Science - 06.12.2019

(singke) #1

The probability ofkor more events occurring
inthetimeintervalisthen


PðX≥kÞ¼ 1 Qðk;lÞ

which can be solved forlnumerically using
the inverse incomplete regularized gamma
function,


l¼Q^1 ½ 1 PðX≥kÞ;kŠ

The total time to acquirekor more mu-
tations is thenlΤ.
The probability of acquiring at leastk=4
improbable mutations given a rate parameter
of 1 improbable mutation every 12 weeks is
plotted as a function of time in fig. S19C. For
P(X≥4) = 0.99, the number of 12-week inter-
vals is 10.05 to acquire at least four improbable
mutations. Thus, mice would need to be im-
munized biweekly for ~120 weeks in order to
achieve 99% probability of acquiring at least
four improbable mutations.


Quantification and statistical analysis


The statistical analyses for this paper were per-
formed in SAS 9.4 to calculate exact Wilcoxon
tests for group comparisons. Due to the ex-
ploratorynatureofthisresearchandthesmall
sample size, we are using an alpha level of
0.05 as a descriptive level for significance
and have not made any adjustments to con-
trol for multiple testing. For group sizes less
than 5, no paired-sample comparisons were
performed due to the small sample size; only
descriptive statistics are provided in these
instances.


REFERENCES AND NOTES



  1. B. F. Haynes, D. R. Burton, Developing an HIV vaccine.
    Science 355 , 1129–1130 (2017). doi:10.1126/science.aan0662;
    pmid: 28302812

  2. B. F. Haynes, J. R. Mascola, The quest for an antibody-based
    HIV vaccine.Immunol. Rev. 275 ,5–10 (2017). doi:10.1111/
    imr.12517; pmid: 28133795

  3. B. F. Hayneset al., Cardiolipin polyspecific autoreactivity in two
    broadly neutralizing HIV-1 antibodies.Science 308 , 1906– 1908
    (2005). doi:10.1126/science.1111781; pmid: 15860590

  4. B. F. Hayneset al., HIV-Host Interactions: Implications for
    Vaccine Design.Cell Host Microbe 19 , 292–303 (2016).
    doi:10.1016/j.chom.2016.02.002; pmid: 26922989

  5. F. Kleinet al., Somatic mutations of the immunoglobulin
    framework are generally required for broad and potent
    HIV-1 neutralization.Cell 153 , 126–138 (2013). doi:10.1016/
    j.cell.2013.03.018; pmid: 23540694

  6. H. X. Liaoet al., Co-evolution of a broadly neutralizing
    HIV-1 antibody and founder virus.Nature 496 , 469– 476
    (2013). doi:10.1038/nature12053; pmid: 23552890

  7. X. Wuet al., Maturation and Diversity of the VRC01-Antibody
    Lineage over 15 Years of Chronic HIV-1 Infection.Cell 161 ,
    470 – 485 (2015). doi:10.1016/j.cell.2015.03.004;pmid:25865483

  8. J. M. Di Noia, M. S. Neuberger, Molecular mechanisms of
    antibody somatic hypermutation.Annu. Rev. Biochem. 76 ,1– 22
    (2007). doi:10.1146/annurev.biochem.76.061705.090740;
    pmid: 17328676

  9. A. G. Betz, C. Rada, R. Pannell, C. Milstein, M. S. Neuberger,
    Passenger transgenes reveal intrinsic specificity of the
    antibody hypermutation mechanism: Clustering, polarity, and
    specific hotspots.Proc. Natl. Acad. Sci. U.S.A. 90 , 2385– 2388
    (1993). doi:10.1073/pnas.90.6.2385; pmid: 8460148

  10. K. Wieheet al., Functional Relevance of Improbable Antibody
    Mutations for HIV Broadly Neutralizing Antibody Development.


