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• PGT137: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. PGT137 was isolated from human B cell clones and is functionally similar to super-Abs PGT121, PGT128 and PGT135. Antigenic region V3 glycan (Table:1). Walker2018 (antibody binding site, review, broad neutralizer)
• PGT137: HIV-1 bNAb eptiope networks were predicted using 4 algorithms informed by neutralization assays using 282 Env from multiclade viruses. Patch clusters of possible Ab epitope regions were tested for significant sensitivity by site-directed mutagenesis. Epitope (Ab binding site) networks of critical Env residues for 21 bNAb (b12, PG9, PG16, PGT121, PGT122, PGT123, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT135, PGT136, PGT137, PGT141, PGT142, PGT143, PGT144, PGT145 and PGV04) were delineated and found to be located mostly in variable loops of gp120, particularly in V1/V2. Evans2014 (antibody binding site, computational epitope prediction)
• PGT137: The IGHV region is central to Ag binding and consists of 48 functional genes. IGHV repertoire of 28 HIV-infected South African women, 13 of whom developed bNAbs, was sequenced. Novel IGHV repertoires were reported, including 85 entirely novel sequences and 38 sequences that matched rearranged sequences in non-IMGT databases. There were no significant differences in germline IGHV repertoires between individuals who do and do not develop bNAbs. IGHV gene usage of multiple well known HIV-1 bNAbs was also analyzed and 14 instances were identified where the novel non-IMGT alleles identified in this study, provided the same or a better match than their currently defined IMGT allele. For PGT137 the published IMGT predicted allele was IGHV4-39*07 and alternate alleles predicted from IGHV alleles in 28 South African individuals were IGHV4-39*7m1, IGHV3-39*7m2 and IGHV3-39*7mm, with C4G nucleotide and L2V change and synonymous G298C nucleotide change. Scheepers2015 (antibody lineage)
• PGT137: This study describes a new level of complexity in antibody recognition of the mixed glycan-protein epitopes of the N332 region of HIV gp120. A combination of three antibody families that target the high-mannose patch can lead to 99% neutralization coverage of a large panel of viruses containing the N332/334 glycan site and up to 66% coverage for viruses that lack the N332/334 glycan site. PGT137 was completely unable to neutralize N334 variants. Sok2014a (antibody interactions, glycosylation)
• PGT137: Incomplete neutralization may decrease the ability of bnAbs to protect against HIV exposure. In order to determine the extent of non-sigmoidal slopes that plateau at <100% neutralization, a panel of 24 bnMAbs targeting different regions on Env was tested in a quantitative pseudovirus neutralization assay on a panel of 278 viral clones. All bNAbs had some viruses that they neutralized with a plateau <100%, but those targeting the V2 apex and MPER did so more often. All bnMAbs assayed had some viruses for which they had incomplete neutralization and non-sigmoidal neutralization curves. bNAbs were grouped into 3 groups based on their neutralization curves: group 1 antibodies neutralized more than 90% of susceptible viruses to >95% (PGT121-123, PGT125-128, PGT136, PGV04); group 2 was less effective, resulting in neutralization of 60-84% of susceptible viruses to >95% (b12, PGT130-131, PGT135, PGT137, PGT141-143, PGT145, 2G12, PG9); group 3 neutralized only 36-60% of susceptible viruses to >95% (PG16, PGT144, 2F5, 4E10). Among the panel tested, antibodies b12, 2G12, PGT136, and PGT137 had relatively few viruses neutralized with an IC50 <1 ug/ml. McCoy2015 (neutralization)
• PGT137: Vectored Immuno Prophylaxis (VIP), involves passive immunization by viral vector-mediated delivery of genes encoding bnAbs for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing Abs. This review article surveyed the status of antibody gene transfer, VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics. Yang2014 (immunoprophylaxis, review, antibody gene transfer)
• PGT137: Diversity of Ab recognition at the N332 site was assessed using chimeric antibodies made of heavy and light chains of N332-directed bNAbs PGT121-137. Recognition was good when heavy and light chains came from the same donor, and poor when they came from different donors, indicating multiple modes of recognition. Pancera2013a (chimeric antibody)
• PGT137: This study uncovered a potentially significant contribution of V_H replacement products which are highly enriched in IgH genes for the generation of anti-HIV Abs including anti-gp41, anti-V3 loop, anti-gp120, CD4i and PGT Abs. IgH encoding PGT Abs are likely generated from multiple rounds of V_H replacements. The details of PGT137 V_H replacement products in IgH gene and mutations and amino acid sequence analysis are described in Table 1, Table 2 and Fig 4. Liao2013a (antibody sequence)
• PGT137: Identification of broadly neutralizing antibodies, their epitopes on the HIV-1 spike, the molecular basis for their remarkable breadth, and the B cell ontogenies of their generation and maturation are reviewed. Ontogeny and structure-based classification is presented, based on MAb binding site, type (structural mode of recognition), class (related ontogenies in separate donors) and family (clonal lineage). This MAb's classification: gp120 glycan-V3 site, type not yet determined, PGT135 class, PGT135 family. Kwong2012 (review, structure, broad neutralizer)
• PGT137: Glycan Asn332-targeting broadly cross-neutralizing (BCN) antibodies were studied in 2 C-clade infected women. The ASn332 glycan was absent on infecting virus, but the BCN epitope with Asn332 evolved within 6 months though immune escape from earlier antibodies. Plasma from the subject CAP177 neutralized 88% of a large multi-subtype panel of 225 heterologous viruses, whereas CAP 314 neutralized 46% of 41 heterologous viruses but failed to neutralize viruses that lack glycan at 332. CAP177 or CAP314 clones were not sensitive to 2G12. Moore2012 (neutralization, escape)
• PGT137: Next-generation sequencing and bioinformatics methods were used to interrogate the B cell record of a donor from PGT135-137 MAbs were isolated. Using phylogenetic analysis to include closely related sequences, 202 heavy-chain sequences and 72 light-chain sequences were identified out of 141,298 heavy-chain sequences of IGHV4-39 origin and 87,229 light-chain sequences of IGKV3-15 origin. These sequences were clustered into populations of 95% identity comprising 15 for heavy chain and 10 for light chain, and a select sequence from each population was synthesized and reconstituted with a PGT137-partner chain. Even though these Abs are somatically related, both their sequence characteristics and neutralization properties toward clade A and D viruses diverged substantially, demonstrating the utility of a comprehensive sampling by next-generation sequencing. Zhu2012 (antibody lineage)
• PGT137: Neutralizing antibody repertoires of 4 HIV-infected donors with remarkably broad and potent neutralizing responses were probed. 17 new monoclonal antibodies that neutralize broadly across clades were rescued. These MAbs were not polyreactive. All MAbs exhibited broad cross-clade neutralizing activity, but several showed exceptional potency. PGT137 neutralized 22% of 162 isolates from major HIV clades at IC50<50 μg/ml. PGT MAbs 121-123, 130, 131 and 135-137 bound to monomeric gp120 and competed with glycan-specific 2G12 MAb and all MAbs except PGT 135-137 also competed with a V3-loop-specific antibody and did not bind to gp120ΔV3, suggesting that their epitopes are in proximity to or contiguous with V3. Walker2011 (antibody binding site, antibody generation, variant cross-reactivity)

