Research article Special Issues

Quantifying the effect of defective viral genomes in respiratory syncytial virus infections

  • Received: 07 February 2023 Revised: 30 April 2023 Accepted: 04 May 2023 Published: 29 May 2023
  • Defective viral genomes (DVGs) are viral genomes that contain only a partial viral RNA and so cannot replicate within cells on their own. If a cell containing DVGs is subsequently infected with a complete viral genome, the DVG can then use the missing proteins expressed by the full genome in order to replicate itself. Since the cell is producing defective genomes, it has less resources to produce fully functional virions and thus release of complete virions is often suppressed. Here, we use data from challenge studies of respiratory syncytial virus (RSV) in healthy adults to quantify the effect of DVGs. We use a mathematical model to fit the data, finding that late onset of DVGs and prolonged DVG detection are associated with lower infection rates and higher clearance rates. This result could have implications for the use of DVGs as a therapeutic.

    Citation: Zakarya Noffel, Hana M. Dobrovolny. Quantifying the effect of defective viral genomes in respiratory syncytial virus infections[J]. Mathematical Biosciences and Engineering, 2023, 20(7): 12666-12681. doi: 10.3934/mbe.2023564

    Related Papers:

  • Defective viral genomes (DVGs) are viral genomes that contain only a partial viral RNA and so cannot replicate within cells on their own. If a cell containing DVGs is subsequently infected with a complete viral genome, the DVG can then use the missing proteins expressed by the full genome in order to replicate itself. Since the cell is producing defective genomes, it has less resources to produce fully functional virions and thus release of complete virions is often suppressed. Here, we use data from challenge studies of respiratory syncytial virus (RSV) in healthy adults to quantify the effect of DVGs. We use a mathematical model to fit the data, finding that late onset of DVGs and prolonged DVG detection are associated with lower infection rates and higher clearance rates. This result could have implications for the use of DVGs as a therapeutic.


