Experimental piscine alphavirus RNA recombination in vivo yields both viable virus and defective viral RNA | journal = Scientific Reports | volume = 6 | pages = 36317 | date = November 2016 | pmid = 27805034 | pmc = 5090867 | doi = 10.1038/srep36317 | bibcode = 2016NatSR...636317P }}</ref><ref>{{cite journal | vauthors = Cattaneo R, Schmid A, Eschle D, Baczko K, ter Meulen V, Billeter MA | title = Biased hypermutation and other genetic changes in defective measles viruses in human brain infections | journal = Cell | volume = 55 | issue = 2 | pages = 255–265 | date = October 1988 | pmid = 3167982 | pmc = 7126660 | doi = 10.1016/0092-8674(88)90048-7 }}</ref><ref>{{cite journal | vauthors = Makino S, Yokomori K, Lai MM | title = Analysis of efficiently packaged defective interfering RNAs of murine coronavirus: localization of a possible RNA-packaging signal | journal = Journal of Virology | volume = 64 | issue = 12 | pages = 6045–6053 | date = December 1990 | pmid = 2243386 | pmc = 248778 | doi = 10.1128/JVI.64.12.6045-6053.1990 }}</ref><ref>{{cite journal | vauthors = Lundquist RE, Sullivan M, Maizel JV | title = Characterization of a new isolate of poliovirus defective interfering particles | journal = Cell | volume = 18 | issue = 3 | pages = 759–769 | date = November 1979 | pmid = 229964 | doi = 10.1016/0092-8674(79)90129-6 | s2cid = 35964939 }}</ref><ref>{{cite journal | vauthors = Stauffer Thompson KA, Rempala GA, Yin J | title = Multiple-hit inhibition of infection by defective interfering particles | journal = The Journal of General Virology | volume = 90 | issue = Pt 4 | pages = 888–899 | date = April 2009 | pmid = 19264636 | pmc = 2889439 | doi = 10.1099/vir.0.005249-0 }}</ref>

==Defection==
DIPs are a naturally occurring phenomenon that can be recreated under experimental conditions in the lab and can also be synthesized for experimental use. They are spontaneously produced by error-prone [[viral replication]], something particularly prevalent in RNA viruses over DNA viruses due to the enzyme used (replicase, or [[RNA-dependent RNA polymerase]].)<ref name=Pathak /><ref name=Chiba>{{cite journal | vauthors = Chiba S, Lin YH, Kondo H, Kanematsu S, Suzuki N | title = Effects of defective interfering RNA on symptom induction by, and replication of, a novel partitivirus from a phytopathogenic fungus, Rosellinia necatrix | journal = Journal of Virology | volume = 87 | issue = 4 | pages = 2330–2341 | date = February 2013 | pmid = 23236074 | pmc = 3571465 | doi = 10.1128/JVI.02835-12 }}</ref> DIP genomes typically retain the terminal sequences needed for recognition by viral polymerases, and sequences for packaging of their genome into new particles, but little else.<ref name=DimmockBook>{{cite book |chapter=Innate and intrinsic immunity |pages=201–217 |chapter-url=https://books.google.com/books?id=8OVbCwAAQBAJ&pg=PA201 | veditors = Dimmock NJ, Easton AJ, Leppard KN |title=Introduction to Modern Virology |date=2015 |publisher=John Wiley & Sons |isbn=978-1-119-09453-1 }}</ref><ref name=Resende>{{cite journal | vauthors = Resende R, de Haan P, van de Vossen E, de Avila AC, Goldbach R, Peters D | title = Defective interfering L RNA segments of tomato spotted wilt virus retain both virus genome termini and have extensive internal deletions | journal = The Journal of General Virology | volume = 73 | issue = 10 | pages = 2509–2516 | date = October 1992 | pmid = 1402797 | doi = 10.1099/0022-1317-73-10-2509 | doi-access = free }}</ref> The size of the genomic deletion event can vary greatly, with one such example in a DIP derived from rabies virus exhibiting a 6.1 kb deletion.<ref>{{cite journal | vauthors = Conzelmann KK, Cox JH, Thiel HJ | title = An L (polymerase)-deficient rabies virus defective interfering particle RNA is replicated and transcribed by heterologous helper virus L proteins | journal = Virology | volume = 184 | issue = 2 | pages = 655–663 | date = October 1991 | pmid = 1887588 | doi = 10.1016/0042-6822(91)90435-e }}</ref> In another example, the size of several DI-DNA plant virus genomes varied from one tenth of the size of the original genome to one half.<ref>{{cite journal | vauthors = Patil BL, Dasgupta I |title=Defective Interfering Dnas of Plant Viruses. |journal=Critical Reviews in Plant Sciences |volume=25 |issue=1 |year=2006 |pages=47–64 |doi=10.1080/07352680500391295|bibcode=2006CRvPS..25...47P |s2cid=85790514 }}</ref>

