FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2134803208> ?p ?o ?g. }

• W2134803208 endingPage "138" @default.
• W2134803208 startingPage "126" @default.
• W2134803208 abstract "Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and less tolerant of mutations. Here, we report that in contrast to most antibodies, including those with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural and functional analyses reveal that somatic mutations in FWR residues enhance breadth and potency by providing increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role beyond scaffolding the CDR loops and their unusual contribution to potency and breadth should be considered in HIV-1 vaccine design. Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and less tolerant of mutations. Here, we report that in contrast to most antibodies, including those with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural and functional analyses reveal that somatic mutations in FWR residues enhance breadth and potency by providing increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role beyond scaffolding the CDR loops and their unusual contribution to potency and breadth should be considered in HIV-1 vaccine design. Framework mutations play a crucial role in broadly neutralizing HIV-1 antibodies Mutations in the antibody framework are critical for HIV-1 neutralization Increased antibody flexibility can enhance HIV-1 neutralization activity FWR mutations can extend direct antigen contact resulting in improved activity A fraction of HIV-1-infected individuals mount a broadly neutralizing serologic response (Doria-Rose et al., 2010Doria-Rose N.A. Klein R.M. Daniels M.G. O’Dell S. Nason M. Lapedes A. Bhattacharya T. Migueles S.A. Wyatt R.T. Korber B.T. et al.Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables.J. Virol. 2010; 84: 1631-1636Crossref PubMed Scopus (262) Google Scholar; Simek et al., 2009Simek M.D. Rida W. Priddy F.H. Pung P. Carrow E. Laufer D.S. Lehrman J.K. Boaz M. Tarragona-Fiol T. Miiro G. et al.Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm.J. Virol. 2009; 83: 7337-7348Crossref PubMed Scopus (468) Google Scholar) 2–3 years after infection (Mikell et al., 2011Mikell I. Sather D.N. Kalams S.A. Altfeld M. Alter G. Stamatatos L. Characteristics of the earliest cross-neutralizing antibody response to HIV-1.PLoS Pathog. 2011; 7: e1001251Crossref PubMed Scopus (259) Google Scholar). Antibodies generated by these individuals are of great interest for vaccine design because they can protect macaques from infection (Mascola et al., 2000Mascola J.R. Stiegler G. VanCott T.C. Katinger H. Carpenter C.B. Hanson C.E. Beary H. Hayes D. Frankel S.S. Birx D.L. Lewis M.G. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies.Nat. Med. 2000; 6: 207-210Crossref PubMed Scopus (1162) Google Scholar; Moldt et al., 2012Moldt B. Rakasz E.G. Schultz N. Chan-Hui P.Y. Swiderek K. Weisgrau K.L. Piaskowski S.M. Bergman Z. Watkins D.I. Poignard P. Burton D.R. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo.Proc. Natl. Acad. Sci. USA. 2012; 109: 18921-18925Crossref PubMed Scopus (380) Google Scholar; Shibata et al., 1999Shibata R. Igarashi T. Haigwood N. Buckler-White A. Ogert R. Ross W. Willey R. Cho M.W. Martin M.A. Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely block HIV-1/SIV chimeric virus infections of macaque monkeys.Nat. Med. 1999; 5: 204-210Crossref PubMed Scopus (504) Google Scholar). Moreover, combinations of broadly neutralizing antibodies can control an established HIV-1 infection in humanized mice (Klein et al., 2012bKlein F. Halper-Stromberg A. Horwitz J.A. Gruell H. Scheid J.F. Bournazos S. Mouquet H. Spatz L.A. Diskin R. Abadir A. et al.HIV therapy by a combination of broadly neutralizing antibodies in humanized mice.Nature. 