    [1] A. Chatterjee, K. Mavunda, L. R. Krilov, Current state of respiratory syncytial virus disease and management, Infect. Dis. Ther., 10 (2021), 5–16. doi: 10.1007/s40121-020-00387-2
    [2] D. M. Bowser, K. R. Rowlands, D. Hariharan, R. M. Gervasio, L. Buckley, Y. Halasa-Rappel, et al., Cost of respiratory syncytial virus infections in us infants: Systematic literature review and analysis, J. Infect. Dis., 226 (2022), S225–S235. doi: 10.1093/infdis/jiac172
    [3] K. Wagatsuma, I. S. Koolhof, Y. Shobugawa, R. Saito, Decreased human respiratory syncytial virus activity during the COVID-19 pandemic in japan: An ecological time-series analysis, BMC Infect. Dis., 21 (2021), 734.
    [4] D. Danino, S. Ben-Shimol, B. A. Van der Beek, N. Givon-Lavi, Y. S. Avni, D. Greenberg, et al., Decline in pneumococcal disease in young children during the coronavirus disease 2019 (COVID-19) pandemic in Israel associated with suppression of seasonal respiratory viruses, despite persistent pneumococcal carriage: A prospective cohort study, Clin. Infect. Dis., 75 (2022), E1154–E1164. doi: 10.1093/cid/ciab1014
    [5] I. Kuitunen, M. Artama, M. Haapanen, M. Renko, Respiratory virus circulation in children after relaxation of COVID-19 restrictions in fall 2021-A nationwide register study in Finland, J. Med. Virol., 94 (2022), 4528–4532. doi: 10.1002/jmv.27857
    [6] P. Hodjat, P. A. Christensen, S. Subedi, D. W. Bernard, R. J. Olsen, S. W. Long, The reemergence of seasonal respiratory viruses in Houston, Texas, after relaxing COVID-19 restrictions, Microbiol. Spectrum, 9 (2021), e00430–21. doi: 10.1128/Spectrum.00430-21
    [7] E. E. Walsh, D. R. Peterson, A. R. Falsey, Viral shedding and immune responses to respiratory syncytial virus infection in older adults, J. Infect. Dis., 207 (2013), 1424–1432. doi: 10.1093/infdis/jit038
    [8] R. C. Welliver, The immune response to respiratory syncytial virus infection: Friend or foe?, Clin. Rev. Allergy Immunol., 24 (2008), 163–173. doi: 10.1007/s12016-007-8033-2
    [9] S. A. Felt, Y. Sun, A. Jozwik, A. Paras, M. S. Habibi, D. Nickle, et al., Detection of respiratory syncytial virus defective genomes in nasal secretions is associated with distinct clinical outcomes, Nat. Microbiol., 6 (2021), 672–681. doi: 10.1038/s41564-021-00882-3
    [10] M. Treuhaft, M. Beem, Defective interfering particles of respiratory syncytial virus, J. Bacteriol., 91 (1966), 1282–1288.
    [11] L. E. Liao, S. Iwami, C. A. A. Beauchemin, (in)validating experimentally derived knowledge about influenza A defective interfering particles, J. R. Soc. Interface, 13 (2016), 20160412. doi: 10.1098/rsif.2016.0412
    [12] N. Kaverin, I. Rudneva, V. Kolodkina, Y. Smirnov, Autocomplementation of influenza-virus defective interfering particles –- cells at high multiplicity infected with defective interfering particles produce defective virions, Acta Virol., 26 (1982), 512–516.
    [13] R. Penn, J. S. Tregoning, K. E. Flight, L. Baillon, R. Frise, D. H. Goldhill, et al., Levels of influenza A virus defective viral genomes determine pathogenesis in the BALB/c mouse model, J. Virol., 96 (2022). doi: 10.1128/jvi.01178-22
    [14] T. Shenk, V. Stollar, Defective interfering particles of sindbis virus.2. homologous interference, Virology, 55 (1973), 530–534. doi: 10.1016/0042-6822(73)90197-9
    [15] C. Kang, R. Allen, Host function dependent induction of defective interfering particles of vesicular stomatitis virus, J. Virol., 25 (1978), 202–206. doi: 10.1128/JVI.25.1.202-206.1978
    [16] J. Keene, M. Rosenberg, R. Lazzarini, Characterization of 3' terminus of RNA isolated from vesicular stomatitis virus and from its defective interfering particles, Proc. Natl. Acad. Sci. U.S.A., 74 (1977), 1353–1357. doi: 10.1073/pnas.74.4.1353
    [17] C. Cole, D. Smoler, E. Wimmer, D. Baltimore, Defective interfering particles of poliovirus.2. isolation and physical properties, J. Virol., 7 (1971), 478. doi: 10.1128/JVI.7.4.478-485.1971
    [18] C. Cole, D. Baltimore, Defective interfering particles of poliovirus.2. nature of defect, J. Mol. Biol., 76 (1973), 325–343. doi: 10.1016/0022-2836(73)90508-1
    [19] Y. Shirogane, Elsa Rousseau, Jakub Voznica, Yinghong Xiao, Weiheng Su, Adam Catching, Z. J. Whitfield, I. M. Rouzine, Simone Bianco, Raul Andino, Experimental and mathematical insights on the interactions between poliovirus and a defective interfering genome, Plos Path., 17 (2021), e1009277. doi: 10.1371/journal.ppat.1009277