==Interference==
The particles are considered interfering when they affect the function of the parent virus through [[competitive inhibition]]<ref name=Pathak/> during coinfection. In other words, defective and non-defective viruses replicate simultaneously, but when defective particles increase, the amount of replicated non-defective virus is decreased.  The extent of interference depends on the type and size of defection in the genome; large deletions of genomic data allow rapid replication of the defective genome.<ref name=DimmockBook /> In SARS-CoV-2, synthetic DIPs made by removing 90% of the genome replicate three times faster than the virus.<ref name=":0" /> During the coinfection of a host cell, a critical ratio will eventually be reached in which more viral factors are being used to produce the non-infectious DIPs than infectious particles.<ref name=DimmockBook /> Defective particles and defective genomes have also been demonstrated to stimulate the host innate immune responses and their presence during a viral infection correlates with the strength of the antiviral response.<ref name="ReferenceA"/> However, in some viruses such as SARS-CoV-2, the effect of competitive inhibition by interfering particles reduces viral-mediated innate immune responses and inflammation producing a therapeutic effect.<ref name="Chaturvedi_2021">{{cite journal | vauthors = Chaturvedi S, Vasen G, Pablo M, Chen X, Beutler N, Kumar A, Tanner E, Illouz S, Rahgoshay D, Burnett J, Holguin L, Chen PY, Ndjamen B, Ott M, Rodick R, Rogers T, Smith DM, Weinberger LS | display-authors = 6 | title = Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance | journal = Cell | volume = 184 | issue = 25 | pages = 6022–6036.e18 | date = December 2021 | pmid = 34838159 | pmc = 8577993 | doi = 10.1016/j.cell.2021.11.004 }}</ref>

This interfering nature is becoming more and more important for research on virus therapies.<ref>{{cite journal | vauthors = Weinberger LS, Schaffer DV, Arkin AP | title = Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection | journal = Journal of Virology | volume = 77 | issue = 18 | pages = 10028–10036 | date = September 2003 | pmid = 12941913 | pmc = 224590 | doi = 10.1128/jvi.77.18.10028-10036.2003 }}</ref><ref name=Thompson>{{cite journal | vauthors = Thompson KA, Yin J | title = Population dynamics of an RNA virus and its defective interfering particles in passage cultures | journal = Virology Journal | volume = 7 | pages = 257 | date = September 2010 | pmid = 20920247 | pmc = 2955718 | doi = 10.1186/1743-422X-7-257 | doi-access = free }}</ref>  It is thought that because of their specificity, DIPs will be targeted to sites of infection. In one example, scientists have used DIPs to create "protecting viruses", which attenuated the [[pathogenicity]] of an influenza A infection in mice, through inducing an [[interferon]] response, to a point that it was no longer lethal.<ref name=Easton>{{cite journal | vauthors = Easton AJ, Scott PD, Edworthy NL, Meng B, Marriott AC, Dimmock NJ | title = A novel broad-spectrum treatment for respiratory virus infections: influenza-based defective interfering virus provides protection against pneumovirus infection in vivo | journal = Vaccine | volume = 29 | issue = 15 | pages = 2777–2784 | date = March 2011 | pmid = 21320545 | doi = 10.1016/j.vaccine.2011.01.102 | url = http://wrap.warwick.ac.uk/37174/1/WRAP_Easton_0380313-lf-310811-easton_et_al_di_protection_revision.pdf }}</ref>  For [[SARS-CoV-2]], the first synthetic DIPs were made in 2020 <ref name=":0">{{cite journal |last1=Yao |first1=Shun |last2=Narayanan |first2=Anoop |last3=Majowicz |first3=Sydney |last4=Jose |first4=Joyce |last5=Archetti |first5=Marco |date=1 July 2021 |title=A Synthetic Defective Interfering SARS-CoV-2 |language=en |volume=9|issue=|pages=e11686 |journal=PeerJ|pmid=34249513|pmc=8255065|doi=10.7717/peerj.11686|doi-access=free}}</ref> and the interference effect was used to generate [[Therapeutic interfering particle|therapeutic interfering particles (TIPs)]] that reduced pathogenesis and protected hamsters from serious disease.<ref>{{cite journal | vauthors = Villanueva MT | title = Interfering viral-like particles inhibit SARS-CoV-2 replication | journal = Nature Reviews. Drug Discovery | pages = d41573–021–00205-5 | date = December 2021 | volume = 21 | issue = 1 | pmid = 34873320 | doi = 10.1038/d41573-021-00205-5 | s2cid = 244935707 }}</ref>