References

Showing 12 of 12 references.

Isolation Paper
Walker2011 Laura M. Walker, Michael Huber, Katie J. Doores, Emilia Falkowska, Robert Pejchal, Jean-Philippe Julien, Sheng-Kai Wang, Alejandra Ramos, Po-Ying Chan-Hui, Matthew Moyle, Jennifer L. Mitcham, Phillip W. Hammond, Ole A. Olsen, Pham Phung, Steven Fling, Chi-Huey Wong, Sanjay Phogat, Terri Wrin, Melissa D. Simek, Protocol G. Principal Investigators, Wayne C. Koff, Ian A. Wilson, Dennis R. Burton, and Pascal Poignard. Broad Neutralization Coverage of HIV by Multiple Highly Potent Antibodies. Nature, 477(7365):466-470, 22 Sep 2011. PubMed ID: 21849977. Show all entries for this paper.

Evans2014 Mark C. Evans, Pham Phung, Agnes C. Paquet, Anvi Parikh, Christos J. Petropoulos, Terri Wrin, and Mojgan Haddad. Predicting HIV-1 Broadly Neutralizing Antibody Epitope Networks Using Neutralization Titers and a Novel Computational Method. BMC Bioinformatics, 15:77, 19 Mar 2014. PubMed ID: 24646213. Show all entries for this paper.

Kwong2012 Peter D. Kwong and John R. Mascola. Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies. Immunity, 37(3):412-425, 21 Sep 2012. PubMed ID: 22999947. Show all entries for this paper.

Liao2013a Hongyan Liao, Jun-tao Guo, Miles D. Lange, Run Fan, Michael Zemlin, Kaihong Su, Yongjun Guan, and Zhixin Zhang. Contribution of V(H) Replacement Products to the Generation of Anti-HIV Antibodies. Clin. Immunol., 146(1):46-55, Jan 2013. PubMed ID: 23220404. Show all entries for this paper.