Cell Host Microbe 23 , 759–765.e6 (2018). doi:10.1016/
j.chom.2018.04.018; pmid: 29861171


  1. C. A. Schramm, D. C. Douek, Beyond Hot Spots: Biases in
    Antibody Somatic Hypermutation and Implications for Vaccine
    Design.Front. Immunol. 9 , 1876 (2018). doi:10.3389/
    fimmu.2018.01876; pmid: 30154794

  2. J. K. Hwanget al., Sequence intrinsic somatic mutation
    mechanisms contribute to affinity maturation of VRC01-class
    HIV-1 broadly neutralizing antibodies.Proc. Natl. Acad. Sci. U.S.A.
    114 ,8614–8619 (2017). doi:10.1073/pnas.1709203114;
    pmid: 28747530

  3. B. F. Haynes, G. Kelsoe, S. C. Harrison, T. B. Kepler,
    B-cell-lineage immunogen design in vaccine development with
    HIV-1 as a case study.Nat. Biotechnol. 30 , 423–433 (2012).
    doi:10.1038/nbt.2197; pmid: 22565972

  4. A. Escolanoet al., Sequential Immunization Elicits Broadly
    Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice.Cell
    166 , 1445–1458.e12 (2016). doi:10.1016/j.cell.2016.07.030;
    pmid: 27610569

  5. A. Escolanoet al., Immunization expands B cells specific to
    HIV-1 V3 glycan in mice and macaques.Nature 570 , 468– 473
    (2019). doi:10.1038/s41586-019-1250-z; pmid: 31142836

  6. R. N. Germain, The art of the probable: System control in
    the adaptive immune system.Science 293 , 240–245 (2001).
    doi:10.1126/science.1062946; pmid: 11452112

  7. A. Ribas, J. D. Wolchok, Cancer immunotherapy using
    checkpoint blockade.Science 359 , 1350–1355 (2018).
    doi: 10 .1126/science.aar4060; pmid:^29567705

  8. M. Bonsignoriet al., Staged induction of HIV-1 glycan-dependent
    broadly neutralizing antibodies.Sci. Transl. Med. 9 , eaai7514
    (2017). doi:10.1126/scitranslmed.aai7514;pmid:28298420

  9. L. M. Walkeret al., Broad neutralization coverage of HIV by
    multiple highly potent antibodies.Nature 477 , 466–470 (2011).
    doi:10.1038/nature10373; pmid: 21849977

  10. C. N. Daniels, K. O. Saunders, Antibody responses to the
    HIV-1 envelope high mannose patch.Adv. Immunol. 143 ,11– 73
    (2019). doi:10.1016/bs.ai.2019.08.002; pmid: 31607367

  11. L. Konget al., Supersite of immune vulnerability on the
    glycosylated face of HIV-1 envelope glycoprotein gp120.
    Nat. Struct. Mol. Biol. 20 , 796–803 (2013). doi:10.1038/
    nsmb.2594; pmid: 23708606

  12. F. Gaoet al., Cooperation of B cell lineages in induction of
    HIV-1-broadly neutralizing antibodies.Cell 158 , 481–491 (2014).
    doi:10.1016/j.cell.2014.06.022; pmid: 25065977

  13. M. Bonsignoriet al., Maturation Pathway from Germline to
    Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.Cell 165 ,
    449 – 463 (2016). doi:10.1016/j.cell.2016.02.022;pmid:26949186

  14. Y. D. Kwonet al., Crystal structure, conformational fixation and
    entry-related interactions of mature ligand-free HIV-1 Env.
    Nat. Struct. Mol. Biol. 22 , 522–531 (2015). doi:10.1038/
    nsmb.3051; pmid: 26098315

  15. S. W. de Taeyeet al., Immunogenicity of Stabilized HIV-1 Envelope
    Trimers with Reduced Exposure of Non-neutralizing Epitopes.
    Cell 163 ,1702–1715 (2015). doi:10.1016/j.cell.2015.11.056;
    pmid: 26687358

  16. A. Torrents de la Peñaet al., Improving the Immunogenicity
    of Native-like HIV-1 Envelope Trimers by Hyperstabilization.
    Cell Rep. 20 , 1805–1817 (2017). doi:10.1016/
    j.celrep.2017.07.077; pmid: 28834745