==Pathogenesis==
DIPs have been shown to play a role in pathogenesis of certain viruses. One study demonstrates the relationship between a pathogen and its defective variant, showing how regulation of DI production allowed the virus to attenuate its own infectious replication, decreasing viral load and thus enhance its parasitic efficiency by preventing the host from dying too fast.<ref>{{cite journal | vauthors = Lukhovitskaya NI, Thaduri S, Garushyants SK, Torrance L, Savenkov EI | title = Deciphering the mechanism of defective interfering RNA (DI RNA) biogenesis reveals that a viral protein and the DI RNA act antagonistically in virus infection | journal = Journal of Virology | volume = 87 | issue = 11 | pages = 6091–6103 | date = June 2013 | pmid = 23514891 | pmc = 3648117 | doi = 10.1128/JVI.03322-12 }}</ref> This also provides the virus with more time to spread and infect new hosts. DIP generation is regulated within viruses: the [[Coronavirus SL-III cis-acting replication element]] (shown in the image) is a higher-order genomic structure implicated in the mediation of DIP production in [[bovine coronavirus]], with apparent homologs detected in other [[coronavirus]] groups.<ref name=BovineCorona /> A more in-depth introduction can be found in Alice Huang and David Baltimore's work from 1970.<ref name=Huang>{{cite journal | vauthors = Huang AS, Baltimore D | title = Defective viral particles and viral disease processes | journal = Nature | volume = 226 | issue = 5243 | pages = 325–327 | date = April 1970 | pmid = 5439728 | doi = 10.1038/226325a0 | s2cid = 4184206 | bibcode = 1970Natur.226..325H }}</ref>

==Types of defective RNA genomes==

#  Deletions defections are when a fragment of the template is skipped. Examples of this type of defection can be found in tomato spotted wilt virus and Flock House virus.<ref>{{cite journal | vauthors = Jaworski E, Routh A | title = Parallel ClickSeq and Nanopore sequencing elucidates the rapid evolution of defective-interfering RNAs in Flock House virus | journal = PLOS Pathogens | volume = 13 | issue = 5 | pages = e1006365 | date = May 2017 | pmid = 28475646 | pmc = 5435362 | doi = 10.1371/journal.ppat.1006365 | doi-access = free }}</ref><ref name=Resende />
#  Snapbacks defections are when replicase transcribes part of one strand then uses this new strand as a template. The result of this can produce a hairpin. Snapback defections have been observed in [[Human respiratory syncytial virus|vesicular stomatitis virus]].<ref name=Schubert>{{cite journal | vauthors = Schubert M, Lazzarini RA | title = Structure and origin of a snapback defective interfering particle RNA of vesicular stomatitis virus | journal = Journal of Virology | volume = 37 | issue = 2 | pages = 661–672 | date = February 1981 | pmid = 6261012 | pmc = 171054 | doi = 10.1128/JVI.37.2.661-672.1981 }}</ref>
#  Panhandle defections are when the polymerase carries a partially made strand and then switches back to transcribe the 5' end, forming the panhandle shape. Panhandle defections are found in influenza viruses.<ref name=Fodor>{{cite journal | vauthors = Fodor E, Pritlove DC, Brownlee GG | title = The influenza virus panhandle is involved in the initiation of transcription | journal = Journal of Virology | volume = 68 | issue = 6 | pages = 4092–4096 | date = June 1994 | pmid = 8189550 | pmc = 236924 | doi = 10.1128/JVI.68.6.4092-4096.1994 }}</ref>
# Compound defections are when both a deletion and snapback defection happens together.
# Mosaic or complex DI genome, in which the various regions may come from the same helper virus genome but in the wrong order; from different helper genome segments, or could include segments of host RNA. Duplications may also occur.<ref name=AntiviralDIPs />

