Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer
Colin Havenar-Daughton, Diane G Carnathan, Alba Torrents de la Peña, Matthias Pauthner, Bryan Briney, Samantha M Reiss, Jennifer S Wood, Kirti Kaushik, Marit J van Gils, Sandy L Rosales, Patricia van der Woude, Michela Locci, Khoa M Le, Steven W de Taeye, Devin Sok, Ata Ur Rasheed Mohammed, Jessica Huang, Sanjeev Gumber, AnaPatricia Garcia, Sudhir P Kasturi, Bali Pulendran, John P Moore, Rafi Ahmed, Grégory Seumois, Dennis R Burton, Rogier W Sanders, Guido Silvestri, Shane Crotty, Colin Havenar-Daughton, Diane G Carnathan, Alba Torrents de la Peña, Matthias Pauthner, Bryan Briney, Samantha M Reiss, Jennifer S Wood, Kirti Kaushik, Marit J van Gils, Sandy L Rosales, Patricia van der Woude, Michela Locci, Khoa M Le, Steven W de Taeye, Devin Sok, Ata Ur Rasheed Mohammed, Jessica Huang, Sanjeev Gumber, AnaPatricia Garcia, Sudhir P Kasturi, Bali Pulendran, John P Moore, Rafi Ahmed, Grégory Seumois, Dennis R Burton, Rogier W Sanders, Guido Silvestri, Shane Crotty
Abstract
Generating tier 2 HIV-neutralizing antibody (nAb) responses by immunization remains a challenging problem, and the immunological barriers to induction of such responses with Env immunogens remain unclear. Here, some rhesus monkeys developed autologous tier 2 nAbs upon HIV Env trimer immunization (SOSIP.v5.2) whereas others did not. This was not because HIV Env trimers were immunologically silent because all monkeys made similar ELISA-binding antibody responses; the key difference was nAb versus non-nAb responses. We explored the immunological barriers to HIV nAb responses by combining a suite of techniques, including longitudinal lymph node fine needle aspirates. Unexpectedly, nAb development best correlated with booster immunization GC B cell magnitude and Tfh characteristics of the Env-specific CD4 T cells. Notably, these factors distinguished between successful and unsuccessful antibody responses because GC B cell frequencies and stoichiometry to GC Tfh cells correlated with nAb development, but did not correlate with total Env Ab binding titers.
Keywords: vaccines.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
Figures
References
- Burton DR, Hangartner L. Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. Annu. Rev. Immunol. 2016;34:635–659.
- Burton DR, Mascola JR. Antibody responses to envelope glycoproteins in HIV-1 infection. Nat Immunol. 2015;16:571–576.
- Cohen K, Altfeld M, Alter G, Stamatatos L. Early preservation of CXCR5+ PD-1+ helper T cells and B cell activation predict the breadth of neutralizing antibody responses in chronic HIV-1 infection. J. Virol. 2014;88:13310–13321.
- Corti D, Lanzavecchia A. Broadly neutralizing antiviral antibodies. Annu. Rev. Immunol. 2013;31:705–742.
- Crotty S. Follicular helper CD4 T cells (TFH) Annu. Rev. Immunol. 2011;29:621–663.
- Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41:529–542.
- Dan JM, Lindestam Arlehamn CS, Weiskopf D, da Silva Antunes R, Havenar-Daughton C, Reiss SM, Brigger M, Bothwell M, Sette A, Crotty S. A Cytokine-Independent Approach To Identify Antigen-Specific Human Germinal Center T Follicular Helper Cells and Rare Antigen-Specific CD4+ T Cells in Blood. The Journal of Immunology. 2016;197:983–993.
- de Taeye SW, Ozorowski G, Torrents de la Peña A, Guttman M, Julien J-P, van den Kerkhof TLGM, Burger JA, Pritchard LK, Pugach P, Yasmeen A, et al. Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes. Cell. 2015;163:1702–1715.
- Diamantis A, Magiorkinis E, Koutselini H. Fine-needle aspiration (FNA) biopsy: historical aspects. Folia Histochem. Cytobiol. 2009;47:191–197.
