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• NIH45-46G54W: Novel Env pseudoviruses were derived from 22 patients in China infected with subtype CRF01_AE viruses. Neutralization IC50 was determined for 11 bNAbs: VRC01, NIH45-46G54W, 3BNC117, PG9, PG16, 2G12, PGT121, 10-1074, 2F5, 4E10, and 10E8. The CRF01_AE pseudoviruses exhibited different susceptibility to these bNAbs. Overall, 4E10, 10E8, and 3BNC117 neutralized all 22 env-pseudotyped viruses, followed by NIH45-46G54W and VRC01, which neutralized more than 90% of the viruses. 2F5, PG9, and PG16 showed only moderate breadth, while the other three bNAbs neutralized none of these pseudoviruses. Specifically, 10E8, NIH45-46G54Wand 3BNC117 showed the highest efficiency, combining neutralization potency and breadth. Mutations at position 160, 169, 171 were associated with resistance to PG9 and PG16, while loss of a potential glycan at position 332 conferred insensitivity to V3-glycan-targeting bNAbs. These results may help in choosing bNAbs that can be used preferentially for prophylactic or therapeutic approaches in China. Wang2018a (assay or method development, neutralization, subtype comparisons)
• NIH45-46-G54W: 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. NIH45-46-G54W was used for analyzing clade sensitivity, structural mapping and analyses of CD4bs Ab signatures. Bricault2019 (antibody binding site, vaccine antigen design, computational epitope prediction, broad neutralizer)
• NIH45-46W: Polyreactive properties of natural and artificially engineered HIV-1 bNAbs were studied, with almost 60% of the tested HIV-1 bNAbs (including this one) exhibiting low to high polyreactivity in different immunoassays. A previously unappreciated polyreactive binding for PGT121, PGT128, NIH45-46W, m2, and m7 was reported. Binding affinity, thermodynamic, and molecular dynamics analyses revealed that the co-emergence of enhanced neutralizing capacities and polyreactivity was due to an intrinsic conformational flexibility of the antigen-binding sites of bNAbs, allowing a better accommodation of divergent HIV-1 Env variants. Prigent2018 (antibody polyreactivity)
• NIH45-46G54W: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades. Bouvin-Pley2014 (neutralization)
• NIH45-46G54W: In neutralization assays of antibody mixtures, there was a modest synergy between the CD4bs VRC01 and either of the two CD4i MAbs E51 and 412d. The synergy is likely the result of the ability of CD4i antibodies (E51 or 412d) to induce the open state and facilitate access to the CD4 binding site. The presence of E51 enhanced the Env binding of VRC01, NIH45-46, NIH45-46^G54W, and to a lesser extent 3BNC117. Gardner2016 (antibody interactions)
• NIH45-46G54W: Two clade C recombinant Env glycoprotein trimers, DU422 and ZM197M, with native-like structural and antigenic properties involving epitopes for all known classes of bNAbs, were produced and characterized. These Clade C trimers (10-15% of which are in a partially open form) were more like B41 Clade B trimers which have 50-75% trimers in the partially open configuration than like B505 Clade B trimers, almost 100% in the closed, prefusion state. The Clade C trimer ZM197M binds strongly to the CD4bs bNAb 45-46W but trimer DU442 and its pseudotyped virus as well as ZM197M pseudotyped virus are non-reactive or barely reactive to 45-46W. Julien2015 (assay or method development, structure)
• NIH45-46G54W: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs bNAb 45-46W neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too. Sanders2013 (assay or method development, neutralization, binding affinity)
• NIH45-46G54W: This review discusses an array of methods to engineer more effective bNAbs for immunotherapy. Antibody NIH45-46G54W is an example of engineering through rational mutations; its neutralization is improved by improving hydophobic interactions. It is also an example of rational mutations used to decrease polyreactivity or aggregation propensity. Hua2016 (immunotherapy, review)
• NIH45-46G54W: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC₅₀ below 1 ug/mL, except for 2 group O strains. Anti-CD4bs bNAb NIH45-46^G54W was able to neutralize only 1/16 tested non-M primary isolates at an IC₅₀< 10µg/ml, RBF208,M/O at 1.5 µg/ml. Morgand2015 (neutralization, subtype comparisons)
