Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies.

A major advance in the search for an HIV vaccine has been the development of a near-native Envelope trimer (BG505 SOSIP.664) that can induce robust autologous Tier 2 neutralization. Here, potently neutralizing monoclonal antibodies (nAbs) from rabbits immunized with BG505 SOSIP.664 are shown to recognize an immunodominant region of gp120 centered on residue 241. Residue 241 occupies a hole in the glycan defenses of the BG505 isolate, with fewer than 3% of global isolates lacking a glycan site at this position. However, at least one conserved glycan site is missing in 89% of viruses, suggesting the presence of glycan holes in most HIV isolates. Serum evidence is consistent with targeting of holes in natural infection. The immunogenic nature of breaches in the glycan shield has been under-appreciated in previous attempts to understand autologous neutralizing antibody responses and has important potential consequences for HIV vaccine design.

[1]  J. Benschop,et al.  Immune Focusing and Enhanced Neutralization Induced by HIV-1 gp140 Chemical Cross-Linking , 2013, Journal of Virology.

[2]  Wayne C Koff,et al.  Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. , 2014, Immunity.

[3]  S. Reddy,et al.  Systematic Characterization and Comparative Analysis of the Rabbit Immunoglobulin Repertoire , 2014, PloS one.

[4]  John P. Moore,et al.  A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies , 2013, PLoS pathogens.

[5]  L. Morris,et al.  Viral Escape from HIV-1 Neutralizing Antibodies Drives Increased Plasma Neutralization Breadth through Sequential Recognition of Multiple Epitopes and Immunotypes , 2013, PLoS pathogens.

[6]  Lynn Morris,et al.  Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape , 2012, Nature Medicine.

[7]  John R Mascola,et al.  Antibody responses to envelope glycoproteins in HIV-1 infection , 2015, Nature Immunology.

[8]  A. Ward,et al.  Cryo-EM structure of a native, fully glycosylated, cleaved HIV-1 envelope trimer , 2016, Science.

[9]  Robin A. Weiss,et al.  Molecular Evolution of Broadly Neutralizing Llama Antibodies to the CD4-Binding Site of HIV-1 , 2014, PLoS pathogens.

[10]  S. Zolla-Pazner,et al.  Characterization of Structural Features and Diversity of Variable-Region Determinants of Related Quaternary Epitopes Recognized by Human and Rhesus Macaque Monoclonal Antibodies Possessing Unusually Potent Neutralizing Activities , 2011, Journal of Virology.

[11]  L. Morris,et al.  Virological features associated with the development of broadly neutralizing antibodies to HIV-1. , 2015, Trends in microbiology.

[12]  John P. Moore,et al.  Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer , 2015, PLoS pathogens.

[13]  Lynn Morris,et al.  Limited Neutralizing Antibody Specificities Drive Neutralization Escape in Early HIV-1 Subtype C Infection , 2009, PLoS pathogens.

[14]  James C Paulson,et al.  Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers. , 2014, Immunity.

[15]  Anchi Cheng,et al.  Automated molecular microscopy: the new Leginon system. , 2005, Journal of structural biology.

[16]  B. Korber,et al.  Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses. , 2015, Cell host & microbe.

[17]  Martin A. Nowak,et al.  Antibody neutralization and escape by HIV-1 , 2003, Nature.

[18]  Lynn Morris,et al.  Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies , 2015, Nature Medicine.

[19]  D. Montefiori,et al.  Characterization of a Large Panel of Rabbit Monoclonal Antibodies against HIV-1 gp120 and Isolation of Novel Neutralizing Antibodies against the V3 Loop , 2015, PloS one.

[20]  Barbra A. Richardson,et al.  Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant , 2006, Journal of Virology.

[21]  Daniel W. Kulp,et al.  Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site , 2015, PLoS pathogens.

[22]  B. Korber,et al.  Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection , 2014, AIDS.

[23]  Saikat Banerjee,et al.  Detailed characterization of antibody responses against HIV-1 group M consensus gp120 in rabbits , 2014, Retrovirology.

[24]  David Nemazee,et al.  Rational immunogen design to target specific germline B cell receptors , 2012, Retrovirology.