    [20] W. Hall, S. Martin, Defective interfering particles produced during replication of measles-virus, Med. Microbiol. Immunol., 160 (1974), 155–164. doi: 10.1007/BF02121722
    [21] S. Girgis, Z. K. Xu, S. Oikonomopoulos, A. D. Fedorova, E. P. Tchesnokov, C. J. Gordon, et al., Evolution of naturally arising SARS-CoV-2 defective interfering particles, Comm. Biol., 5 (2022), 1140. doi: 10.1038/s42003-022-04058-5
    [22] S. Rhode, Defective interfering particles of parvovirus H-1, J. Virol., 27 (1978), 347–356. doi: 10.1128/JVI.27.2.347-356.1978
    [23] C. Bangham, T. Kirkwood, Defective interfering particles — effects in modulating virus growth and persistance, Virology, 179 (1990), 821–826. doi: 10.1016/0042-6822(90)90150-P
    [24] C. M. Ziegler, J. W. Botten, Defective interfering particles of negative-strand rna viruses, Trends in Microbiol., 28 (2020), 554–565. doi: 10.1016/j.tim.2020.02.006
    [25] M. Valdovinos, B. Gomez, Establishment of respiratory syncytial virus persistence in cell lines: Association with defective interfering particles, Intervirol., 46 (2003), 90–198. doi: 10.1159/000071461
    [26] Y. Sun, D. Jain, C. J. Koziol-White, E. Genoyer, M. Gilbert, K. Tapia, et al., Immunostimulatory defective viral genomes from respiratory syncytial virus promote a strong innate antiviral response during infection in mice and humans, Plos Path., 11 (2015), e1005122. doi: 10.1371/journal.ppat.1005122
    [27] C. Wang, C. V. Forst, T.-W. Chou, A. Geber, M. Wang, W. Hamou, et al., Cell-to-cell variation in defective virus expression and effects on host responses during influenza virus infection, MBIO, 11 (2020), e02880–19. doi: 10.1128/mBio.02880-19
    [28] X. Mercado-Lopez, C. R. Cotter, W. keun Kim, Y. Sun, L. Munoz, K. Tapia, et al., Highly immunostimulatory RNA derived from a Sendai virus defective viral genome, Vaccine, 31 (2013), 5713–5721. doi: 10.1016/j.vaccine.2013.09.040
    [29] Y. Xiao, P. V. Lidsky, Y. Shirogane, R. Aviner, C.-T. Wu, W. Y. Li, et al., A defective viral genome strategy elicits broad protective immunity against respiratory viruses, Cell, 184 (2021), 6037. doi: 10.1016/j.cell.2021.11.023
    [30] C. Bangham, T. Kirkwood, Defective interfering particles and virus evolution, Trends Microbiol., 1 (1993), 260–264. doi: 10.1016/0966-842X(93)90048-V
    [31] V. V. Rezelj, L. I. Levi, M. Vignuzzi, The defective component of viral populations, Curr. Opin. Virol., 33 (2018), 74–80. doi: 10.1016/j.coviro.2018.07.014
    [32] T. Bhat, A. Cao, J. Yin, Virus-like particles: Measures and biological functions, Viruses, 14 (2022), 383. doi: 10.3390/v14020383
    [33] K. A. Stauffer, G. A. Rempala, J. Yin, Multiple-hit inhibition of infection by defective interfering particles, J. Gen. Virol., 90 (2009), 888–899. doi: 10.1099/vir.0.005249-0
    [34] T. Mapder, S. Clifford, J. Aaskov, K. Burrage, A population of bang-bang switches of defective interfering particles makes within-host dynamics of dengue virus controllable, PLOS Comp. Biol., 15 (2009), e1006668. doi: 10.1371/journal.pcbi.1006668
    [35] F. Fatehi, R. J. Bingham, Pierre-Philippe Dechant, P. G. Stockley, R. Twarock, Therapeutic interfering particles exploiting viral replication and assembly mechanisms show promising performance: a modelling study, Sci. Rep., 11 (2021), 23847. doi: 10.1038/s41598-021-03168-0
    [36] V. Sharov, V. V. Rezelj, V. V. Galatenko, A. Titievsky, J. Panov, K. Chumakov, et al., Intra- and inter-cellular modeling of dynamic interaction between zika virus and its naturally occurring defective viral genomes, J. Virol., 95 (2021), e00977.–21 doi: 10.1128/JVI.00977–21
    [37] D. Ruediger, S. Y. Kupke, T. Laske, P. Zmora, U. Reichl, Multiscale modeling of influenza A virus replication in cell cultures predicts infection dynamics for highly different infection conditions, Plos Comp. Biol., 15 (2019), e1006819. doi: 10.1371/journal.pcbi.1006819
    [38] D. Ruediger, L. Pelz, M. D. Hein, S. Y. Kupke, U. Reichl, Multiscale model of defective interfering particle replication for influenza A virus infection in animal cell culture, Plos Comp. Biol., 17 (2021), e1009357. doi: 10.1371/journal.pcbi.1009357
