Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

Bonsignori, Mattia; Zhou, Tongqing; Sheng, Zizhang; Chen, Lei; Gao, Feng; Joyce, M. Gordon; Ozorowski, Gabriel; Chuang, Gwo-Yu; Schramm, Chaim A.; Wiehe, Kevin; Alam, S. Munir; Bradley, Todd; Gladden, Morgan A.; Hwang, Kwan-Ki; Iyengar, Sheelah; Kumar, Amit; Lu, Xiaozhi; Luo, Kan; Mangiapani, Michael C.; Parks, Robert J.; Song, Hongshuo; Acharya, Priyamvada; Bailer, Robert T.; Cao, Allen; Druz, Aliaksandr; Georgiev, Ivelin S.; Kwon, Young D.; Louder, Mark K.; Zhang, Baoshan; Zheng, Anqi; Hill, Brenna J.; Kong, Rui; Soto, Cinque; Mullikin, James C.; Douek, Daniel C.; Montefiori, David C.; Moody, Michael A.; Shaw, George M.; Hahn, Beatrice H.; Kelsoe, Garnett; Hraber, Peter T.; Korber, Bette T.; Boyd, Scott D.; Fire, Andrew Z.; Kepler, Thomas B.; Shapiro, Lawrence; Ward, Andrew B.; Mascola, John R.; Liao, Hua-Xin; Kwong, Peter D.; Haynes, Barton F.

doi:10.1016/j.cell.2016.02.022

Title: Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

Journal Article · Fri Apr 01 00:00:00 EDT 2016 · Cell

DOI:https://doi.org/10.1016/j.cell.2016.02.022· OSTI ID:1350149

Bonsignori, Mattia; Zhou, Tongqing; Sheng, Zizhang; Chen, Lei; Gao, Feng; Joyce, M. Gordon; Ozorowski, Gabriel; Chuang, Gwo-Yu; Schramm, Chaim A.; Wiehe, Kevin; Alam, S. Munir; Bradley, Todd; Gladden, Morgan A.; Hwang, Kwan-Ki; Iyengar, Sheelah; Kumar, Amit; Lu, Xiaozhi; Luo, Kan; Mangiapani, Michael C.; Parks, Robert J. more »

Here, we report that antibodies with ontogenies from V_H1-2 or V_H1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. We define with longitudinal sampling from time-of-infection the development of a V_H1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled V_H1-2. Lastly, we integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.

View Journal Article

Cite

Export

Save

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: W-31-109-Eng-38; AC52-06NA25396; UM1 AI100645; UM1 AI100663; P01-AI104722

OSTI ID:: 1350149

Alternate ID(s):: OSTI ID: 1259969; OSTI ID: 1324843

Report Number(s):: LA-UR-15-29619; S0092867416301246; PII: S0092867416301246

Journal Information:: Cell, Journal Name: Cell Vol. 165 Journal Issue: 2; ISSN 0092-8674

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 212 works

Citation information provided by
Web of Science

Cited By (43)

