Estimating the basic reproduction number of a pathogen in a single host when only a single founder successfully infects

Autoři: Vruj Patel aff001;  John L. Spouge aff001
Působiště autorů: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America aff001
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227127


If viruses or other pathogens infect a single host, the outcome of infection may depend on the initial basic reproduction number R0, the expected number of host cells infected by a single infected cell. This article shows that sometimes, phylogenetic models can estimate the initial R0, using only sequences sampled from the pathogenic population during its exponential growth or shortly thereafter. When evaluated by simulations mimicking the bursting viral reproduction of HIV and simultaneous sampling of HIV gp120 sequences during early viremia, the estimated R0 displayed useful accuracies in achievable experimental designs. Estimates of R0 have several potential applications to investigators interested in the progress of infection in single hosts, including: (1) timing a pathogen’s movement through different microenvironments; (2) timing the change points in a pathogen’s mode of spread (e.g., timing the change from cell-free spread to cell-to-cell spread, or vice versa, in an HIV infection); (3) quantifying the impact different initial microenvironments have on pathogens (e.g., in mucosal challenge with HIV, quantifying the impact that the presence or absence of mucosal infection has on R0); (4) quantifying subtle changes in infectability in therapeutic trials (either human or animal), even when therapies do not produce total sterilizing immunity; and (5) providing a variable predictive of the clinical efficacy of prophylactic therapies.

Klíčová slova:

Approximation methods – HIV – HIV infections – Infectious disease epidemiology – Mutation detection – Sequence alignment – Viral pathogens – Viremia


1. Giorgi EE, Funkhouser B, Athreya G, Perelson AS, Korber BT, et al. (2010) Estimating time since infection in early homogeneous HIV-1 samples using a poisson model. BMC Bioinformatics 11.

2. Koff WC, Johnson PR, Watkins DI, Burton DR, Lifson JD, et al. (2006) HIV vaccine design: insights from live attenuated SIV vaccines. Nature Immunology 7: 19–23. doi: 10.1038/ni1296 16357854

3. Nolen TL, Hudgens MG, Senb PK, Koch GG (2015) Analysis of repeated low-dose challenge studies. Statistics in Medicine 34: 1981–1992. doi: 10.1002/sim.6462 25752266

4. Gordon SN, Liyanage NPM, Doster MN, Vaccari M, Vargas-Inchaustegui DA, et al. (2016) Boosting of ALVAC-SIV Vaccine-Primed Macaques with the CD4-SIVgp120 Fusion Protein Elicits Antibodies to V2 Associated with a Decreased Risk of SIVmac251 Acquisition. Journal of Immunology 197: 2726–2737.

5. Strbo N, Vaccari M, Pahwa S, Kolber MA, Doster MN, et al. (2013) Cutting Edge: Novel Vaccination Modality Provides Significant Protection against Mucosal Infection by Highly Pathogenic Simian Immunodeficiency Virus. Journal of Immunology 190: 2495–2499.

6. Regoes RR, Longini IM, Feinberg MB, Staprans SI (2005) Preclinical assessment of HIV vaccines and microbicides by repeated low-dose virus challenges. Plos Medicine 2: 798–807.

7. Patel P, Borkowf CB, Brooks JT, Lasry A, Lansky A, et al. (2014) Estimating per-act HIV transmission risk: a systematic review. Aids 28: 1509–1519. doi: 10.1097/QAD.0000000000000298 24809629

8. Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, et al. (2003) Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. Aids 17: 1871–1879. doi: 10.1097/00002030-200309050-00005 12960819

9. Kahn JO, Walker BD (1998) Acute human immunodeficiency virus type 1 infection. New England Journal of Medicine 339: 33–39. doi: 10.1056/NEJM199807023390107 9647878

10. Salazar-Gonzalez JF, Bailes E, Pham KT, Salazar MG, Guffey MB, et al. (2008) Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing. Journal of Virology 82: 3952–3970. doi: 10.1128/JVI.02660-07 18256145

11. Stafford MA, Corey L, Cao YZ, Daar ES, Ho DD, et al. (2000) Modeling plasma virus concentration during primary HIV infection. Journal of Theoretical Biology 203: 285–301. doi: 10.1006/jtbi.2000.1076 10716909

12. Ribeiro RM, Qin L, Chavez LL, Li DF, Self SG, et al. (2010) Estimation of the Initial Viral Growth Rate and Basic Reproductive Number during Acute HIV-1 Infection. Journal of Virology 84: 6096–6102. doi: 10.1128/JVI.00127-10 20357090

13. Kosaka PM, Pini V, Calleja M, Tamayo J (2017) Ultrasensitive detection of HIV-1 p24 antigen by a hybrid nanomechanical-optoplasmonic platform with potential for detecting HIV-1 at first week after infection. Plos One 12.