• NIH45-46G54W: This review summarized bNAb immunotherapy studies. Several bnAbs have been shown to decrease viremia in vivo, and are a prospect for preventative vaccinations. bNAbs have 3 possible immune effector functions: (1) directly neutralizing virions, (2) mediating anti-viral activity through Fc-FcR interactions, and (3) binding to viral antigen to be taken up by dendritic cells. In contrast to anti-HIV mAbs, antibodies against host cell CD4 and CCR5 receptors (iMab and PRO 140) are hindered by their short half-life in vivo. MAb NIH45-46^G54W has been associated with viral suppression in a study of humanized mice. Halper-Stromberg2016 (immunotherapy, review)
• NIH45-46^G54W: Study evaluated 4 gp140 Env protein vaccine immunogens derived from an elite neutralizer donor VC10042, an HIV+ African American male from Vanderbilt cohort. Env immunogens, VC10042.05, VC10042.05RM, VC10042.08 and VC10042.ela, elicited high titers of cross-reactive Abs recognizing V1/V2 regions. VC10042 showed moderate sensitivity to NIH45-46^G54W. Carbonetti2014 (elite controllers, vaccine-induced immune responses)
• NIH45-46G54W: A set of potent VRC01-like (PVL) MAbs were generated from VRC01-derivatve NIH45-46^G54W and they were more potent than even NIH45-46 or NIH45-46^G54W, cross-recognizing viruses across clades. The novel antibodies designed based on crystal structure were NIH45-46m2, NIH45-46m7, NIH45-46m25 and NIH45-46m28, with NIH45-46m2 being the single most broad and potent antibody till date. 45-46m2 and 45-46m7 in combination with each other and a third antibody were able to thwart viral escape routes. Diskin2013 (antibody generation, variant cross-reactivity, structure)
• NIH45-46W: Neutralizing antibody response was studied in elite controller. Subject VC10042 is an African American male, infected with clade B for 2 decades (since 1984) without any signs of disease and no antiretroviral treatment. The neutralizing activity of autologous CD4bs NAbs was very similar to that of NIH45-46W, but very different from other anti-CD4bs MAbs tested. The viral autologous variants that were resistant to neutralization by autologous and most bnMAbs tested had an extremely rare R272/N368 combination. This mutation was shown in the study to impart a fitness cost to the virus. Sather2012 (autologous responses, elite controllers, neutralization, escape, polyclonal antibodies)
• NIH45-46W: Neutralization profiles of 7 bnAbs were analyzed against 45 Envs (A, C, D clades), obtained soon after infection (median 59 days). The transmitted variants have distinct characteristics compared to variants from chronic patients, such as shorter variable loops and fewer potential N-linked glycosylation sites (PNGS). NIG45-46W neutralized 91% of these viruses. PGT128 and NIH45-46W did not compete for neutralization and a combination of these MAbs neutralized 96% of these viruses, with PGT121 neutralizing the only 2 viruses not neutralized by this combination. This suggests that optimal neutralization coverage of transmitted variants can be achieved by combining a potent CD4bs NAb with one or more glycan-dependent MAbs. Goo2012 (antibody interactions, neutralization, rate of progression)
• NIH45-46G54W: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC₅₀ based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC₅₀. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database. West2013 (glycosylation, computational epitope prediction)
• 45-46W: HIV therapy by combinations of 5 bNAbs was tested in YU2-infected humanized mice. Penta-mix (PG16, 45-46W, 3BC176, PGT128 and 10-1074) was the most effective in controlling viraemia compared to tri-mix (PG16, 45-46, 3BC176) and monotherapy (Fig S9). Viral escape with 45-46W monotherapy was associated with mutations at residues 276-281, 458 or 459, located in or near the CD4bs. The viruses from the mice that rebounded after tri-mix therapy either did not have bNAbs-associated mutations or had K28R mapped to NIH45-46W or N162P mapped to PG16, but not both. Klein2012a (immunotherapy)
• 45-46W: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. 45-46W was used as a control in virus neutralization assay. Detail information on the binding and neutralization assays are described in the figures S2-S11. Mouquet2012a (glycosylation, neutralization, binding affinity)
• NIH45-46G54W: NIH45-46 is a potent clonal variant of VRC01. Structure-based design was used to create NIH45-46 mutants with a single substitution at position 54 in CDRH2 to increase contact with the gp120 bridging sheet. NIH45-46_G54W was significantly more potent than NIH45-46. On a panel of 82 viruses from all clades, NIH45-46_G54W showed de novo neutralization activity against 6 NIH45-46–resistant strains, including 3 that were sensitive to VRC01 but resistant to NIH45-46. For some strains that NIH45-46 neutralizes poorly, NIH45-46_G54W was significantly more potent. Diskin2011 (antibody generation, neutralization, binding affinity)