    [39] L. T. Pinilla, B. P. Holder, Y. Abed, G. Boivin, C. A. A. Beauchemin, The H275Y neuraminidase mutation of the pandemic A/H1N1 influenza virus lengthens the eclipse phase and reduces viral output of infected cells, potentially compromising fitness in ferrets, J. Virol., 86 (2012), 10651–10660. doi: 10.1128/JVI.0724411
    [40] E. Paradis, L. Pinilla, B. Holder, Y. Abed, G. Boivin, C. Beauchemin, Impact of the H275Y and I223V mutations in the neuraminidase of the 2009 pandemic influenza virus in vitro and evaluating experimental reproducibility, PLoS One, 10 (2015), e0126115. doi: 10.1371/journal.pone.0126115
    [41] D. Wethington, O. Harder, K. Uppulury, W. C. Stewart, P. Chen, T. King, et al., Mathematical modelling identifies the role of adaptive immunity as a key controller of respiratory syncytial virus in cotton rats, J. Roy. Soc. Interface, 16 (2019), 20190389. doi: 10.1098/rsif.2019.0389
    [42] S. Khan, H. M. Dobrovolny, A study of the effects of age on the dynamics of RSV in animal models, Virus Res., 304 (2021), 198524. doilink doi: 10.1016/j.virusres.2021.198524
    [43] T. Rodriguez, H. M. Dobrovolny, Estimation of viral kinetics model parameters in young and aged SARS-CoV-2 infected macaques, R. Soc. Open Sci., 8 (2021), 202345. doi: 10.1098/rsos.202345
    [44] H. M. Dobrovolny, Quantifying the effect of remdesivir in rhesus macaques infected with SARS-CoV-2, Virology, 550 (2020), 61–69. doi: 10.1016/j.virol.2020.07.015
    [45] P. Baccam, C. Beauchemin, C. A. Macken, F. G. Hayden, A. S. Perelson, Kinetics of influenza A virus infection in humans, J. Virol., 80 (2006), 7590–7599. doi: 10.1128/JVI.01623-05
    [46] A. M. Smith, F. R. Adler, A. S. Perelson, An accurate two-phase approximate solution to an acute viral infection model, J. Math. Biol., 60 (2010), 711–726. doi: 10.1007/s00285-009-0281-8
    [47] B. P. Holder, C. A. Beauchemin, Exploring the effect of biological delays in kinetic models of influenza within a host or cell culture, BMC Public Health, 11 (2011), S10. doi: 10.1186/1471-2458-11-S1-S10
    [48] B. Efron, R. Tibshirani, Bootstrap methods for standard errors, confidence intervals, and other measures of statistical accuracy, Stat. Sci., 1 (1986), 54–75.
    [49] G. González-Parra, H. M. Dobrovolny, Modeling of fusion inhibitor treatment of RSV in African green monkeys, J. Theor. Biol., 456 (2018), 62–73. doi: 10.1016/j.jtbi.2018.07.029
    [50] G. González-Parra, F. De Ridder, D. Huntjens, D. Roymans, G. Ispas, H. M. Dobrovolny, A comparison of RSV and influenza in vitro kinetic parameters reveals differences in infecting time, Plos One, 13 (2018), e0192645. doi: 10.1371/journal.pone.0192645
    [51] L. Pelz, D. Rudiger, T. Dogra, F. G. Alnaji, Y. Genzel, C. B. Brooke, et al., Semi-continuous propagation of influenza A virus and its defective interfering particles: Analyzing the dynamic competition to select candidates for antiviral therapy, J. Virol., 95 (2021), e01174–21. doi: 10.1128/JVI.01174-21
    [52] N. J. Dimmock, A. J. Easton, Cloned defective interfering influenza RNA and a possible pan-specific treatment of respiratory virus diseases, Viruses, 7 (2015), 3768–3788. doi: 10.3390/v7072796
    [53] H. M. Dobrovolny, M. B. Reddy, M. A. Kamal, C. R. Rayner, C. A. Beauchemin, Assessing mathematical models of influenza infections using features of the immune response, PLoS One, 8 (2013), e57088. doi: 10.1371/journal.pone.0057088
    [54] X. I. Yan, Y. H. Li, Y. J. Tang, Z. P. Xie, H. C. Gao, X. M. Yang, et al., Clinical characteristics and viral load of respiratory syncytial virus and human metapneumovirus in children hospitaled for acute lower respiratory tract infection, J. Med. Virol., 89 (2017), 589–597. doi: 10.1002/jmv.24687
    [55] R. A. S. Watanabe, J. S. Cruz, L. K. Luna, V. R. G. Alves, D. D. Conte, L. Lyra, et al., Respiratory syncytial virus: viral load, viral decay, and disease progression in children with bronchiolitis, Brazil. J. Microbiol., 53 (2022), 1241–1247. doi: 10.1007/s42770-022-00742-0
    [56] L. Zhou, Q. Y. Xiao, Y. Zhao, A. L. Huang, L. Ren, E. M. Liu, The impact of viral dynamics on the clinical severity of infants with respiratory syncytial virus bronchiolitis, J. Med. Virol., 87 (2015), 1276–1284. doi: 10.1002/jmv.24111
