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  • 1
    Publication Date: 2014-09-05
    Description: The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC50) 〈50 mug ml(-1). The median IC50 of neutralized viruses was 0.033 mug ml(-1), among the most potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP.664. Mutagenesis and a reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224615/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224615/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Jinghe -- Kang, Byong H -- Pancera, Marie -- Lee, Jeong Hyun -- Tong, Tommy -- Feng, Yu -- Imamichi, Hiromi -- Georgiev, Ivelin S -- Chuang, Gwo-Yu -- Druz, Aliaksandr -- Doria-Rose, Nicole A -- Laub, Leo -- Sliepen, Kwinten -- van Gils, Marit J -- de la Pena, Alba Torrents -- Derking, Ronald -- Klasse, Per-Johan -- Migueles, Stephen A -- Bailer, Robert T -- Alam, Munir -- Pugach, Pavel -- Haynes, Barton F -- Wyatt, Richard T -- Sanders, Rogier W -- Binley, James M -- Ward, Andrew B -- Mascola, John R -- Kwong, Peter D -- Connors, Mark -- 280829/European Research Council/International -- AI84714/AI/NIAID NIH HHS/ -- AI93278/AI/NIAID NIH HHS/ -- P01 AI082362/AI/NIAID NIH HHS/ -- R01 AI100790/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- ZIA AI000855-15/Intramural NIH HHS/ -- ZIA AI001090-05/Intramural NIH HHS/ -- England -- Nature. 2014 Nov 6;515(7525):138-42. doi: 10.1038/nature13601. Epub 2014 Sep 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] The Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA [2] International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA. ; San Diego Biomedical Research Institute, San Diego, California 92121, USA. ; International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA. ; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1100 DD, The Netherlands. ; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10065, USA. ; Duke Human Vaccine Institute, Duke University, Durham, North Carolina 27710, USA. ; 1] Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam 1100 DD, The Netherlands [2] Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25186731" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Antibodies, Monoclonal/chemistry/genetics/immunology/pharmacology ; Antibodies, Neutralizing/chemistry/genetics/*immunology/pharmacology ; *Antibody Affinity ; Antibody Specificity ; Antigens, CD4/metabolism ; Cell Line ; Cell Membrane/virology ; Conserved Sequence ; Epitope Mapping ; Epitopes/chemistry/immunology ; HIV Antibodies/chemistry/genetics/*immunology/pharmacology ; HIV Envelope Protein gp120/*chemistry/*immunology ; HIV Envelope Protein gp41/*chemistry/*immunology ; HIV-1/drug effects/immunology ; Humans ; Immunoglobulin Fab Fragments/chemistry/genetics/immunology/ultrastructure ; Inhibitory Concentration 50 ; Leukocytes, Mononuclear ; Models, Molecular ; Molecular Sequence Data ; Receptors, CCR5/metabolism ; Virus Internalization/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-11-16
    Description: Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes approximately 98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical arginine or lysine just before the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 envelope glycoprotein.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Jinghe -- Ofek, Gilad -- Laub, Leo -- Louder, Mark K -- Doria-Rose, Nicole A -- Longo, Nancy S -- Imamichi, Hiromi -- Bailer, Robert T -- Chakrabarti, Bimal -- Sharma, Shailendra K -- Alam, S Munir -- Wang, Tao -- Yang, Yongping -- Zhang, Baoshan -- Migueles, Stephen A -- Wyatt, Richard -- Haynes, Barton F -- Kwong, Peter D -- Mascola, John R -- Connors, Mark -- HSN261200800001E/PHS HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):406-12. doi: 10.1038/nature11544. Epub 2012 Sep 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23151583" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Antibodies, Neutralizing/chemistry/*metabolism ; Antibody Specificity ; Cells, Cultured ; HEK293 Cells ; HIV Antibodies/chemistry/isolation & purification/*metabolism ; HIV Envelope Protein gp41/chemistry/*immunology ; HIV-1/*physiology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    ISSN: 0021-9673
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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