2012; 492: 118-122Crossref PubMed Scopus (409) Google Scholar). Despite their potential importance to vaccine development and HIV-1 therapy, little was known about the molecular composition of the human anti-HIV-1 antibody response until single-cell antibody cloning techniques were developed and used for characterizing IgGs from the sera of HIV-1-infected individuals with broadly neutralizing activity (Scheid et al., 2009aScheid J.F. Mouquet H. Feldhahn N. Seaman M.S. Velinzon K. Pietzsch J. Ott R.G. Anthony R.M. Zebroski H. Hurley A. et al.Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals.Nature. 2009; 458: 636-640Crossref PubMed Scopus (709) Google Scholar; Scheid et al., 2009bScheid J.F. Mouquet H. Feldhahn N. Walker B.D. Pereyra F. Cutrell E. Seaman M.S. Mascola J.R. Wyatt R.T. Wardemann H. Nussenzweig M.C. A method for identification of HIV gp140 binding memory B cells in human blood.J. Immunol. Methods. 2009; 343: 65-67Crossref PubMed Scopus (172) Google Scholar). This analysis revealed highly potent bNAbs, all of which might eventually be used in vaccine development (Corti et al., 2010Corti D. Langedijk J.P. Hinz A. Seaman M.S. Vanzetta F. Fernandez-Rodriguez B.M. Silacci C. Pinna D. Jarrossay D. Balla-Jhagjhoorsingh S. et al.Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.PLoS ONE. 2010; 5: e8805Crossref PubMed Scopus (378) Google Scholar; Huang et al., 2012Huang J. Ofek G. Laub L. Louder M.K. Doria-Rose N.A. Longo N.S. Imamichi H. Bailer R.T. Chakrabarti B. Sharma S.K. et al.Broad and potent neutralization of HIV-1 by a gp41-specific human antibody.Nature. 2012; 491: 406-412Crossref PubMed Scopus (632) Google Scholar; Morris et al., 2011Morris L. Chen X. Alam M. Tomaras G. Zhang R. Marshall D.J. Chen B. Parks R. Foulger A. Jaeger F. et al.Isolation of a human anti-HIV gp41 membrane proximal region neutralizing antibody by antigen-specific single B cell sorting.PLoS ONE. 2011; 6: e23532Crossref PubMed Scopus (128) Google Scholar; Mouquet et al., 2012Mouquet H. Scharf L. Euler Z. Liu Y. Eden C. Scheid J.F. Halper-Stromberg A. Gnanapragasam P.N. Spencer D.I. Seaman M.S. et al.Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies.Proc. Natl. Acad. Sci. USA. 2012; 109: E3268-E3277Crossref PubMed Scopus (404) Google Scholar; Scheid et al., 2011Scheid J.F. Mouquet H. Ueberheide B. Diskin R. Klein F. Oliveira T.Y. Pietzsch J. Fenyo D. Abadir A. Velinzon K. et al.Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding.Science. 2011; 333: 1633-1637Crossref PubMed Scopus (876) Google Scholar; Walker et al., 2009Walker L.M. Phogat S.K. Chan-Hui P.Y. Wagner D. Phung P. Goss J.L. Wrin T. Simek M.D. Fling S. Mitcham J.L. et al.Protocol G Principal InvestigatorsBroad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target.Science. 2009; 326: 285-289Crossref PubMed Scopus (1391) Google Scholar, Walker et al., 2011bWalker L.M. Sok D. Nishimura Y. Donau O. Sadjadpour R. Gautam R. Shingai M. Pejchal R. Ramos A. Simek M.D. et al.Rapid development of glycan-specific, broad, and potent anti-HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque.Proc. Natl. Acad. Sci. USA. 2011; 108: 20125-20129Crossref PubMed Scopus (73) Google Scholar; Wu et al., 2010Wu X. Yang Z.Y. Li Y. Hogerkorp C.M. Schief W.R. Seaman M.S. Zhou T. Schmidt S.D. Wu L. Xu L. et al.Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1.Science. 2010; 329: 856-861Crossref PubMed Scopus (1342) Google Scholar). A surprising observation was that anti-HIV-1 antibodies are highly somatically mutated when compared to other immunoglobulins (IgGs) cloned from the same patients (Scheid et al., 2009aScheid J.F. Mouquet H. Feldhahn N. Seaman M.S. Velinzon K. Pietzsch J. Ott R.G. Anthony R.M. Zebroski H. Hurley A. et al.Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals.Nature. 2009; 458: 636-640Crossref PubMed Scopus (709) Google Scholar; Xiao et al., 2009aXiao X. Chen W. Feng Y. Dimitrov D.S. Maturation Pathways of Cross-Reactive HIV-1 Neutralizing Antibodies.Viruses. 2009; 1: 802-817Crossref PubMed Scopus (52) Google Scholar, Xiao et al., 2009bXiao X. Chen W. Feng Y. Zhu Z. Prabakaran P. Wang Y. Zhang M.Y. Longo N.S. Dimitrov D.S. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens.Biochem. Biophys. Res. Commun. 2009; 390: 404-409Crossref PubMed Scopus (200) Google Scholar). Whereas most human antibodies that have undergone affinity maturation carry 15–20 VH-gene somatic mutations (Tiller et al., 2007Tiller T. Tsuiji M. Yurasov S. Velinzon K. Nussenzweig M.C. Wardemann H. Autoreactivity in human IgG+ memory B cells.Immunity. 2007; 26: 205-213Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar), potent broadly neutralizing antibodies carry 40–100 VH-gene mutations (Corti et al., 2010Corti D. Langedijk J.P. Hinz A. Seaman M.S. Vanzetta F. Fernandez-Rodriguez B.M. Silacci C. Pinna D. Jarrossay D. Balla-Jhagjhoorsingh S. et al.Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.PLoS ONE. 2010; 5: e8805Crossref PubMed Scopus (378) Google Scholar; Scheid et al., 2011Scheid J.F. Mouquet H. Ueberheide B. Diskin R. Klein F. Oliveira T.Y. Pietzsch J. Fenyo D. Abadir A. Velinzon K. et al.Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding.Science. 2011; 333: 1633-1637Crossref PubMed Scopus (876) Google Scholar; Walker et al., 2009Walker L.M. Phogat S.K. Chan-Hui P.Y. Wagner D. Phung P. Goss J.L. Wrin T. Simek M.D. Fling S. Mitcham J.L. et al.Protocol G Principal InvestigatorsBroad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target.Science. 2009; 326: 285-289Crossref PubMed Scopus (1391) Google Scholar, Walker et al., 2011bWalker L.M. Sok D. Nishimura Y. Donau O. Sadjadpour R. Gautam R. Shingai M. Pejchal R. Ramos A. Simek M.D. et al.Rapid development of glycan-specific, broad, and potent anti-HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque.Proc. Natl. Acad. Sci. USA. 2011; 108: 20125-20129Crossref PubMed Scopus (73) Google Scholar; Wu et al., 2010Wu X. Yang Z.Y. Li Y. Hogerkorp C.M. Schief W.R. Seaman M.S. Zhou T. Schmidt S.D. Wu L. Xu L. et al.Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1.Science. 2010; 329: 856-861Crossref PubMed Scopus (1342) Google Scholar; Xiao et al., 2009aXiao X. Chen W. Feng Y. Dimitrov D.S. Maturation Pathways of Cross-Reactive HIV-1 Neutralizing Antibodies.Viruses. 2009; 1: 802-817Crossref PubMed Scopus (52) Google Scholar, Xiao et al., 2009bXiao X. Chen W. Feng Y. Zhu Z. Prabakaran P. Wang Y. Zhang M.Y. Longo N.S. Dimitrov D.S. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens.Biochem. Biophys. Res. Commun. 2009; 390: 404-409Crossref PubMed Scopus (200) Google Scholar). These mutations are essential because reversion to the antibody germline sequence drastically reduces neutralizing potency and breadth (Mouquet et al., 2010Mouquet H. Scheid J.F. Zoller M.J. Krogsgaard M. Ott R.G. Shukair S. Artyomov M.N. Pietzsch J. Connors M. Pereyra F. et al.Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.Nature. 2010; 467: 591-595Crossref PubMed Scopus (327) Google Scholar; Scheid et al., 2011Scheid J.F. Mouquet H. Ueberheide B. Diskin R. Klein F. Oliveira T.Y. Pietzsch J. Fenyo D. Abadir A. Velinzon K. et al.Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding.Science. 2011; 333: 1633-1637Crossref PubMed Scopus (876) Google Scholar; Wu et al., 2011Wu X. Zhou T. Zhu J. Zhang B. Georgiev I. Wang C. Chen X. Longo N.S. Louder M. McKee K. et al.NISC Comparative Sequencing ProgramFocused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.Science. 