References

Showing 18 of 18 references.

Isolation Paper
Diskin2011 Ron Diskin, Johannes F. Scheid, Paola M. Marcovecchio, Anthony P. West, Jr., Florian Klein, Han Gao, Priyanthi N. P. Gnanapragasam, Alexander Abadir, Michael S. Seaman, Michel C. Nussenzweig, and Pamela J. Bjorkman. Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design. Science, 334(6060):1289-1293, 2 Dec 2011. PubMed ID: 22033520. Show all entries for this paper.

Carbonetti2014 Sara Carbonetti, Brian G. Oliver, Jolene Glenn, Leonidas Stamatatos, and D. Noah Sather. Soluble HIV-1 Envelope Immunogens Derived from an Elite Neutralizer Elicit Cross-Reactive V1V2 Antibodies and Low Potency Neutralizing Antibodies. PLoS One, 9(1):e86905, 2014. PubMed ID: 24466285. Show all entries for this paper.

Diskin2013 Ron Diskin, Florian Klein, Joshua A. Horwitz, Ariel Halper-Stromberg, D. Noah Sather, Paola M. Marcovecchio, Terri Lee, Anthony P. West, Jr., Han Gao, Michael S. Seaman, Leonidas Stamatatos, Michel C. Nussenzweig, and Pamela J. Bjorkman. Restricting HIV-1 Pathways for Escape Using Rationally Designed Anti-HIV-1 Antibodies. J. Exp. Med., 210(6):1235-1249, 3 Jun 2013. PubMed ID: 23712429. Show all entries for this paper.

Goo2012 Leslie Goo, Zahra Jalalian-Lechak, Barbra A. Richardson, and Julie Overbaugh. A Combination of Broadly Neutralizing HIV-1 Monoclonal Antibodies Targeting Distinct Epitopes Effectively Neutralizes Variants Found in Early Infection. J. Virol., 86(19):10857-10861, Oct 2012. PubMed ID: 22837204. Show all entries for this paper.

Halper-Stromberg2016 Ariel Halper-Stromberg and Michel C Nussenzweig. Towards HIV-1 Remission: Potential Roles for Broadly Neutralizing Antibodies. J. Clin. Invest., 126(2):415-423, Feb 2016. PubMed ID: 26752643. Show all entries for this paper.

Hua2016 Casey K. Hua and Margaret E. Ackerman. Engineering Broadly Neutralizing Antibodies for HIV Prevention and Therapy. Adv. Drug Deliv. Rev., 103:157-173, 1 Aug 2016. PubMed ID: 26827912. Show all entries for this paper.

Julien2015 Jean-Philippe Julien, Jeong Hyun Lee, Gabriel Ozorowski, Yuanzi Hua, Alba Torrents de la Peña, Steven W. de Taeye, Travis Nieusma, Albert Cupo, Anila Yasmeen, Michael Golabek, Pavel Pugach, P. J. Klasse, John P. Moore, Rogier W. Sanders, Andrew B. Ward, and Ian A. Wilson. Design and Structure of Two HIV-1 Clade C SOSIP.664 Trimers That Increase the Arsenal of Native-Like Env Immunogens. Proc. Natl. Acad. Sci. U.S.A., 112(38):11947-11952, 22 Sep 2015. PubMed ID: 26372963. Show all entries for this paper.

Klein2012a Florian Klein, Ariel Halper-Stromberg, Joshua A. Horwitz, Henning Gruell, Johannes F. Scheid, Stylianos Bournazos, Hugo Mouquet, Linda A. Spatz, Ron Diskin, Alexander Abadir, Trinity Zang, Marcus Dorner, Eva Billerbeck, Rachael N. Labitt, Christian Gaebler, Paola M. Marcovecchio, Reha-Baris Incesu, Thomas R. Eisenreich, Paul D. Bieniasz, Michael S. Seaman, Pamela J. Bjorkman, Jeffrey V. Ravetch, Alexander Ploss, and Michel C. Nussenzweig. HIV Therapy by a Combination of Broadly Neutralizing Antibodies in Humanized Mice. Nature, 492(7427):118-122, 6 Dec 2012. PubMed ID: 23103874. Show all entries for this paper.

Morgand2015 Marion Morgand, Mélanie Bouvin-Pley, Jean-Christophe Plantier, Alain Moreau, Elodie Alessandri, François Simon, Craig S. Pace, Marie Pancera, David D. Ho, Pascal Poignard, Pamela J. Bjorkman, Hugo Mouquet, Michel C. Nussenzweig, Peter D. Kwong, Daniel Baty, Patrick Chames, Martine Braibant, and Francis Barin. A V1V2 Neutralizing Epitope Is Conserved in Divergent Non-M Groups of HIV-1. J. Acquir. Immune Defic. Syndr., 21 Sep 2015. PubMed ID: 26413851. Show all entries for this paper.