Progress toward active or passive HIV-1 vaccination Escolano, Amelia; Dosenovic, Pia; Nussenzweig, Michel C. The Journal of Experimental Medicine, Vol. 214, Issue 1 https://doi.org/10.1084/jem.20161765	journal	December 2016
Human adaptive immune receptor repertoire analysis-Past, present, and future Nielsen, Sandra C. A.; Boyd, Scott D. Immunological Reviews, Vol. 284, Issue 1 https://doi.org/10.1111/imr.12667	journal	June 2018
Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation Sheng, Zizhang; Schramm, Chaim A.; Kong, Rui Frontiers in Immunology, Vol. 8 https://doi.org/10.3389/fimmu.2017.00537	journal	May 2017
Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design Schramm, Chaim A.; Douek, Daniel C. Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.01876	journal	August 2018
Mechanisms of Adaptive Immunity to Porcine Reproductive and Respiratory Syndrome Virus Rahe, Michael; Murtaugh, Michael Viruses, Vol. 9, Issue 6 https://doi.org/10.3390/v9060148	journal	June 2017
Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers Landais, Elise; Moore, Penny L. Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0443-0	journal	September 2018
Germinal center entry not selection of B cells is controlled by peptide-MHCII complex density Yeh, Chen-Hao; Nojima, Takuya; Kuraoka, Masayuki Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03382-x	journal	March 2018
Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection Song, Hongshuo; Giorgi, Elena E.; Ganusov, Vitaly V. Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-04217-5	journal	May 2018
Selection of immunoglobulin elbow region mutations impacts interdomain conformational flexibility in HIV-1 broadly neutralizing antibodies Henderson, Rory; Watts, Brian E.; Ergin, Hieu N. Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-08415-7	journal	February 2019
Improvement of antibody functionality by structure-guided paratope engraftment Liu, Qingbo; Lai, Yen-Ting; Zhang, Peng Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-08658-4	journal	February 2019
Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies Adachi, Yu; Tonouchi, Keisuke; Nithichanon, Arnone Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-11821-6	journal	August 2019
Antibody responses to viral infections: a structural perspective across three different enveloped viruses Murin, Charles D.; Wilson, Ian A.; Ward, Andrew B. Nature Microbiology, Vol. 4, Issue 5 https://doi.org/10.1038/s41564-019-0392-y	journal	March 2019
Recent progress in broadly neutralizing antibodies to HIV Sok, Devin; Burton, Dennis R. Nature Immunology, Vol. 19, Issue 11 https://doi.org/10.1038/s41590-018-0235-7	journal	October 2018
Aberrant B cell repertoire selection associated with HIV neutralizing antibody breadth Roskin, Krishna M.; Jackson, Katherine J. L.; Lee, Ji-Yeun Nature Immunology, Vol. 21, Issue 2 https://doi.org/10.1038/s41590-019-0581-0	journal	January 2020
Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques Li, Hui; Wang, Shuyi; Kong, Rui Proceedings of the National Academy of Sciences, Vol. 113, Issue 24 https://doi.org/10.1073/pnas.1606636113	journal	May 2016
Anti-idiotypic antibodies elicit anti-HIV-1–specific B cell responses Dosenovic, Pia; Pettersson, Anna-Klara; Wall, Abigail Journal of Experimental Medicine, Vol. 216, Issue 10 https://doi.org/10.1084/jem.20190446	journal	July 2019
Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses Phad, Ganesh E.; Pushparaj, Pradeepa; Tran, Karen Journal of Experimental Medicine, Vol. 217, Issue 2 https://doi.org/10.1084/jem.20191155	journal	November 2019
Native-like Env trimers as a platform for HIV-1 vaccine design Sanders, Rogier W.; Moore, John P. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12481	journal	January 2017
Germline-targeting immunogens Stamatatos, Leonidas; Pancera, Marie; McGuire, Andrew T. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12483	journal	January 2017
Immunologic characteristics of HIV-infected individuals who make broadly neutralizing antibodies Borrow, Persephone; Moody, M. Anthony Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12504	journal	January 2017
Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development Bonsignori, Mattia; Liao, Hua-Xin; Gao, Feng Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12509	journal	January 2017
Use of broadly neutralizing antibodies for HIV-1 prevention Pegu, Amarendra; Hessell, Ann J.; Mascola, John R. Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12511	journal	January 2017
Tfh cells and HIV bnAbs, an immunodominance model of the HIV neutralizing antibody generation problem Havenar-Daughton, Colin; Lee, Jeong Hyun; Crotty, Shane Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12512	journal	January 2017
Targeted selection of HIV-specific antibody mutations by engineering B cell maturation Saunders, Kevin O.; Wiehe, Kevin; Tian, Ming Science, Vol. 366, Issue 6470 https://doi.org/10.1126/science.aay7199	journal	December 2019
Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies Bonsignori, Mattia; Kreider, Edward F.; Fera, Daniela Science Translational Medicine, Vol. 9, Issue 381 https://doi.org/10.1126/scitranslmed.aai7514	journal	March 2017
Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller Freund, Natalia T.; Wang, Haoqing; Scharf, Louise Science Translational Medicine, Vol. 9, Issue 373 https://doi.org/10.1126/scitranslmed.aal2144	journal	January 2017
Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance Bailey, Justin R.; Flyak, Andrew I.; Cohen, Valerie J. JCI Insight, Vol. 2, Issue 9 https://doi.org/10.1172/jci.insight.92872	journal	May 2017
Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site Cheng, Hao D.; Grimm, Sebastian K.; Gilman, Morgan S. A. JCI Insight, Vol. 3, Issue 5 https://doi.org/10.1172/jci.insight.97018	journal	March 2018
Broadly neutralizing antibodies: What is needed to move from a rare event in HIV-1 infection to vaccine efficacy? Subbaraman, Harini; Schanz, Merle; Trkola, Alexandra Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0433-2	journal	July 2018
The role of follicular helper CD4 T cells in the development of HIV-1 specific broadly neutralizing antibody responses Moysi, Eirini; Petrovas, Constantinos; Koup, Richard A. Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0437-y	journal	August 2018
HIV-1 immunogens and strategies to drive antibody responses towards neutralization breadth van Schooten, Jelle; van Gils, Marit J. Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0457-7	journal	November 2018
A human inferred germline antibody binds to an immunodominant epitope and neutralizes Zika virus Magnani, Diogo M.; Silveira, Cassia G. T.; Rosen, Brandon C. PLOS Neglected Tropical Diseases, Vol. 11, Issue 6 https://doi.org/10.1371/journal.pntd.0005655	journal	June 2017
Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth Chukwuma, Valentine U.; Kose, Nurgun; Sather, D. Noah PLOS ONE, Vol. 13, Issue 12 https://doi.org/10.1371/journal.pone.0209437	journal	December 2018
Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens Mesa, Kathryn A.; Yu, Bin; Wrin, Terri PLOS ONE, Vol. 14, Issue 4 https://doi.org/10.1371/journal.pone.0213409	journal	April 2019
Consistent elicitation of cross-clade HIV-neutralizing responses achieved in guinea pigs after fusion peptide priming by repetitive envelope trimer boosting Cheng, Cheng; Xu, Kai; Kong, Rui PLOS ONE, Vol. 14, Issue 4 https://doi.org/10.1371/journal.pone.0215163	journal	April 2019
HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies LaBranche, Celia C.; McGuire, Andrew T.; Gray, Matthew D. PLOS Pathogens, Vol. 14, Issue 11 https://doi.org/10.1371/journal.ppat.1007431	journal	November 2018
Somatic hypermutation to counter a globally rare viral immunotype drove off-track antibodies in the CAP256-VRC26 HIV-1 V2-directed bNAb lineage Sacks, David; Bhiman, Jinal N.; Wiehe, Kevin PLOS Pathogens, Vol. 15, Issue 9 https://doi.org/10.1371/journal.ppat.1008005	journal	September 2019
Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies LaBranche, Celia C.; Henderson, Rory; Hsu, Allen PLOS Pathogens, Vol. 15, Issue 9 https://doi.org/10.1371/journal.ppat.1008026	journal	September 2019
In-Depth Analysis of Human Neonatal and Adult IgM Antibody Repertoires Hong, Binbin; Wu, Yanling; Li, Wei Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.00128	journal	February 2018
Development of Antibodies with Broad Neutralization Specificities against HIV-1 after Long Term SHIV Infection in Macaques Gao, Nan; Gai, Yanxin; Meng, Lina Viruses, Vol. 12, Issue 2 https://doi.org/10.3390/v12020163	journal	January 2020
Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies Kreer, Christoph; Gruell, Henning; Mora, Thierry Vaccines, Vol. 8, Issue 1 https://doi.org/10.3390/vaccines8010013	journal	January 2020
Observed Antibody Space: A Resource for Data Mining Next-Generation Sequencing of Antibody Repertoires Kovaltsuk, Aleksandr; Leem, Jinwoo; Kelm, Sebastian The Journal of Immunology, Vol. 201, Issue 8 https://doi.org/10.4049/jimmunol.1800708	journal	September 2018
Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies Ovchinnikov, Victor; Louveau, Joy E.; Barton, John P. eLife, Vol. 7 https://doi.org/10.7554/elife.33038	journal	February 2018

Similar Records

Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies

Journal Article · Tue Sep 17 00:00:00 EDT 2019 · PLoS Pathogens · OSTI ID:1350149

LaBranche, Celia C.; Henderson, Rory; Hsu, Allen; +25 more

Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

Journal Article · Tue Nov 12 00:00:00 EST 2019 · Immunity · OSTI ID:1350149

Dubrovskaya, Viktoriya; Tran, Karen; Ozorowski, Gabriel; +25 more

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

Journal Article · Wed Jul 04 00:00:00 EDT 2018 · Science Translational Medicine · OSTI ID:1350149

Havenar-Daughton, Colin; Sarkar, Anita; Kulp, Daniel W.; +20 more

Related Subjects

60 APPLIED LIFE SCIENCES
59 BASIC BIOLOGICAL SCIENCES

Title: Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

Citation Formats

Cited By (43)

Similar Records

Related Subjects