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Displaying record number 3059
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MAb ID |
VRC07 |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
|
Epitope |
|
Subtype |
B |
Ab Type |
gp120 CD4bs |
Neutralizing |
P View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG1) |
Patient |
NIH45 |
Immunogen |
HIV-1 infection |
Keywords |
antibody binding site, antibody lineage, antibody polyreactivity, assay or method development, autoantibody or autoimmunity, binding affinity, bispecific/trispecific, broad neutralizer, computational prediction, glycosylation, HAART, ART, immunoprophylaxis, immunotherapy, neutralization, recombinant antibodies, structure, therapeutic vaccine, vaccine antigen design, vaccine-induced immune responses |
Notes
Showing 15 of
15 notes.
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VRC07: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
-
VRC07: Some CD4-binding site Abs have greater env trimer binding due to quaternary contacts. This study engrafted the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bnAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface was delineated by solving the crystal structure of 2 of the chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, the chimeric antibodies displayed lower autoreactivity and prolonged in vivo half-life in huFcRn mice and macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality. VRC07-FR3-03 had more potent neutralization than VRC07. In two assays of autoreactivity, VRC07 was mildly reactive on one assay, while VRC07-FR3-03 was not reactive in either assay.
Liu2019
(autoantibody or autoimmunity, neutralization)
-
VRC07: In this report of the phase 1 dose-escalation clinical trial NCT03374202, administration of an adeno-associated virus vector coding for the CD4bs-targeting bnAb VRC07 (AAV8-VRC07) to 8 HIV-1-infected adults (patient records #5281-5288) maintaining ART was safe and well tolerated. All 8 participants produced measurable amounts of serum VRC07 that displayed neutralizing activity similar to in vitro-produced VRC07 but no clinically significant changes in CD4 T cell count or VL were observed during 1-3 years of follow-up. 3/8 participants developed a non-idiotypic anti-drug antibody response directed against the Fab portion of VRC07 which likely resulted in decreased VRC07 serum concentrations in 2 participants. This is the first demonstration that adeno-associated viral vectors can durably produce biologically active difficult-to-elicit bnAbs in vivo in HIV-1-infected individuals.
Casazza2022
(immunoprophylaxis, therapeutic vaccine, HAART, ART, recombinant antibodies)
-
VRC07: This study inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation, including a phylogeny of 45 naturally-paired mAbs from donor NIH45. Nine new lineage members were isolated from donor NIH45, named DH651.1 - DH561.9. The study also derived VH and VL reverted forms of several VRC01-class mAbs derived from other donors (12A12, 3BNC60, 3BNC117, VRC20, VRC23, and VRC18b). Early mutations within the VRC01 lineage defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B-cell maturation toward the development of neutralization breadth. VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan. An X-ray structure and molecular dynamics simulation of VRC08 were studied to elucidate this process.
Bonsignori2018
(neutralization, structure, antibody lineage)
-
VRC07: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. VRC07 was used for analyzing clade sensitivity and not significantly potent against A clade (Fig S4).
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
-
VRC07: A simple method to quantify and compare serum neutralization probabilities in described. The method uses logistic regression to model the probability that a serum neutralizes a virus with an ID50 titer above a cutoff. The neutralization potency (NP) identifies where the probabilities of neutralizing and not neutralizing a virus are equal and is not absolute as it depends on the ID50 cutoff. It provides a continuous measure for sera, which builds upon established tier categories now used to rate virus sensitivity. These potency comparisons are similar to comparing geometric mean neutralization titers, but instead are represented in tier-like terms. Increasing the number of bNAbs increases NP and slope, where the higher the slope, the sharper the boundary (lower scatter) between viruses neutralized and not neutralized. VRC07 was used in analysis of monoclonal bNAb combinations.
Hraber2018
(assay or method development, neutralization)
-
VRC07: Assays of poly- and autoreactivity demonstrated that broadly neutralizing NAbs are significantly more poly- and autoreactive than non-neutralizing NAbs. VRC07 is polyreactive, but not autoreactive.
Liu2015a
(autoantibody or autoimmunity, antibody polyreactivity)
-
VRC07: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
VRC07: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. All the neutralizing rabbit sera showed significant competition with CD4bs mAbs VRC03, VRC07, b12 and 1F7.
