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
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. https://doi.org/10.1007/s40121-020-00387-2 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. https://doi.org/10.1093/infdis/jiac172 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. https://doi.org/0.1186/s12879-021-06461-5 |
[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. https://doi.org/10.1093/cid/ciab1014 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. https://doi.org/10.1002/jmv.27857 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. https://doi.org/10.1128/Spectrum.00430-21 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. https://doi.org/10.1093/infdis/jit038 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. https://doi.org/10.1007/s12016-007-8033-2 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. https://doi.org/10.1038/s41564-021-00882-3 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. https://doi.org/10.1098/rsif.2016.0412 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). https://doi.org/10.1128/jvi.01178-22 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. https://doi.org/10.1016/0042-6822(73)90197-9 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. https://doi.org/10.1128/JVI.25.1.202-206.1978 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. https://doi.org/10.1073/pnas.74.4.1353 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. https://doi.org/10.1128/JVI.7.4.478-485.1971 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. https://doi.org/10.1016/0022-2836(73)90508-1 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. https://doi.org/10.1371/journal.ppat.1009277 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. https://doi.org/10.1007/BF02121722 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. https://doi.org/10.1038/s42003-022-04058-5 doi: 10.1038/s42003-022-04058-5 |
[22] | S. Rhode, Defective interfering particles of parvovirus H-1, J. Virol., 27 (1978), 347–356. https://doi.org/10.1128/JVI.27.2.347-356.1978 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. https://doi.org/10.1016/0042-6822(90)90150-P 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. https://doi.org/10.1016/j.tim.2020.02.006 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. https://doi.org/10.1159/000071461 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. https://doi.org/10.1371/journal.ppat.1005122 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. https://doi.org/10.1128/mBio.02880-19 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. https://doi.org/10.1016/j.vaccine.2013.09.040 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. https://doi.org/10.1016/j.cell.2021.11.023 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. https://doi.org/10.1016/0966-842X(93)90048-V 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. https://doi.org/10.1016/j.coviro.2018.07.014 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. https://doi.org/10.3390/v14020383 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. https://doi.org/10.1099/vir.0.005249-0 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. https://doi.org/10.1371/journal.pcbi.1006668 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. https://doi.org/10.1038/s41598-021-03168-0 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. https://doi.org/10.1128/JVI.00977–21 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. https://doi.org/10.1371/journal.pcbi.1006819 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. https://doi.org/10.1371/journal.pcbi.1009357 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. https://doi.org/10.1128/JVI.0724411 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. https://doi.org/10.1371/journal.pone.0126115 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. https://doi.org/10.1098/rsif.2019.0389 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. doilinkhttps://doi.org/10.1016/j.virusres.2021.198524 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. https://doi.org/10.1098/rsos.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. https://doi.org/10.1016/j.virol.2020.07.015 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. https://doi.org/10.1128/JVI.01623-05 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. https://doi.org/10.1007/s00285-009-0281-8 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. https://doi.org/doi:10.1186/1471-2458-11-S1-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. https://doi.org/10.1016/j.jtbi.2018.07.029 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. https://doi.org/10.1371/journal.pone.0192645 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. https://doi.org/10.1128/JVI.01174-21 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. https://doi.org/10.3390/v7072796 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. https://doi.org/10.1371/journal.pone.0057088 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. https://doi.org/10.1002/jmv.24687 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. https://doi.org/10.1007/s42770-022-00742-0 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. https://doi.org/10.1002/jmv.24111 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. https://doi.org/10.3390/ijms18030654 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. https://doi.org/10.1016/j.cmi.2020.03.023 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. https://doi.org/10.1093/infdis/jiaa076 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. https://doi.org/10.1164/rccm.201002-0221OC 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. https://doi.org/10.3851/IMP2629 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. https://doi.org/10.1186/1743-422X-8-212 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. https://doi.org/10.1128/mbio.03294-21 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. https://doi.org/10.1016/0168-1702(93)90058-U 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. https://doi.org/10.1016/j.vaccine.2011.01.102 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. https://doi.org/10.1016/j.vaccine.2006.03.004 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. https://doi.org/10.1007/s00253-020-11029-5 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). https://doi.org/10.1128/spectrum.03949-22 |
[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. https://doi.org/10.1016/j.cell.2021.11.004 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. https://doi.org/10.1016/j.jtbi.2015.07.003 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. https://doi.org/10.1137/090757009 doi: 10.1137/090757009 |