==Research==
Research has been conducted by virologists to learn more about the interference in infection of host cells and how DI genomes could potentially work as [[immunostimulatory]] antiviral agents.<ref name=AntiviralDIPs /> Another branch of research has pursued the concept of engineering DIPs into antiviral [[Therapeutic interfering particle|therapeutic interfering particles (TIPs)]],<ref>{{cite journal | vauthors = Metzger VT, Lloyd-Smith JO, Weinberger LS | title = Autonomous targeting of infectious superspreaders using engineered transmissible therapies | journal = PLOS Computational Biology | volume = 7 | issue = 3 | pages = e1002015 | date = March 2011 | pmid = 21483468 | pmc = 3060167 | doi = 10.1371/journal.pcbi.1002015 | bibcode = 2011PLSCB...7E2015M | doi-access = free }}</ref> a purely theoretical concept until recently.<ref>{{cite press release | author = Gladstone Institutes |title=A New Class of Antiviral Therapy Could Treat COVID-19|url=https://www.prnewswire.com/news-releases/a-new-class-of-antiviral-therapy-could-treat-covid-19-301441601.html|access-date=2021-12-28|website=www.prnewswire.com|language=en}}</ref> A 2014 article describes the pre-clinical work to test the immunostimulatory effectiveness of a DIP against influenza viruses by inducing the innate antiviral immune responses (i.e., interferon).<ref name=Dimmock>{{cite journal | vauthors = Dimmock NJ, Easton AJ | title = Defective interfering influenza virus RNAs: time to reevaluate their clinical potential as broad-spectrum antivirals? | journal = Journal of Virology | volume = 88 | issue = 10 | pages = 5217–5227 | date = May 2014 | pmid = 24574404 | pmc = 4019098 | doi = 10.1128/JVI.03193-13 }}</ref>  Subsequent work tested the pre-clinical efficacy of TIPs against [[HIV]]<ref>{{cite web| vauthors = Tanner EJ, Jung SY, Glazier J, Thompson C, Zhou Y, Martin B, Son HI, Riley JL, Weinberger LS |date=2019-10-30|title=Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral |language=en|doi=10.1101/820456|s2cid=208600143|url=https://www.biorxiv.org/content/biorxiv/early/2019/10/30/820456.full.pdf}}</ref> and [[SARS-CoV-2]].<ref name=":0" /><ref name="Chaturvedi_2021" />  DI-RNAs have also been found to aid in the infection of fungi via viruses of the family ''[[Partitiviridae]]'' for the first time, which makes room for more interdisciplinary work.<ref name="Chiba"/>

Several tools as ViReMa<ref>{{cite journal | vauthors = Routh A, Johnson JE | title = Discovery of functional genomic motifs in viruses with ViReMa-a Virus Recombination Mapper-for analysis of next-generation sequencing data | journal = Nucleic Acids Research | volume = 42 | issue = 2 | pages = e11 | date = January 2014 | pmid = 24137010 | pmc = 3902915 | doi = 10.1093/nar/gkt916 }}</ref> and DI-tector<ref>{{cite journal | vauthors = Beauclair G, Mura M, Combredet C, Tangy F, Jouvenet N, Komarova AV | title = ''DI-tector'': defective interfering viral genomes' detector for next-generation sequencing data | journal = RNA | volume = 24 | issue = 10 | pages = 1285–1296 | date = October 2018 | pmid = 30012569 | pmc = 6140465 | doi = 10.1261/rna.066910.118 }}</ref> have been developed to help to detect defective viral genomes in next-generation sequencing data and [[High-throughput screening|high-throughput]] approaches, such as random-deletion library [[sequencing]] (RanDeL-Seq),<ref>{{cite journal | vauthors = Notton T, Glazier JJ, Saykally VR, Thompson CE, Weinberger LS | title = RanDeL-Seq: a High-Throughput Method to Map Viral ''cis''- and ''trans''-Acting Elements | journal = mBio | volume = 12 | issue = 1 | pages = e01724–20 | date = January 2021 | pmid = 33468683 | pmc = 7845639 | doi = 10.1128/mBio.01724-20 }}</ref> allow rational mapping of the viral genetic elements that are required for DI-particle propagation.

== References ==
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{{Self-replicating organic structures}}
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[[Category:Virology]]
[[Category:Subviral agents]]