- Dogan I, Bertocci B, Vilmont V, Delbos F, Mégret J, Storck S, Reynaud C-A, Weill J-C. Multiple layers of B cell memory with different effector functions. Nat Immunol. 2009;10:1292–1299.
- Evans TG, McElrath MJ, Matthews T, Montefiori D, Weinhold K, Wolff M, Keefer MC, Kallas EG, Corey L, Gorse GJ, et al. QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immunization in humans. Vaccine. 2001;19:2080–2091.
- Francica JR, Sheng Z, Zhang Z, Nishimura Y, Shingai M, Ramesh A, Keele BF, Schmidt SD, Flynn BJ, Darko S, et al. Analysis of immunoglobulin transcripts and hypermutation following SHIV(AD8) infection and protein-plus-adjuvant immunization. Nature Communications. 2015;6:6565.
- Gautam R, Nishimura Y, Pegu A, Nason MC, Klein F, Gazumyan A, Golijanin J, Buckler-White A, Sadjadpour R, Wang K, et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature. 2016
- Guenaga J, Dubrovskaya V, de Val N, Sharma SK, Carrette B, Ward AB, Wyatt RT. Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J. Virol. 2016;90:2806–2817.
- Havenar-Daughton C, Lindqvist M, Heit A, Wu JE, Reiss SM, Kendric K, Belanger S, Kasturi SP, Landais E, Akondy RS, et al. CXCL13 is a plasma biomarker of germinal center activity. Proceedings of the National Academy of Sciences. 2016a;113:2702–2707.
- Havenar-Daughton C, Reiss SM, Carnathan DG, Wu JE, Kendric K, Torrents de la Peña A, Kasturi SP, Dan JM, Bothwell M, Sanders RW, et al. Cytokine-Independent Detection of Antigen-Specific Germinal Center T Follicular Helper Cells in Immunized Nonhuman Primates Using a Live Cell Activation-Induced Marker Technique. The Journal of Immunology. 2016b;197:994–1002.
- Haynes BF, Shaw GM, Korber B, Kelsoe G, Sodroski J, Hahn BH, Borrow P, McMichael AJ. HIV-Host Interactions: Implications for Vaccine Design. Cell Host and Microbe. 2016;19:292–303.
- Hessell AJ, Haigwood NL. Animal models in HIV-1 protection and therapy. Curr Opin HIV AIDS. 2015;10:170–176.
- Hessell AJ, Malherbe DC, Pissani F, McBurney S, Krebs SJ, Gomes M, Pandey S, Sutton WF, Burwitz BJ, Gray M, et al. Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens. The Journal of Immunology. 2016;196:3064–3078.
- Hong JJ, Amancha PK, Rogers KA, Courtney CL, Havenar-Daughton C, Crotty S, Ansari AA, Villinger F. Early lymphoid responses and germinal center formation correlate with lower viral load set points and better prognosis of simian immunodeficiency virus infection. The Journal of Immunology. 2014;193:797–806.
- Hu JK, Crampton JC, Cupo A, Ketas T, van Gils MJ, Sliepen K, de Taeye SW, Sok D, Ozorowski G, Deresa I, et al. Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity. J. Virol. 2015;89:10383–10398.
- Jardine JG, Kulp DW, Havenar-Daughton C, Sarkar A, Briney B, Sok D, Sesterhenn F, Ereño-Orbea J, Kalyuzhniy O, Deresa I, et al. HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science. 2016;351:1458–1463.
- Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, Dent AL, Craft J, Crotty S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325:1006–1010.
- Julien J-P, Cupo A, Sok D, Stanfield RL, Lyumkis D, Deller MC, Klasse P-J, Burton DR, Sanders RW, Moore JP, et al. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science. 2013;342:1477–1483.
- Kaji T, Ishige A, Hikida M, Taka J, Hijikata A, Kubo M, Nagashima T, Takahashi Y, Kurosaki T, Okada M, et al. Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. Journal of Experimental Medicine. 2012;209:2079–2097.