2011; 333: 1593-1602Crossref PubMed Scopus (678) Google Scholar; Xiao et al., 2009bXiao X. Chen W. Feng Y. Zhu Z. Prabakaran P. Wang Y. Zhang M.Y. Longo N.S. Dimitrov D.S. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens.Biochem. Biophys. Res. Commun. 2009; 390: 404-409Crossref PubMed Scopus (200) Google Scholar; Zhou et al., 2010Zhou T. Georgiev I. Wu X. Yang Z.Y. Dai K. Finzi A. Kwon Y.D. Scheid J.F. Shi W. Xu L. et al.Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.Science. 2010; 329: 811-817Crossref PubMed Scopus (889) Google Scholar). However, why so many mutations appear to be required is not known. Wu and Kabat first divided antibody variable regions into complementarity determining regions (CDRs) and framework regions (FWRs) based on the number of somatic hypermutations in these regions (Wu and Kabat, 1970Wu T.T. Kabat E.A. An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity.J. Exp. Med. 1970; 132: 211-250Crossref PubMed Scopus (934) Google Scholar) (Figures 1A and 1B ). The CDRs consist primarily of loops that form the sites of contact between the antibody and antigen (Amzel and Poljak, 1979Amzel L.M. Poljak R.J. Three-dimensional structure of immunoglobulins.Annu. Rev. Biochem. 1979; 48: 961-997Crossref PubMed Google Scholar) and account for the specificities of most antibody molecules as demonstrated by CDR grafting experiments (Jones et al., 1986Jones P.T. Dear P.H. Foote J. Neuberger M.S. Winter G. Replacing the complementarity-determining regions in a human antibody with those from a mouse.Nature. 1986; 321: 522-525Crossref PubMed Scopus (1128) Google Scholar). The structural integrity of the variable domains is maintained by the FWRs, which encode nine antiparallel β strands arranged into two β sheets (one sheet containing strands A, B, E, and D and the other containing strands C,” C’, C, F and G; Figures 1A and 1B). The relatively invariant β strands of the FWRs serve as a scaffold for three CDR loops, which connect strands B and C, C’ and C,” and F and G (Figures 1A and 1B) (Amzel and Poljak, 1979Amzel L.M. Poljak R.J. Three-dimensional structure of immunoglobulins.Annu. Rev. Biochem. 1979; 48: 961-997Crossref PubMed Google Scholar). Somatic mutations are preferentially found in the CDR loops where they can alter the antibody combining site without affecting the overall structure of the variable domain (Wu and Kabat, 1970Wu T.T. Kabat E.A. An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity.J. Exp. Med. 1970; 132: 211-250Crossref PubMed Scopus (934) Google Scholar). Mutations in the FWR are usually poorly tolerated and generally biased to neutral substitutions to avoid changes that would destroy the structural underpinnings of the variable domain (Reynaud et al., 1995Reynaud C.A. Garcia C. Hein W.R. Weill J.C. Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process.Cell. 1995; 80: 115-125Abstract Full Text PDF PubMed Scopus (270) Google Scholar; Wagner et al., 1995Wagner S.D. Milstein C. Neuberger M.S. Codon bias targets mutation.Nature. 1995; 376: 732Crossref PubMed Scopus (153) Google Scholar). Here we examine the role of somatic mutations in the development of broadly neutralizing anti-HIV-1 antibodies. In contrast to most other antibodies, including anti-HIV-1 antibodies with limited neutralization activity, we found that FWR mutations, including noncontact residues, are essential for the neutralizing activity of most potent bNAbs. We propose that the requirement to alter the FWR, without destroying its essential structural elements, accounts for the high mutation load found in broadly neutralizing anti-HIV-1 antibodies and possibly for the difficulty and prolonged latency with which such antibodies develop. To examine the role of somatic hypermutations in anti-HIV-1 antibody neutralization breadth and potency, we selected a group of 9 HIV-1-reactive antibodies with activity limited to easy to neutralize (Tier 1) HIV-1 strains (Seaman et al., 2010Seaman M.S. Janes H. Hawkins N. Grandpre L.E. Devoy C. Giri A. Coffey R.T. Harris L. Wood B. Daniels M.G. et al.Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies.J. Virol. 2010; 84: 1439-1452Crossref PubMed Scopus (507) Google Scholar), and 17 antibodies with broad neutralization activity (Figures 1C and S1 and Table S1 available online). The antibodies with limited neutralizing activity included antibodies recognizing the CD4-binding site (CD4bs; 6-187, 9–913, and 11–989) (Mouquet et al., 2011Mouquet H. Klein F. Scheid J.F. Warncke M. Pietzsch J. Oliveira T.Y. Velinzon K. Seaman M.S. Nussenzweig M.C. Memory B cell antibodies to HIV-1 gp140 cloned from individuals infected with clade A and B viruses.PLoS ONE. 2011; 6: e24078Crossref PubMed Scopus (92) Google Scholar; Scheid et al., 2009aScheid J.F. Mouquet H. Feldhahn N. Seaman M.S. Velinzon K. Pietzsch J. Ott R.G. Anthony R.M. Zebroski H. Hurley A. et al.Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals.Nature. 2009; 458: 636-640Crossref PubMed Scopus (709) Google Scholar), the core epitope (1–479, 2–491, and 11–591) (Mouquet et al., 2011Mouquet H. Klein F. Scheid J.F. Warncke M. Pietzsch J. Oliveira T.Y. Velinzon K. Seaman M.S. Nussenzweig M.C. Memory B cell antibodies to HIV-1 gp140 cloned from individuals infected with clade A and B viruses.PLoS ONE. 2011; 6: e24078Crossref PubMed Scopus (92) Google Scholar; Pietzsch et al., 2010Pietzsch J. Scheid J.F. Mouquet H. Klein F. Seaman M.S. Jankovic M. Corti D. Lanzavecchia A. Nussenzweig M.C. Human anti-HIV-neutralizing antibodies frequently target a conserved epitope essential for viral fitness.J. Exp. Med. 2010; 207: 1995-2002Crossref PubMed Scopus (56) Google Scholar; Scheid et al., 2009aScheid J.F. Mouquet H. Feldhahn N. Seaman M.S. Velinzon K. Pietzsch J. Ott R.G. Anthony R.M. Zebroski H. Hurley A. et al.Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals.Nature. 2009; 458: 636-640Crossref PubMed Scopus (709) Google Scholar), the V3-loop (447-52D and 10–188) (Gorny et al., 1993Gorny M.K. Xu J.Y. Karwowska S. Buchbinder A. Zolla-Pazner S. Repertoire of neutralizing human monoclonal antibodies specific for the V3 domain of HIV-1 gp120.J. Immunol. 1993; 150: 635-643PubMed Google Scholar; Mouquet et al., 2011Mouquet H. Klein F. Scheid J.F. Warncke M. Pietzsch J. Oliveira T.Y. Velinzon K. Seaman M.S. Nussenzweig M.C. Memory B cell antibodies to HIV-1 gp140 cloned from individuals infected with clade A and B viruses.PLoS ONE. 2011; 6: e24078Crossref PubMed Scopus (92) Google Scholar), and the CD4-induced site (17b) (Thali et al., 1993Thali M. Moore J.P. Furman C. Charles M. Ho D.D. Robinson J. Sodroski J. Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding.J. Virol. 1993; 67: 3978-3988Crossref PubMed Google Scholar) (Table S1). Eight of the 17 bNAbs also recognize the CD4bs (VRC01, NIH45-46, 3BNC60, 12A12, 1NC9, 8ANC131, 12A21, and 3BNC117) (Scheid et al., 2011Scheid J.F. Mouquet H. Ueberheide B. Diskin R. Klein F. Oliveira T.Y. Pietzsch J. Fenyo D. Abadir A. Velinzon K. et al.Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding.Science. 2011; 333: 1633-1637Crossref PubMed Scopus (876) Google Scholar; Wu et al., 2010Wu X. Yang Z.Y. Li Y. Hogerkorp C.M. Schief W.R. Seaman M.S. Zhou T. Schmidt S.D. Wu L. Xu L. et al.Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1.Science. 2010; 329: 856-861Crossref PubMed Scopus (1342) Google Scholar), whereas others recognized the V1/V2 loop (PG16) (Walker et al., 2009Walker L.M. Phogat S.K. Chan-Hui P.Y. Wagner D. Phung P. Goss J.L. Wrin T. Simek M.D. Fling S. Mitcham J.L. et al.Protocol G Principal InvestigatorsBroad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target.Science. 