[25]  Dennis R Burton,et al.  Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. , 2016, Annual review of immunology.

[26]  Daniel W. Kulp,et al.  Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice , 2015, Cell.

[27]  Hanneke Schuitemaker,et al.  Autologous Neutralizing Humoral Immunity and Evolution of the Viral Envelope in the Course of Subtype B Human Immunodeficiency Virus Type 1 Infection , 2008, Journal of Virology.

[28]  John P. Moore,et al.  Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes , 2015, Cell.

[29]  Tongqing Zhou,et al.  Structure and immune recognition of trimeric prefusion HIV-1 Env , 2014, Nature.

[30]  R. Doms,et al.  Antibodies elicited by yeast glycoproteins recognize HIV-1 virions and potently neutralize virions with high mannose N-glycans. , 2015, Vaccine.

[31]  Young Do Kwon,et al.  Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility , 2009, Proceedings of the National Academy of Sciences.

[32]  Robyn L Stanfield,et al.  Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans. , 2015, Immunity.

[33]  J. Mascola,et al.  Diverse Antibody Genetic and Recognition Properties Revealed following HIV-1 Envelope Glycoprotein Immunization , 2015, The Journal of Immunology.

[34]  T. Kepler,et al.  Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site. , 2016, Cell reports.

[35]  S. Gnanakaran,et al.  Escape from Autologous Neutralizing Antibodies in Acute/Early Subtype C HIV-1 Infection Requires Multiple Pathways , 2009, PLoS pathogens.

[36]  G. Debnath,et al.  D-101 HIV-1 neutralizing antibodies induced by native-like envelope trimers , 2016 .

[37]  Holly Janes,et al.  Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies , 2009, Journal of Virology.

[38]  Xiping Wei,et al.  Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies , 2005, Journal of Virology.

[39]  R. Weiss,et al.  Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization , 2012, The Journal of experimental medicine.

[40]  J. Mascola,et al.  Single-Cell and Deep Sequencing of IgG-Switched Macaque B Cells Reveal a Diverse Ig Repertoire following Immunization , 2014, The Journal of Immunology.

[41]  Florian Klein,et al.  Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy , 2014, Cell.

[42]  T. Wrin,et al.  Prime-Boost Immunization of Rabbits with HIV-1 gp120 Elicits Potent Neutralization Activity against a Primary Viral Isolate , 2013, PloS one.

[43]  R. Sanders,et al.  In vivo protection by broadly neutralizing HIV antibodies. , 2014, Trends in microbiology.

[44]  Terri Wrin,et al.  Rapid Escape from Preserved Cross-Reactive Neutralizing Humoral Immunity without Loss of Viral Fitness in HIV-1-Infected Progressors and Long-Term Nonprogressors , 2010, Journal of Virology.

[45]  William R. Schief,et al.  Promiscuous Glycan Site Recognition by Antibodies to the High-Mannose Patch of gp120 Broadens Neutralization of HIV , 2014, Science Translational Medicine.

[46]  Chaim A. Schramm,et al.  Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus , 2013, Nature.

[47]  J. Mascola,et al.  Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates , 2010, The Journal of experimental medicine.

[48]  David Nemazee,et al.  Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen , 2015, Science.

[49]  J. Mascola,et al.  High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site , 2012, Science Translational Medicine.

[50]  J. Mascola,et al.  HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies , 2015, Journal of Virology.

[51]  D. Montefiori,et al.  A Novel Rabbit Monoclonal Antibody Platform To Dissect the Diverse Repertoire of Antibody Epitopes for HIV-1 Env Immunogen Design , 2013, Journal of Virology.

[52]  Christopher Irving,et al.  Appion: an integrated, database-driven pipeline to facilitate EM image processing. , 2009, Journal of structural biology.

[53]  Daphne Koller,et al.  The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies , 2013, PLoS pathogens.

[54]  John P. Moore,et al.  Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity , 2015, Journal of Virology.

[55]  J. Binley,et al.  Improved Induction of Antibodies against Key Neutralizing Epitopes by Human Immunodeficiency Virus Type 1 gp120 DNA Prime-Protein Boost Vaccination Compared to gp120 Protein-Only Vaccination , 2008, Journal of Virology.