14. Wolinsky SM, Wike CM, Korber BTM, Hutto C, Parks WP, et al. (1992) Selective Transmission of Human-Immunodeficiency-Virus Type-1 Variants from Mothers to Infants. Science 255: 1134–1137. doi: 10.1126/science.1546316 1546316

15. Delwart E, Magierowska M, Royz M, Foley B, Peddada L, et al. (2002) Homogeneous quasispecies in 16 out of 17 individuals during very early HIV-1 primary infection. Aids 16: 189–195. doi: 10.1097/00002030-200201250-00007 11807302

16. Derdeyn CA, Decker JM, Bibollet-Ruche F, Mokili JL, Muldoon M, et al. (2004) Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science 303: 2019–2022. doi: 10.1126/science.1093137 15044802

17. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, et al. (2008) Identification and characterisation of transmitted and early founder virus envelopes in primary HIV-1 infection. Proceedings of the National Academy of Sciences of the United States of America 105: 7552–7557. doi: 10.1073/pnas.0802203105 18490657

18. Haaland RE, Hawkins PA, Salazar-Gonzalez J, Johnson A, Tichacek A, et al. (2009) Inflammatory Genital Infections Mitigate a Severe Genetic Bottleneck in Heterosexual Transmission of Subtype A and C HIV-1. Plos Pathogens 5.

19. Love TMT, Park SY, Giorgi EE, Mack WJ, Perelson AS, et al. (2016) SPMM: estimating infection duration of multivariant HIV-1 infections. Bioinformatics 32: 1308–1315. doi: 10.1093/bioinformatics/btv749 26722117

20. Spouge JL (2019) An accurate approximation for the expected site frequency spectrum in a Galton-Watson process under an infinite sites mutation model. Theor Popul Biol 12: 30151–30155.

21. Bellman R, Harris TE (1948) On the Theory of Age-Dependent Stochastic Branching Processes. Proceedings of the National Academy of Sciences of the United States of America 34: 601–604. doi: 10.1073/pnas.34.12.601 16588841

22. Knuth DE (1992) 2 Notes on Notation. American Mathematical Monthly 99: 403–422.

23. Kimura M (1969) Number of heterozygous nucleotide sites maintained in a finite population due to steady flux of mutations. Genetics 61: 893–903. 5364968

24. Park SY, Love TMT, Perelson AS, Mack WJ, Lee HY (2016) Molecular clock of HIV-1 envelope genes under early immune selection. Retrovirology 13.

25. Fu YX (1995) Statistical properties of segregating sites. Theoretical Population Biology 48: 172–197. doi: 10.1006/tpbi.1995.1025 7482370

26. Athreya KB, Ney PE (2004) Branching Processes. Mineola, New York: Dover.

27. Wakeley J (2009) Coalescent Theory. Greenwood Village CO: Roberts and Company.

28. Graham RL, Knuth DE, Ptashnik O (1994) Concrete mathematics: a foundation for computer science. New York: Addison-Wesley.

29. Markowitz M, Louie M, Hurley A, Sun E, Di Mascio M (2003) A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-Cell decay in vivo. Journal of Virology 77: 5037–5038. doi: 10.1128/JVI.77.8.5037-5038.2003 12663814

30. Lee HY, Giorgi EE, Keele BF, Gaschen B, Athreya GS, et al. (2009) Modeling sequence evolution in acute HIV-1 infection. Journal of Theoretical Biology 261: 341–360. doi: 10.1016/j.jtbi.2009.07.038 19660475

31. Zhang CW, Zhou S, Groppelli E, Pellegrino P, Williams I, et al. (2015) Hybrid Spreading Mechanisms and T Cell Activation Shape the Dynamics of HIV-1 Infection. Plos Computational Biology 11.

32. Layne SP, Merges MJ, Dembo M, Spouge JL, Nara PL (1990) {HIV} requires multiple gp120 molecules for {CD4}-mediated infection. Nature 346: 277–279. doi: 10.1038/346277a0 2374593

33. Spouge JL (1994) Viral multiplicity of attachment and its implications for human-immunodeficiency-virus therapies. Journal of Virology 68: 1782–1789. 8107240

34. Ward H, Rönn M (2010) The contribution of STIs to the sexual transmission of HIV. Current opinion in HIV and AIDS 5: 305–310. doi: 10.1097/COH.0b013e32833a8844 20543605

35. Carneiro MO, Russ C, Ross MG, Gabriel SB, Nusbaum C, et al. (2012) Pacific biosciences sequencing technology for genotyping and variation discovery in human data. BMC Genomics 13: 375. doi: 10.1186/1471-2164-13-375 22863213

36. McElroy K, Thomas T, Luciani F (2014) Deep sequencing of evolving pathogen populations: applications, errors, and bioinformatic solutions. Microbial Informatics and Experimentation 4: 1. doi: 10.1186/2042-5783-4-1 24428920

37. Moore RD, Keruly JC (2007) CD4(+) cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clinical Infectious Diseases 44: 441–446. doi: 10.1086/510746 17205456

38. Fidler (2013) Short-Course Antiretroviral Therapy in Primary HIV Infection. The New England journal of medicine 368: 207–217. doi: 10.1056/NEJMoa1110039 23323897

39. Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLOS Pathogens 9: e1003211. doi: 10.1371/journal.ppat.1003211 23516360

Článek vyšel v časopise


2020 Číslo 1