  17. D. Jung, C. Giallourakis, R. Mostoslavsky, F. W. Alt, Mechanism
    and control of V(D)J recombination at the immunoglobulin
    heavy chain locus.Annu. Rev. Immunol. 24 , 541– 570
    (2006). doi:10.1146/annurev.immunol.23.021704.115830;
    pmid: 16551259

  18. L. R. Covey, P. Ferrier, F. W. Alt, VH to VHDJH rearrangement is
    mediated by the internal VH heptamer.Int. Immunol. 2 ,
    579 – 583 (1990). doi:10.1093/intimm/2.6.579; pmid: 2085492

  19. R. Kleinfieldet al., Recombination between an expressed
    immunoglobulin heavy-chain gene and a germline variable
    gene segment in a Ly 1+ B-cell lymphoma.Nature 322 ,
    843 – 846 (1986). doi:10.1038/322843a0; pmid: 3092106

  20. R. W. Kleinfield, M. G. Weigert, Analysis of VH gene
    replacement events in a B cell lymphoma.J. Immunol. 142 ,
    4475 – 4482 (1989). pmid: 2498430

  21. C. Chen, Z. Nagy, E. L. Prak, M. Weigert, Immunoglobulin heavy
    chain gene replacement: A mechanism of receptor editing.
    Immunity 3 , 747–755 (1995). doi:10.1016/1074-7613(95)
    90064-0; pmid: 8777720

  22. S. L. Tiegs, D. M. Russell, D. Nemazee, Receptor editing in self-
    reactive bone marrow B cells.J. Exp. Med. 177 , 1009– 1020
    (1993). doi:10.1084/jem.177.4.1009; pmid: 8459201

  23. D. Gay, T. Saunders, S. Camper, M. Weigert, Receptor editing:
    An approach by autoreactive B cells to escape tolerance.


J. Exp. Med. 177 , 999–1008 (1993). doi:10.1084/
jem.177.4.999; pmid: 8459227


  1. E. L. Prak, M. Weigert, Light chain replacement: A new model
    for antibody gene rearrangement.J. Exp. Med. 182 , 541– 548
    (1995). doi: 10 .1084/jem.182.2.541; pmid: 7629511

  2. G. Kelsoe, L. Verkoczy, B. F. Haynes, Immune System
    Regulation in the Induction of Broadly Neutralizing
    HIV-1 Antibodies.Vaccines 2 ,1–14 (2014). doi:10.3390/
    vaccines2010001; pmid: 24932410

  3. L. Verkoczyet al., Autoreactivity in an HIV-1 broadly reactive
    neutralizing antibody variable region heavy chain induces
    immunologic tolerance.Proc. Natl. Acad. Sci. U.S.A. 107 ,181– 186
    (2010). doi:10.1073/pnas.0912914107;pmid: 20018688

  4. C. Doyle-Cooperet al., Immune tolerance negatively regulates
    B cells in knock-in mice expressing broadly neutralizing
    HIV antibody 4E10.J. Immunol. 191 , 3186–3191 (2013).
    doi:10.4049/jimmunol.1301285; pmid: 23940276

  5. Y. Chenet al., Common tolerance mechanisms, but distinct
    cross-reactivities associated with gp41 and lipids, limit
    production of HIV-1 broad neutralizing antibodies 2F5 and
    4E10.J. Immunol. 191 , 1260–1275 (2013). doi:10.4049/
    jimmunol.1300770; pmid: 23825311

  6. P. Martinez-Murilloet al., Particulate Array of Well-Ordered
    HIV Clade C Env Trimers Elicits Neutralizing Antibodies that
    Display a Unique V2 Cap Approach.Immunity 46 , 804–817.e7
    (2017). doi:10.1016/j.immuni.2017.04.021; pmid: 28514687

  7. C. D. Morriset al., Differential Antibody Responses to
    Conserved HIV-1 Neutralizing Epitopes in the Context of
    Multivalent Scaffolds and Native-Like gp140 Trimers.mBio 8 ,
    e00036-17 (2017). doi:10.1128/mBio.00036-17; pmid: 28246356