Mouquet2012a Hugo Mouquet, Louise Scharf, Zelda Euler, Yan Liu, Caroline Eden, Johannes F. Scheid, Ariel Halper-Stromberg, Priyanthi N. P. Gnanapragasam, Daniel I. R. Spencer, Michael S. Seaman, Hanneke Schuitemaker, Ten Feizi, Michel C. Nussenzweig, and Pamela J. Bjorkman. Complex-Type N-Glycan Recognition by Potent Broadly Neutralizing HIV Antibodies. Proc. Natl. Acad. Sci. U.S.A, 109(47):E3268-E3277, 20 Nov 2012. PubMed ID: 23115339. Show all entries for this paper.

Sanders2013 Rogier W. Sanders, Ronald Derking, Albert Cupo, Jean-Philippe Julien, Anila Yasmeen, Natalia de Val, Helen J. Kim, Claudia Blattner, Alba Torrents de la Peña, Jacob Korzun, Michael Golabek, Kevin de los Reyes, Thomas J. Ketas, Marit J. van Gils, C. Richter King, Ian A. Wilson, Andrew B. Ward, P. J. Klasse, and John P. Moore. 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., 9(9):e1003618, Sep 2013. PubMed ID: 24068931. Show all entries for this paper.

Sather2012 D. Noah Sather, Sara Carbonetti, Jenny Kehayia, Zane Kraft, Iliyana Mikell, Johannes F. Scheid, Florian Klein, and Leonidas Stamatatos. Broadly Neutralizing Antibodies Developed by an HIV-Positive Elite Neutralizer Exact a Replication Fitness Cost on the Contemporaneous Virus. J. Virol., 86(23):12676-12685, Dec 2012. PubMed ID: 22973035. Show all entries for this paper.

West2013 Anthony P. West, Jr., Louise Scharf, Joshua Horwitz, Florian Klein, Michel C. Nussenzweig, and Pamela J. Bjorkman. Computational Analysis of Anti-HIV-1 Antibody Neutralization Panel Data to Identify Potential Functional Epitope Residues. Proc. Natl. Acad. Sci. U.S.A., 110(26):10598-10603, 25 Jun 2013. PubMed ID: 23754383. Show all entries for this paper.

Gardner2016 Matthew R. Gardner, Christoph H. Fellinger, Neha R. Prasad, Amber S. Zhou, Hema R. Kondur, Vinita R. Joshi, Brian D. Quinlan, and Michael Farzan. CD4-Induced Antibodies Promote Association of the HIV-1 Envelope Glycoprotein with CD4-Binding Site Antibodies. J. Virol., 90(17):7822-7832, 1 Sep 2016. PubMed ID: 27334589. Show all entries for this paper.

Bouvin-Pley2014 M. Bouvin-Pley, M. Morgand, L. Meyer, C. Goujard, A. Moreau, H. Mouquet, M. Nussenzweig, C. Pace, D. Ho, P. J. Bjorkman, D. Baty, P. Chames, M. Pancera, P. D. Kwong, P. Poignard, F. Barin, and M. Braibant. Drift of the HIV-1 Envelope Glycoprotein gp120 Toward Increased Neutralization Resistance over the Course of the Epidemic: A Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies. J. Virol., 88(23):13910-13917, Dec 2014. PubMed ID: 25231299. Show all entries for this paper.

Prigent2018 Julie Prigent, Annaëlle Jarossay, Cyril Planchais, Caroline Eden, Jérémy Dufloo, Ayrin Kök, Valérie Lorin, Oxana Vratskikh, Thérèse Couderc, Timothée Bruel, Olivier Schwartz, Michael S. Seaman, Ohlenschläger, Jordan D. Dimitrov, and Hugo Mouquet. Conformational Plasticity in Broadly Neutralizing HIV-1 Antibodies Triggers Polyreactivity. Cell Rep., 23(9):2568-2581, 29 May 2018. PubMed ID: 29847789. Show all entries for this paper.

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. Show all entries for this paper.

Wang2018a Hongye Wang, Ting Yuan, Tingting Li, Yanpeng Li, Feng Qian, Chuanwu Zhu, Shujia Liang, Daniel Hoffmann, Ulf Dittmer, Binlian Sun, and Rongge Yang. Evaluation of Susceptibility of HIV-1 CRF01\_AE Variants to Neutralization by a Panel of Broadly Neutralizing Antibodies. Arch. Virol., 163(12):3303-3315, Dec 2018. PubMed ID: 30196320. Show all entries for this paper.