2009; 326: 285-289Crossref PubMed Scopus (1391) Google Scholar), carbohydrates (2G12) (Calarese et al., 2003Calarese D.A. Scanlan C.N. Zwick M.B. Deechongkit S. Mimura Y. Kunert R. Zhu P. Wormald M.R. Stanfield R.L. Roux K.H. et al.Antibody domain exchange is an immunological solution to carbohydrate cluster recognition.Science. 2003; 300: 2065-2071Crossref PubMed Scopus (673) Google Scholar; Trkola et al., 1996Trkola A. Purtscher M. Muster T. Ballaun C. Buchacher A. Sullivan N. Srinivasan K. Sodroski J. Moore J.P. Katinger H. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1.J. Virol. 1996; 70: 1100-1108Crossref PubMed Google Scholar), the core epitope (HJ16) (Corti et al., 2010Corti D. Langedijk J.P. Hinz A. Seaman M.S. Vanzetta F. Fernandez-Rodriguez B.M. Silacci C. Pinna D. Jarrossay D. Balla-Jhagjhoorsingh S. et al.Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.PLoS ONE. 2010; 5: e8805Crossref PubMed Scopus (378) Google Scholar), the base of the V3-loop (10-1074 and PGT128) (Mouquet et al., 2012Mouquet H. Scharf L. Euler Z. Liu Y. Eden C. Scheid J.F. Halper-Stromberg A. Gnanapragasam P.N. Spencer D.I. Seaman M.S. et al.Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies.Proc. Natl. Acad. Sci. USA. 2012; 109: E3268-E3277Crossref PubMed Scopus (404) Google Scholar; Walker et al., 2011aWalker L.M. Huber M. Doores K.J. Falkowska E. Pejchal R. Julien J.P. Wang S.K. Ramos A. Chan-Hui P.Y. Moyle M. et al.Protocol G Principal InvestigatorsBroad neutralization coverage of HIV by multiple highly potent antibodies.Nature. 2011; 477: 466-470Crossref PubMed Scopus (1172) Google Scholar), the membrane proximal external region (MPER; 4E10 and 2F5) (Buchacher et al., 1994Buchacher A. Predl R. Strutzenberger K. Steinfellner W. Trkola A. Purtscher M. Gruber G. Tauer C. Steindl F. Jungbauer A. et al.Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization.AIDS Res. Hum. Retroviruses. 1994; 10: 359-369Crossref PubMed Scopus (477) Google Scholar; Muster et al., 1993Muster T. Steindl F. Purtscher M. Trkola A. Klima A. Himmler G. Rüker F. Katinger H. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1.J. Virol. 1993; 67: 6642-6647Crossref PubMed Google Scholar) and two antibodies (3BC176 and 8ANC195) (Klein et al., 2012aKlein F. Gaebler C. Mouquet H. Sather D.N. Lehmann C. Scheid J.F. Kraft Z. Liu Y. Pietzsch J. Hurley A. et al.Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein.J. Exp. Med. 2012; 209: 1469-1479Crossref PubMed Scopus (132) Google Scholar; Scheid et al., 2011Scheid J.F. Mouquet H. Ueberheide B. Diskin R. Klein F. Oliveira T.Y. Pietzsch J. Fenyo D. Abadir A. Velinzon K. et al.Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding.Science. 2011; 333: 1633-1637Crossref PubMed Scopus (876) Google Scholar) for which the precise epitopes are not yet determined (Figure 1C and Table S1). Antibodies with limited neutralizing activity differ from bNAbs in that they generally carry fewer somatic mutations (Figures 1C and S1 and Table S1). We used the well-accepted Kabat system (Wu and Kabat, 1970Wu T.T. Kabat E.A. An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity.J. Exp. Med. 1970; 132: 211-250Crossref PubMed Scopus (934) Google Scholar) that utilizes sequence comparisons for FWR/CDR assignments. However, direct comparisons between Kabat and the IMGT numbering system (Giudicelli et al., 2006Giudicelli V. Duroux P. Ginestoux C. Folch G. Jabado-Michaloud J. Chaume D. Lefranc M.P. IMGT/LIGM-DB, the IMGT comprehensive database of immunoglobulin and T cell receptor nucleotide sequences.Nucleic Acids Res. 2006; 34: D781-D784Crossref PubMed Scopus (212) Google Scholar) (Figure 1B), which includes antibody structural data, were also performed for a subset of antibodies. Complete reversion of somatic mutations in the heavy and light chain V genes (FWR1-3 and CDR1/2) drastically reduces anti-HIV-1 antibody binding and neutralization activity (Buchacher et al., 1994Buchacher A. Predl R. Strutzenberger K. Steinfellner W. Trkola A. Purtscher M. Gruber G. Tauer C. Steindl F. Jungbauer A. et al.Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization.AIDS Res. Hum. Retroviruses. 1994; 10: 359-369Crossref PubMed Scopus (477) Google Scholar; Mouquet et al., 2010Mouquet H. Scheid J.F. Zoller M.J. Krogsgaard M. Ott R.G. Shukair S. Artyomov M.N. Pietzsch J. Connors M. Pereyra F. et al.Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation.Nature. 2010; 467: 591-595Crossref PubMed Scopus (327) Google Scholar; Scheid et al., 2011Scheid J.F. Mouquet H. Ueberheide B. Diskin R. Klein F. Oliveira T.Y. Pietzsch J. Fenyo D. Abadir A. Velinzon K. et al.Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding.Science. 2011; 333: 1633-1637Crossref PubMed Scopus (876) Google Scholar; Xiao et al., 2009bXiao X. Chen W. Feng Y. Zhu Z. Prabakaran P. Wang Y. Zhang M.Y. Longo N.S. Dimitrov D.S. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens.Biochem. Biophys. Res. Commun. 2009; 390: 404-409Crossref PubMed Scopus (200) Google Scholar; Zhou et al., 2010Zhou T. Georgiev I. Wu X. Yang Z.Y. Dai K. Finzi A. Kwon Y.D. Scheid J.F. Shi W. Xu L. et al.Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.Science. 2010; 329: 811-817Crossref PubMed Scopus (889) Google Scholar). Moreover, reverting only the CDR1 and CDR2 in 3BNC60 and NIH45-46 strongly diminished binding and neutralization (Figure S2A and Data S1A). To determine the functional consequences of FWR mutations, we reverted the framework residues to their germline counterparts (FWR-GL) in each of the 26 selected antibodies (Data S1B–1D) and evaluated binding to the HIV-1 envelope protein as well as their neutralization activities. As expected, reversion of somatic mutations in the FWR residues (FWR-GL) of the HIV-1 antibodies with limited breadth had only minimal effects on binding of most of these antibodies to gp140YU2 (Figure S2B) as measured by ELISA and confirmed by surface plasmon resonance (SPR) (data not shown). Only two of these FWR-GL antibodies (9-913 and 10-188) showed a decrease in binding (Figure S2B). In agreement with the ELISA and SPR experiments, we found little or no change in neutralizing activity in most of the FWR-GL antibodies with limited neutralization activity on a panel of up to six Tier 1 viruses representing clades A, B, and C (Figure S2B and Table S2). Only antibodies 9-913 and 10-188, which displayed decreased binding to gp140YU2, showed a decrease (9-913) or complete loss (10-188) in neutralizing activity (Figure S2B and Table S2). We conclude that with two exceptions out of nine antibodies tested, FWR mutations do not alter the binding or neutralizing activity of anti-HIV-1 antibodies with limited neutralizing activity. Thus, despite their significantly higher levels of somatic mutation, HIV-1-neutralizing antibodies with limited breadth resemble previously characterized antibodies to other antigens in that FWR mutations seem not to be essential. In contrast, reversion of the FWR mutations in most of the 17 broadly neutralizing antibodies decreased their binding to gp140YU2 (Figures 2 and 3). Thr" @default.
• W2134803208 created "2016-06-24" @default.
• W2134803208 creator A5003170920 @default.
• W2134803208 creator A5003699560 @default.
• W2134803208 creator A5031197890 @default.
• W2134803208 creator A5031748920 @default.
• W2134803208 creator A5033326746 @default.
• W2134803208 creator A5043677118 @default.
• W2134803208 creator A5047995631 @default.
• W2134803208 creator A5060230238 @default.
• W2134803208 creator A5060661085 @default.