  8. J. Ingaleet al., High-Density Array of Well-Ordered HIV-1 Spikes
    on Synthetic Liposomal Nanoparticles Efficiently Activate B
    Cells.Cell Rep. 15 , 1986–1999 (2016). doi:10.1016/
    j.celrep.2016.04.078; pmid: 27210756

  9. L. Heet al., Presenting native-like trimeric HIV-1 antigens with
    self-assembling nanoparticles.Nat. Commun. 7 , 12041
    (2016). doi:10.1038/ncomms12041; pmid: 27349934

  10. M. Kanekiyoet al., Self-assembling influenza nanoparticle
    vaccines elicit broadly neutralizing H1N1 antibodies.Nature
    499 , 102–106 (2013). doi:10.1038/nature12202;pmid:23698367

  11. F. D. Batista, M. S. Neuberger, B cells extract and present
    immobilized antigen: Implications for affinity discrimination.
    EMBO J. 19 , 513–520 (2000). doi:10.1093/emboj/19.4.513;
    pmid: 10675320

  12. K. Sliepenet al., Presenting native-like HIV-1 envelope trimers
    on ferritin nanoparticles improves their immunogenicity.
    Retrovirology 12 , 82 (2015). doi:10.1186/s12977-015-0210-4;
    pmid: 26410741

  13. T. Tokatlianet al., Innate immune recognition of glycans
    targets HIV nanoparticle immunogens to germinal centers.
    Science 363 , 649–654 (2019). doi:10.1126/science.aat9120;
    pmid: 30573546

  14. D. Feraet al., HIV envelope V3 region mimic embodies key
    features of a broadly neutralizing antibody lineage epitope.
    Nat. Commun. 9 , 1111 (2018). doi:10.1038/s41467-018-03565-6;
    pmid: 29549260

  15. S. Dutta, P. Sengupta, Men and mice: Relating their ages.
    Life Sci. 152 , 244–248 (2016). doi:10.1016/j.lfs.2015.10.025;
    pmid: 26596563

  16. Z. Shenget al., Effects of Darwinian Selection and Mutability on
    Rate of Broadly Neutralizing Antibody Evolution during
    HIV-1 Infection.PLOS Comput. Biol. 12 , e1004940 (2016).
    doi:10.1371/journal.pcbi.1004940; pmid: 27191167

  17. M. Tianet al., Induction of HIV Neutralizing Antibody Lineages
    in Mice with Diverse Precursor Repertoires.Cell 166 ,
    1471 – 1484.e18 (2016). doi:10.1016/j.cell.2016.07.029;
    pmid: 27610571

  18. R.K. Abbottet al., Precursor Frequency and Affinity Determine
    B Cell Competitive Fitness in Germinal Centers, Tested
    with Germline-Targeting HIV Vaccine Immunogens.Immunity
    48 , 133–146.e6 (2018). doi:10.1016/j.immuni.2017.11.023;
    pmid: 29287996

  19. C. C. LaBrancheet al., Neutralization-guided design of
    HIV-1 envelope trimers with high affinity for the unmutated
    common ancestor of CH235 lineage CD4bs broadly
    neutralizing antibodies.PLOS Pathog. 15 , e1008026 (2019).
    doi:10.1371/journal.ppat.1008026; pmid: 31527908

  20. K. M. Cirelliet al., Slow Delivery Immunization Enhances HIV
    Neutralizing Antibody and Germinal Center Responses via
    Modulation of Immunodominance.Cell 177 , 1153–1171.e28
    (2019). doi:10.1016/j.cell.2019.04.012; pmid: 31080066

  21. M. Pauthneret al., Elicitation of Robust Tier 2 Neutralizing
    Antibody Responses in Nonhuman Primates by HIV Envelope


Saunderset al.,Science 366 , eaay7199 (2019) 6 December 2019 16 of 17


RESEARCH | RESEARCH ARTICLE


on December 12, 2019^

http://science.sciencemag.org/

Downloaded from
Free download pdf