    [57] Y. Espinosa, C. Martin, A. A. Torres, M. J. Farfan, J. P. Torres, V. Avadhanula, et al., Genomic loads and genotypes of respiratory syncytial virus: Viral factors during lower respiratory tract infection in chilean hospitalized infants, Intl. J. Mol. Sci., 18 (2017), 654. doi: 10.3390/ijms18030654
    [58] L. Vos, R. Bruyndonckx, N. P. A. Zuithoff, P. Little, J. J. Oosterheert, B. D. L. Broekhuizen, et al., Lower respiratory tract infection in the community: Associations between viral aetiology and illness course, Clin. Microbiol. Infect., 27 (2021), 96–104. doi: 10.1016/j.cmi.2020.03.023
    [59] E. Uusitupa, M. Waris, T. Heikkinen, Association of viral load with disease severity in outpatient children with respiratory syncytial virus infection, J. Infect. Dis., 222 (2020), 298–304. doi: 10.1093/infdis/jiaa076
    [60] J. P. DeVincenzo, T. Wilkinson, A. Vaishnaw, J. Cehelsky, R. Meyers, S. Nochur, et al., Viral load drives disease in humans experimentally infected with respiratory syncytial virus, Am. J. Resp. Crit. Care Med., 182 (2010), 1305–1314. doi: 10.1164/rccm.201002-0221OC
    [61] B. Bagga, C. W. Woods, T. H. Veldman, A. Gilbert, A. Mann, G. Balaratnam, et al., Comparing influenza and RSV viral disease dynamics in experimentally infected adults predicts clinical effectiveness of RSV antivirals, Antivir. Ther., 18 (2013), 785–791. doi: 10.3851/IMP2629
    [62] P. D. Scott, B. Meng, A. C. Marriott, A. J. Easton, N. J. Dimmock, Defective interfering virus protects elderly mice from influenza, Virol. J., 8 (2011), 212. doi: 10.1186/1743-422X-8-212
    [63] S. R. Welch, J. R. Spengler, J. R. Harmon, J. D. Coleman-McCray, F. E. Scholte, S. C. Genzer, et al., Defective interfering viral particle treatment reduces clinical signs and protects hamsters from lethal nipah virus disease, MBIO, 13 (2022), e03294. doi: 10.1128/mbio.03294-21
    [64] D. Morgan, L. McLain, N. Dimmock, Apical budding of a recombinant influenza A virus expressing a hemagglutinin protein with a basolateral localization signal, Virus Res., 29 (1993), 179–193. doi: 10.1016/0168-1702(93)90058-U
    [65] A. J. Easton, P. D. Scott, N. L. Edworthy, B. Meng, A. C. Marriott, N. J. Dimmock, A novel broad-spectrum treatment for respiratory virus infections: Influenza-based defective interfering virus provides protection against pneumovirus infection in vivo, Vaccine, 29 (2011), 2777–2784. doi: 10.1016/j.vaccine.2011.01.102
    [66] A. Mann, A. Marriott, S. Balasingam, R. Lambkin, J. Oxford, N. Dimmock, Interfering vaccine (defective interfering influenza A virus) protects ferrets from influenza, and allows them to develop solid immunity to reinfection, Vaccine, 24 (2006), 4290–4296. doi: 10.1016/j.vaccine.2006.03.004
    [67] M. D. Hein, H. Kollmus, P. Marichal-Gallardo, S. Puttker, D. Benndorf, Y. Genzel, et al., OP7, a novel influenza A virus defective interfering particle: Production, purification, and animal experiments demonstrating antiviral potential, Appl. Microbiol. Biotech., 105 (2021), 129–146. doi: 10.1007/s00253-020-11029-5
    [68] M.-H. Lin, D. S. Li, B. Tang, L. Li, A. Suhrbier, D. Harrich, Defective interfering particles with broad-acting antiviral activity for dengue, zika, yellow fever, respiratory syncytial and SARS-CoV-2 virus infection, Microbiol. Spectrum, (November 2022).
    [69] S. Chaturvedi, G. Vasen, M. Pablo, X. Y. Chen, N. Beutler, A. Kumar, et al., Identification of a therapeutic interfering particle-a single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance, Cell, 184 (2021), 6022. doi: 10.1016/j.cell.2021.11.004
    [70] S. M. Petrie, J. Butler, I. G. Barr, J. McVernon, A. C. Hurt, J. M. McCaw, Quantifying relative within-host replication fitness in influenza virus competition experiments, J. Theor. Biol., 382 (2015), 259–271. doi: 10.1016/j.jtbi.2015.07.003
    [71] H. Miao, X. Xia, A. S. Perelson, H. Wu, On identifiability of nonlinear ODE models and applications in viral dynamics, SIAM Rev., 53 (2011), 3–39. doi: 10.1137/090757009
  • Reader Comments
  • © 2023 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (
通讯作者: 陈斌,
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索


Article views(753) PDF downloads(63) Cited by(0)

Article outline

Figures and Tables

Figures(4)  /  Tables(4)

Other Articles By Authors


DownLoad:  Full-Size Img  PowerPoint