Crooks2015
(glycosylation, neutralization)
-
VRC07: Bispecific IgGs were produced, composed of independent antigen-binding fragments with a common Fc region. Parental antibodies of several classes were assessed (VRC07, 10E8, PGT121, PG9-16). A bispecific antibody composed of VRC07 x PG9-16 displayed the most favorable profile, neutralizing 97% of viruses with a median IC50 of 0.055 ug/ml. This bispecific IgG also demonstrated pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for HIV prevention and treatment. Against a panel of 206 resistant and sensitive viruses, VRC07 neutralizes with median IC80 of 0.443 µg/ml. Bispecific with 10E8, PGT121 and PG916, median neutralization is 1.32, 0.355 and 0.267; while in physical combination with the same bNAbs, median neutralization of the antibodies is 0.41, 0.199 and 0.236 µg/ml respectively.
Asokan2015
(neutralization, immunotherapy, bispecific/trispecific)
-
VRC07: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
VRC07: The rate of maturation and extent of diversity for the VRC01 lineage were characterized through longitudinal sampling of peripheral B cell transcripts from donor 45 over 15 years and co-crystal structures. VRC01-lineage clades underwent continuous evolution, with rates of ˜2 substitutions per 100 nucleotides per year, comparable with HIV-1 evolution. 39 VRC01-lineage Abs segregated into three major clades, and all Abs from donor 45 contained a cysteine at position 98 (99 in some sequences due to a 1-aa insertion) which was used as a signature to assess membership in the VRC01 lineage. Of 1,041 curated NGS sequences assigned to the VRC01 lineage, six did not contain the cysteine while 1,035 did (99.4%).
Wu2015
(antibody lineage)
-
VRC07: In vivo and in vitro studies showed that MAb VRC07, particularly its variant VRC07-523-LS, was 5 times more potent than VRC01 in protecting macaques passively transferred with MAb prior to SHIV challenge. This correlated directly with a previously shown 5-8 fold potency of VRC07 over VRC01 in vitro, suggesting that increased neutralization potency in vitro correlates with improved protection in vivo. 4 VRC07 variants were tested, VRC07-501-LS, VRC07-508-LS, VRC07-523-LS and VRC07-544-LS, LS denoting the presence of mutations M428L/N434S that display a 2-3 fold increase in plasma half life. As compared to control MAbs b12 and NIH45-46, VRCO1 and VRC07 had greater % neutralizations, at 22%, 77%, 77% and 83% respectively. Mean of potency of action was denoted as IC50/80, 0.971, 0.221, 0.136 and 0.114.
Rudicell2014
(neutralization, binding affinity)
-
VRC07: This study demonstrated that vectored immunoprophylaxis (VIP) is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.
Balazs2014
(vaccine-induced immune responses)
-
VRC07: This is an abstract to the oral presentation on AIDS Vaccine 2012 meeting. The crystal structure of gp120 in complex with VRC07 is described. VRC07 is more potent and broadly reactive than its derivative, VRC01. All VRC07 variants, in which Gly54 was replaced with Arg, Leu, Phe, Trp, or Tyr, showed enhanced affinity to a panel of different HIV-1 gp120s. Crystal structures of gp120 in complexes with these VRC07 Gly54 variants confirmed that their side chains mimicked Phe43 of CD4. Computational analysis of the VRC07-gp120 interface in the crystal structure identified residues Ile30 and Ser58 as likely targets for improvement (with Gln and Asn, respectively). These changes introduced additional hydrogen bonds to the VRC07-gp120 interfaces and further enhanced VRC07 potency.
Kwon2012a
(structure)
References
Showing 15 of
15 references.
Isolation Paper
Rudicell2014
Rebecca S. Rudicell, Young Do Kwon, Sung-Youl Ko, Amarendra Pegu, Mark K. Louder, Ivelin S. Georgiev, Xueling Wu, Jiang Zhu, Jeffrey C. Boyington, Xuejun Chen, Wei Shi, Zhi-Yong Yang, Nicole A. Doria-Rose, Krisha McKee, Sijy O'Dell, Stephen D. Schmidt, Gwo-Yu Chuang, Aliaksandr Druz, Cinque Soto, Yongping Yang, Baoshan Zhang, Tongqing Zhou, John-Paul Todd, Krissey E. Lloyd, Joshua Eudailey, Kyle E. Roberts, Bruce R. Donald, Robert T. Bailer, Julie Ledgerwood, NISC Comparative Sequencing Program, James C. Mullikin, Lawrence Shapiro, Richard A. Koup, Barney S. Graham, Martha C. Nason, Mark Connors, Barton F. Haynes, Srinivas S. Rao, Mario Roederer, Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In Vitro Improves Protection against Lentiviral Infection In Vivo. J. Virol., 88(21):12669-12682, 1 Nov 2014. PubMed ID: 25142607.