- Klein F, Mouquet H, Dosenovic P, Scheid JF, Scharf L, Nussenzweig MC. Antibodies in HIV-1 vaccine development and therapy. Science. 2013;341:1199–1204.
- Kuraoka M, Schmidt AG, Nojima T, Feng F, Watanabe A, Kitamura D, Harrison SC, Kepler TB, Kelsoe G. Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. Immunity. 2016;44:542–552.
- Lee JH, Ozorowski G, Ward AB. Cryo-EM structure of a native, fully glycosylated, cleaved HIV-1 envelope trimer. Science. 2016;351:1043–1048.
- Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA, Arlehamn CL, Su LF, Cubas R, Davis MM, Sette A, et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013;39:758–769.
- Locci M, Wu JE, Arumemi F, Mikulski Z, Dahlberg C, Miller AT, Crotty S. Activin A programs the differentiation of human TFH cells. Nat Immunol. 2016;17:976–984.
- Lyumkis D, Julien J-P, de Val N, Cupo A, Potter CS, Klasse P-J, Burton DR, Sanders RW, Moore JP, Carragher B, et al. Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science. 2013;342:1484–1490.
- Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, Arkwright PD, Kreins AY, Averbuch D, Engelhard D, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 2012;119:3997–4008.
- Ma CS, Suryani S, Avery DT, Chan A, Nanan R, Santner-Nanan B, Deenick EK, Tangye SG. Early commitment of naive human CD4+; T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunology and Cell Biology. 2009;87:590–600.
- Mascola JR, Snyder SW, Weislow OS, Belay SM, Belshe RB, Schwartz DH, Clements ML, Dolin R, Graham BS, Gorse GJ, et al. Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. J. Infect. Dis. 1996;173:340–348.
- Mascola JR, Montefiori DC. The role of antibodies in HIV vaccines. Annu. Rev. Immunol. 2010;28:413–444.
- McElrath MJ, Corey L, Montefiori D, Wolff M, Schwartz D, Keefer M, Belshe R, Graham BS, Matthews T, Wright P, et al. A phase II study of two HIV type 1 envelope vaccines, comparing their immunogenicity in populations at risk for acquiring HIV type 1 infection. AIDS Vaccine Evaluation Group. AIDS Res. Hum. Retroviruses. 2000;16:907–919.
- McGuire AT, Dreyer AM, Carbonetti S, Lippy A, Glenn J, Scheid JF, Mouquet H, Stamatatos L. HIV antibodies. Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies. Science. 2014;346:1380–1383.
- McHeyzer-Williams LJ, Milpied PJ, Okitsu SL, McHeyzer-Williams MG. Class-switched memory B cells remodel BCRs within secondary germinal centers. Nat Immunol. 2015;16:296–305.
- Moldt B, Rakasz EG, Schultz N, Chan-Hui PY, Swiderek K, Weisgrau KL, Piaskowski SM, Bergman Z, Watkins DI, Poignard P, et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proceedings of the National Academy of Sciences. 2012;109:18921–18925.
- Mörner A, Douagi I, Forsell MNE, Sundling C, Dosenovic P, O'Dell S, Dey B, Kwong PD, Voss G, Thorstensson R, et al. Human immunodeficiency virus type 1 env trimer immunization of macaques and impact of priming with viral vector or stabilized core protein. J. Virol. 2009;83:540–551.
- Pape KA, Taylor JJ, Maul RW, Gearhart PJ, Jenkins MK. Different B cell populations mediate early and late memory during an endogenous immune response. Science. 2011;331:1203–1207.
- Petrovas C, Yamamoto T, Gerner MY, Boswell KL, Wloka K, Smith EC, Ambrozak DR, Sandler NG, Timmer KJ, Sun X, et al. CD4 T follicular helper cell dynamics during SIV infection. J. Clin. Invest. 2012;122:3281–3294.
- Plotkin SA. Correlates of protection induced by vaccination. Clin. Vaccine Immunol. 2010;17:1055–1065.
