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Title: Genetic Signatures in the Envelope Glycoproteins of HIV-1 that Associate with Broadly Neutralizing Antibodies

Journal Article · · PLoS Computational Biology (Online)
 [1];  [1];  [2];  [1];  [3];  [4];  [4];  [4];  [4];  [5];  [6];  [7];  [8];  [5];  [5];  [4];  [2]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics; Santa Fe Inst. (SFI), Santa Fe, NM (United States)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics; Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Center for Nonlinear Studies
  4. Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery
  5. Duke Univ., Durham, NC (United States). Medical Center. Dept. of Medicine
  6. Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Surgery
  7. Univ. of Alabama, Birmingham, AL (United States). Dept. of Medicine; Univ. of Alabama, Birmingham, AL (United States). Dept. of Microbiology
  8. Beth Israel Deaconess Medical Center, Boston, MA (United States). Division of Viral Pathogenesis
+ Show Author Affiliations

A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1627206
Journal Information:
PLoS Computational Biology (Online), Vol. 6, Issue 10; ISSN 1553-7358
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding journal December 2012
Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues journal June 2013
Genetic and Neutralization Sensitivity of Diverse HIV-1 env Clones from Chronically Infected Patients in China journal February 2011
CATNAP: a tool to compile, analyze and tally neutralizing antibody panels journal June 2015
Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing journal August 2011
Potent and broad HIV-neutralizing antibodies in memory B cells and plasma journal January 2017
Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection journal March 2016
Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains journal July 2013
Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits journal September 2014
Predicting HIV-1 broadly neutralizing antibody epitope networks using neutralization titers and a novel computational method journal January 2014
Impact of amino acid substitutions in the V2 and C2 regions of human immunodeficiency virus type 1 CRF01_AE envelope glycoprotein gp120 on viral neutralization susceptibility to broadly neutralizing antibodies specific for the CD4 binding site journal January 2014
Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models journal January 2013
IDEPI: Rapid Prediction of HIV-1 Antibody Epitopes and Other Phenotypic Features from Sequence Data Using a Flexible Machine Learning Platform journal September 2014
Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial journal February 2015
Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time journal October 2017
Association of Enhanced HIV-1 Neutralization by a Single Y681H Substitution in gp41 with Increased gp120-CD4 Interaction and Macrophage Infectivity journal May 2012
Plasma IgG to Linear Epitopes in the V2 and V3 Regions of HIV-1 gp120 Correlate with a Reduced Risk of Infection in the RV144 Vaccine Efficacy Trial journal September 2013
Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens journal April 2019
Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections journal September 2011
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization journal July 2016
Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies journal June 2019
Broadly neutralizing antibodies: What is needed to move from a rare event in HIV-1 infection to vaccine efficacy? text January 2018
Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models text January 2013
HIV-1 Envelope Glycoprotein Resistance to Monoclonal Antibody 2G12 Is Subject-Specific and Context-Dependent in Macaques and Humans journal September 2013
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