Show all entries for this paper.
Asokan2015
M. Asokan, R. S. Rudicell, M. Louder, K. McKee, S. O'Dell, G. Stewart-Jones, K. Wang, L. Xu, X. Chen, M. Choe, G. Chuang, I. S. Georgiev, M. G. Joyce, T. Kirys, S. Ko, A. Pegu, W. Shi, J. P. Todd, Z. Yang, R. T. Bailer, S. Rao, P. D. Kwong, G. J. Nabel, and J. R. Mascola. Bispecific Antibodies Targeting Different Epitopes on the HIV-1 Envelope Exhibit Broad and Potent Neutralization. J. Virol., 89(24):12501-12512, Dec 2015. PubMed ID: 26446600.
Show all entries for this paper.
Balazs2014
Alejandro B. Balazs, Yong Ouyang, Christin M. Hong, Joyce Chen, Steven M. Nguyen, Dinesh S. Rao, Dong Sung An, and David Baltimore. Vectored immunoprophylaxis protects humanized mice From mucosal HIV Transmission. Nat. Med., 20(3):296-300, Mar 2014. PubMed ID: 24509526.
Show all entries for this paper.
Bonsignori2018
Mattia Bonsignori, Eric Scott, Kevin Wiehe, David Easterhoff, S. Munir Alam, Kwan-Ki Hwang, Melissa Cooper, Shi-Mao Xia, Ruijun Zhang, David C. Montefiori, Rory Henderson, Xiaoyan Nie, Garnett Kelsoe, M. Anthony Moody, Xuejun Chen, M. Gordon Joyce, Peter D. Kwong, Mark Connors, John R. Mascola, Andrew T. McGuire, Leonidas Stamatatos, Max Medina-Ramirez, Rogier W. Sanders, Kevin O. Saunders, Thomas B. Kepler, and Barton F. Haynes. Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier. Immunity, 49(6):1162-1174.e8, 18 Dec 2018. PubMed ID: 30552024.
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Bricault2019
Christine A. Bricault, Karina Yusim, Michael S. Seaman, Hyejin Yoon, James Theiler, Elena E. Giorgi, Kshitij Wagh, Maxwell Theiler, Peter Hraber, Jennifer P. Macke, Edward F. Kreider, Gerald H. Learn, Beatrice H. Hahn, Johannes F. Scheid, James M. Kovacs, Jennifer L. Shields, Christy L. Lavine, Fadi Ghantous, Michael Rist, Madeleine G. Bayne, George H. Neubauer, Katherine McMahan, Hanqin Peng, Coraline Chéneau, Jennifer J. Jones, Jie Zeng, Christina Ochsenbauer, Joseph P. Nkolola, Kathryn E. Stephenson, Bing Chen, S. Gnanakaran, Mattia Bonsignori, LaTonya D. Williams, Barton F. Haynes, Nicole Doria-Rose, John R. Mascola, David C. Montefiori, Dan H. Barouch, and Bette Korber. HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design. Cell Host Microbe, 25(1):59-72.e8, 9 Jan 2019. PubMed ID: 30629920.
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Casazza2022
Joseph P. Casazza, Evan M. Cale, Sandeep Narpala, Galina V. Yamshchikov, Emily E. Coates, Cynthia S. Hendel, Laura Novik, LaSonji A. Holman, Alicia T. Widge, Preeti Apte, Ingelise Gordon, Martin R. Gaudinski, Michelle Conan-Cibotti, Bob C. Lin, Martha C. Nason, Olga Trofymenko, Shinyi Telscher, Sarah H. Plummer, Diane Wycuff, William C. Adams, Janardan P. Pandey, Adrian McDermott, Mario Roederer, Avery N. Sukienik, Sijy O'Dell, Jason G. Gall, Britta Flach, Travis L. Terry, Misook Choe, Wei Shi, Xuejun Chen, Florence Kaltovich, Kevin O. Saunders, Judy A. Stein, Nicole A. Doria-Rose, Richard M. Schwartz, Alejandro B. Balazs, David Baltimore, Gary J. Nabel, Richard A. Koup, Barney S. Graham, Julie E. Ledgerwood, John R. Mascola, and VRC 603 Study Team. Safety and Tolerability of AAV8 Delivery of a Broadly Neutralizing Antibody in Adults Living with HIV: A Phase 1, Dose-Escalation Trial. Nat. Med., 28(5):1022-1030, May 2022. PubMed ID: 35411076.