- Prasad RR, Narasimhan R, Sankaran V, Veliath AJ. Fine-needle aspiration cytology in the diagnosis of superficial lymphadenopathy: an analysis of 2,418 cases. Diagn. Cytopathol. 1996;15:382–386.
- Sanders RW, Derking R, Cupo A, Julien J-P, Yasmeen A, de Val N, Kim HJ, Blattner C, Torrents de la Peña A, Korzun J, et al. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog. 2013;9:e1003618.
- Sanders RW, van Gils MJ, Derking R, Sok D, Ketas TJ, Burger JA, Ozorowski G, Cupo A, Simonich C, Goo L, et al. HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers. Science. 2015;349:aac4223–aac4223.
- Sattentau QJ. Immunogen design to focus the B-cell repertoire. Curr Opin HIV AIDS. 2014;9:217–223.
- Schmitt N, Bustamante J, Bourdery L, Bentebibel S-E, Boisson-Dupuis S, Hamlin F, Tran MV, Blankenship D, Pascual V, Savino DA, et al. IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans. Blood. 2013;121:3375–3385.
- Schwickert TA, Victora GD, Fooksman DR, Kamphorst AO, Mugnier MR, Gitlin AD, Dustin ML, Nussenzweig MC. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. Journal of Experimental Medicine. 2011;208:1243–1252.
- Shingai M, Donau OK, Plishka RJ, Buckler-White A, Mascola JR, Nabel GJ, Nason MC, Montefiori D, Moldt B, Poignard P, et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. Journal of Experimental Medicine. 2014;211:2061–2074.
- Sliepen K, Sanders RW. HIV-1 envelope glycoprotein immunogens to induce broadly neutralizing antibodies. Expert Rev Vaccines. 2016;15:349–365.
- Tam HH, Melo MB, Kang M, Pelet JM, Ruda VM, Foley MH, Hu JK, Kumari S, Crampton J, Baldeon AD, et al. Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination. Proceedings of the National Academy of Sciences. 2016
- Tas JMJ, Mesin L, Pasqual G, Targ S, Jacobsen JT, Mano YM, Chen CS, Weill J-C, Reynaud C-A, Browne EP, et al. Visualizing antibody affinity maturation in germinal centers. Science. 2016;351:1048–1054.
- Tatovic D, Young P, Kochba E, Levin Y, Wong FS, Dayan CM. Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery. The Journal of Immunology. 2015;195:386–392.
- Verschoor EJ, Mooij P, Oostermeijer H, van der Kolk M, Haaft ten P, Verstrepen B, Sun Y, Morein B, Akerblom L, Fuller DH, et al. Comparison of immunity generated by nucleic acid-, MF59-, and ISCOM-formulated human immunodeficiency virus type 1 vaccines in Rhesus macaques: evidence for viral clearance. J. Virol. 1999;73:3292–3300.
- Victora GD, Nussenzweig MC. Germinal centers. Annu. Rev. Immunol. 2012;30:429–457.
- Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M, Dustin ML, Nussenzweig MC. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell. 2010;143:592–605.
- Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien J-P, Wang S-K, Ramos A, Chan-Hui P-Y, Moyle M, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature. 2011;477:466–470.
- West DJ. Clinical experience with hepatitis B vaccines. Am J Infect Control. 1989;17:172–180.
- Xu Y, Fernandez C, Alcantara S, Bailey M, De Rose R, Kelleher AD, Zaunders J, Kent SJ. Serial study of lymph node cell subsets using fine needle aspiration in pigtail macaques. Journal of Immunological Methods. 2013;394:73–83.
- Yamamoto T, Lynch RM, Gautam R, Matus-Nicodemos R, Schmidt SD, Boswell KL, Darko S, Wong P, Sheng Z, Petrovas C, et al. Quality and quantity of TFH cells are critical for broad antibody development in SHIVAD8 infection. Science Translational Medicine. 2015;7:298ra120.
Source: PubMed