McCoy2015 Laura E. McCoy, Emilia Falkowska, Katie J. Doores, Khoa Le, Devin Sok, Marit J. van Gils, Zelda Euler, Judith A. Burger, Michael S. Seaman, Rogier W. Sanders, Hanneke Schuitemaker, Pascal Poignard, Terri Wrin, and Dennis R. Burton. Incomplete Neutralization and Deviation from Sigmoidal Neutralization Curves for HIV Broadly Neutralizing Monoclonal Antibodies. PLoS Pathog., 11(8):e1005110, Aug 2015. PubMed ID: 26267277. Show all entries for this paper.

Moore2012 Penny L. Moore, Elin S. Gray, C. Kurt Wibmer, Jinal N. Bhiman, Molati Nonyane, Daniel J. Sheward, Tandile Hermanus, Shringkhala Bajimaya, Nancy L. Tumba, Melissa-Rose Abrahams, Bronwen E. Lambson, Nthabeleng Ranchobe, Lihua Ping, Nobubelo Ngandu, Quarraisha Abdool Karim, Salim S. Abdool Karim, Ronald I. Swanstrom, Michael S. Seaman, Carolyn Williamson, and Lynn Morris. Evolution of an HIV Glycan-Dependent Broadly Neutralizing Antibody Epitope through Immune Escape. Nat. Med., 18(11):1688-1692, Nov 2012. PubMed ID: 23086475. Show all entries for this paper.

Pancera2013a Marie Pancera, Yongping Yang, Mark K. Louder, Jason Gorman, Gabriel Lu, Jason S. McLellan, Jonathan Stuckey, Jiang Zhu, Dennis R. Burton, Wayne C. Koff, John R. Mascola, and Peter D. Kwong. N332-Directed Broadly Neutralizing Antibodies Use Diverse Modes of HIV-1 Recognition: Inferences from Heavy-Light Chain Complementation of Function. PLoS One, 8(2):e55701, 2013. PubMed ID: 23431362. Show all entries for this paper.

Scheepers2015 Cathrine Scheepers, Ram K. Shrestha, Bronwen E. Lambson, Katherine J. L. Jackson, Imogen A. Wright, Dshanta Naicker, Mark Goosen, Leigh Berrie, Arshad Ismail, Nigel Garrett, Quarraisha Abdool Karim, Salim S. Abdool Karim, Penny L. Moore, Simon A. Travers, and Lynn Morris. Ability to Develop Broadly Neutralizing HIV-1 Antibodies Is Not Restricted by the Germline Ig Gene Repertoire. J. Immunol., 194(9):4371-4378, 1 May 2015. PubMed ID: 25825450. Show all entries for this paper.

Sok2014a Devin Sok, Katie J. Doores, Bryan Briney, Khoa M. Le, Karen L. Saye-Francisco, Alejandra Ramos, Daniel W. Kulp, Jean-Philippe Julien, Sergey Menis, Lalinda Wickramasinghe, Michael S. Seaman, William R. Schief, Ian A. Wilson, Pascal Poignard, and Dennis R. Burton. Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV. Sci. Transl. Med., 6(236):236ra63, 14 May 2014. PubMed ID: 24828077. Show all entries for this paper.

Yang2014 Lili Yang and Pin Wang. Passive Immunization against HIV/AIDS by Antibody Gene Transfer. Viruses, 6(2):428-447, Feb 2014. PubMed ID: 24473340. Show all entries for this paper.

Zhu2012 Jiang Zhu, Sijy O'Dell, Gilad Ofek, Marie Pancera, Xueling Wu, Baoshan Zhang, Zhenhai Zhang, NISC Comparative Sequencing Program, James C. Mullikin, Melissa Simek, Dennis R. Burton, Wayne C. Koff, Lawrence Shapiro, John R. Mascola, and Peter D. Kwong. Somatic Populations of PGT135-137 HIV-1-Neutralizing Antibodies Identified by 454 Pyrosequencing and Bioinformatics. Front. Microbiol., 3:315, 2012. PubMed ID: 23024643. Show all entries for this paper.

Walker2018 Laura M. Walker and Dennis R. Burton. Passive Immunotherapy of Viral Infections: `Super-Antibodies' Enter the Fray. Nat. Rev. Immunol., 18(5):297-308, May 2018. PubMed ID: 29379211. Show all entries for this paper.