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Crooks2015
Ema T. Crooks, Tommy Tong, Bimal Chakrabarti, Kristin Narayan, Ivelin S. Georgiev, Sergey Menis, Xiaoxing Huang, Daniel Kulp, Keiko Osawa, Janelle Muranaka, Guillaume Stewart-Jones, Joanne Destefano, Sijy O'Dell, Celia LaBranche, James E. Robinson, David C. Montefiori, Krisha McKee, Sean X. Du, Nicole Doria-Rose, Peter D. Kwong, John R. Mascola, Ping Zhu, William R. Schief, Richard T. Wyatt, Robert G. Whalen, and James M. Binley. Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site. PLoS Pathog, 11(5):e1004932, May 2015. PubMed ID: 26023780.
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Guzzo2018
Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, and Paolo Lusso. Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation. mBio, 9(6), 11 Dec 2018. PubMed ID: 30538178.
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Hraber2017
Peter Hraber, Cecilia Rademeyer, Carolyn Williamson, Michael S. Seaman, Raphael Gottardo, Haili Tang, Kelli Greene, Hongmei Gao, Celia LaBranche, John R. Mascola, Lynn Morris, David C. Montefiori, and Bette Korber. Panels of HIV-1 Subtype C Env Reference Strains for Standardized Neutralization Assessments. J. Virol., 91(19), 1 Oct 2017. PubMed ID: 28747500.
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Hraber2018
Peter Hraber, Bette Korber, Kshitij Wagh, David Montefiori, and Mario Roederer. A Single, Continuous Metric To Define Tiered Serum Neutralization Potency against Hiv. eLife, 7, 19 Jan 2018. PubMed ID: 29350181.
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Kwon2012a
Y. Kwon, I. Georgiev, S. O'Dell, W. Shi, G. Chuang, Y. Yang, Zhang, J. Zhu, G. J. Nabel, J. R. Mascola, and P. D. Kwong. Structure-Guided Modification and Optimization of Antibody VRC07. Retrovirology, 9(s2):O34, 2012.
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Liu2015a
Mengfei Liu, Guang Yang, Kevin Wiehe, Nathan I. Nicely, Nathan A. Vandergrift, Wes Rountree, Mattia Bonsignori, S. Munir Alam, Jingyun Gao, Barton F. Haynes, and Garnett Kelsoe. Polyreactivity and Autoreactivity among HIV-1 Antibodies. J. Virol., 89(1):784-798, Jan 2015. PubMed ID: 25355869.
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Liu2019
Qingbo Liu, Yen-Ting Lai, Peng Zhang, Mark K. Louder, Amarendra Pegu, Reda Rawi, Mangaiarkarasi Asokan, Xuejun Chen, Chen-Hsiang Shen, Gwo-Yu Chuang, Eun Sung Yang, Huiyi Miao, Yuge Wang, Anthony S. Fauci, Peter D. Kwong, John R. Mascola, and Paolo Lusso. Improvement of Antibody Functionality by Structure-Guided Paratope Engraftment. Nat. Commun., 10(1):721, 13 Feb 2019. PubMed ID: 30760721.
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Wagh2016
Kshitij Wagh, Tanmoy Bhattacharya, Carolyn Williamson, Alex Robles, Madeleine Bayne, Jetta Garrity, Michael Rist, Cecilia Rademeyer, Hyejin Yoon, Alan Lapedes, Hongmei Gao, Kelli Greene, Mark K. Louder, Rui Kong, Salim Abdool Karim, Dennis R. Burton, Dan H. Barouch, Michel C. Nussenzweig, John R. Mascola, Lynn Morris, David C. Montefiori, Bette Korber, and Michael S. Seaman. Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection. PLoS Pathog., 12(3):e1005520, Mar 2016. PubMed ID: 27028935.
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Wu2015
Xueling Wu, Zhenhai Zhang, Chaim A. Schramm, M. Gordon Joyce, Young Do Kwon, Tongqing Zhou, Zizhang Sheng, Baoshan Zhang, Sijy O'Dell, Krisha McKee, Ivelin S. Georgiev, Gwo-Yu Chuang, Nancy S. Longo, Rebecca M. Lynch, Kevin O. Saunders, Cinque Soto, Sanjay Srivatsan, Yongping Yang, Robert T. Bailer, Mark K. Louder, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell, 161(3):470-485, 23 Apr 2015. PubMed ID: 25865483.
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