• W2134803208 creator A5063385270 @default.
• W2134803208 creator A5065401344 @default.
• W2134803208 creator A5068857084 @default.
• W2134803208 creator A5076958095 @default.
• W2134803208 creator A5080175927 @default.
• W2134803208 creator A5085094175 @default.
• W2134803208 creator A5086835391 @default.
• W2134803208 date "2013-03-01" @default.
• W2134803208 modified "2023-10-12" @default.
• W2134803208 title "Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization" @default.
• W2134803208 cites W1528520360 @default.
• W2134803208 cites W1560434917 @default.
• W2134803208 cites W1587830797 @default.
• W2134803208 cites W1635348995 @default.
• W2134803208 cites W1794879226 @default.
• W2134803208 cites W1974273518 @default.
• W2134803208 cites W1974431423 @default.
• W2134803208 cites W1975276582 @default.
• W2134803208 cites W1976232165 @default.
• W2134803208 cites W1981981290 @default.
• W2134803208 cites W1992566288 @default.
• W2134803208 cites W1993084727 @default.
• W2134803208 cites W1997677784 @default.
• W2134803208 cites W2004575181 @default.
• W2134803208 cites W2009151161 @default.
• W2134803208 cites W2012510847 @default.
• W2134803208 cites W2013399404 @default.
• W2134803208 cites W2017533703 @default.
• W2134803208 cites W2018123062 @default.
• W2134803208 cites W2024011553 @default.
• W2134803208 cites W2024287923 @default.
• W2134803208 cites W2025005245 @default.
• W2134803208 cites W2028296100 @default.
• W2134803208 cites W2029023023 @default.
• W2134803208 cites W2031263707 @default.
• W2134803208 cites W2032140209 @default.
• W2134803208 cites W2046230910 @default.
• W2134803208 cites W2047921952 @default.
• W2134803208 cites W2049810408 @default.
• W2134803208 cites W2051364248 @default.
• W2134803208 cites W2057961805 @default.
• W2134803208 cites W2070086938 @default.
• W2134803208 cites W2070505228 @default.
• W2134803208 cites W2070777308 @default.
• W2134803208 cites W2071914798 @default.
• W2134803208 cites W2072974935 @default.
• W2134803208 cites W2075097399 @default.
• W2134803208 cites W2077977162 @default.
• W2134803208 cites W2080089116 @default.
• W2134803208 cites W2081313987 @default.
• W2134803208 cites W2081532018 @default.
• W2134803208 cites W2083726777 @default.
• W2134803208 cites W2098309323 @default.
• W2134803208 cites W2099308199 @default.
• W2134803208 cites W2103712192 @default.
• W2134803208 cites W2107723887 @default.
• W2134803208 cites W2113236498 @default.
• W2134803208 cites W2118274231 @default.
• W2134803208 cites W2118820599 @default.
• W2134803208 cites W2119779320 @default.
• W2134803208 cites W2121096721 @default.
• W2134803208 cites W2122210861 @default.
• W2134803208 cites W2122617162 @default.
• W2134803208 cites W2124026197 @default.
• W2134803208 cites W2125748493 @default.
• W2134803208 cites W2127552260 @default.
• W2134803208 cites W2128579789 @default.
• W2134803208 cites W2131903471 @default.
• W2134803208 cites W2132783668 @default.
• W2134803208 cites W2135151522 @default.
• W2134803208 cites W2135792930 @default.
• W2134803208 cites W2145909184 @default.
• W2134803208 cites W2146704167 @default.
• W2134803208 cites W2147874841 @default.
• W2134803208 cites W2149940797 @default.
• W2134803208 cites W2159866133 @default.
• W2134803208 cites W2162546635 @default.
• W2134803208 cites W2163120094 @default.
• W2134803208 cites W2163341755 @default.
• W2134803208 cites W2164562004 @default.
• W2134803208 cites W2172063653 @default.
• W2134803208 cites W2180229411 @default.
• W2134803208 cites W4235232179 @default.
• W2134803208 cites W4246504300 @default.
• W2134803208 cites W4249802798 @default.
• W2134803208 doi "https://doi.org/10.1016/j.cell.2013.03.018" @default.
• W2134803208 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3792590" @default.

• next