title: Human Antibodies that Recognize Novel Immunodominant Quaternary Epitopes on the HIV-1 Env Protein.
abstract: Numerous broadly neutralizing antibodies (Abs) target epitopes that are formed or enhanced during mature HIV envelope formation (i.e. quaternary epitopes). Generally, it is thought that Env epitopes that induce broadly neutralizing Abs are difficult to access and poorly immunogenic because of the characteristic oligomerization, conformational flexibility, sequence diversity and extensive glycosylation of Env protein. To enhance for isolation of quaternary epitope-targeting Abs (QtAbs), we previously used HIV virus-like particles (VLPs) to bind B cells from long-term non-progressor subjects to identify a panel of monoclonal Abs. When expressed as recombinant full-length Abs, a subset of these novel Abs exhibited the binding profiles of QtAbs, as they either failed to bind to monomeric Env protein or showed much higher affinity for Env trimers and VLPs. These QtAbs represented a significant proportion of the B-cell response identified with VLPs. The Ab genes of these clones were highly mutated, but they did not neutralize common HIV strains. We sought to further define the epitopes targeted by these QtAbs. Competition-binding and mapping studies revealed these Abs targeted four separate epitopes; they also failed to compete for binding by Abs to known major neutralizing epitopes. Detailed epitope mapping studies revealed that two of the four epitopes were located in the gp41 subunit of Env. These QtAbs bound pre-fusion forms of antigen and showed differential binding kinetics depending on whether oligomers were produced as recombinant gp140 trimers or as full-length Env incorporated into VLPs. Antigenic regions within gp41 present unexpectedly diverse structural epitopes, including these QtAb epitopes, which may be targeted by the naturally occurring Ab response to HIV infection.
authors.affiliation: Departments of Pediatrics, University at Buffalo, Buffalo, New York, United States of America.|Departments of Microbiology and Immunology, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hicar
authors.affiliation: Departments of Pediatrics, Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Integral Molecular, Inc., Philadelphia, Pennsylvania, United States of America.
authors.forename: Chidananda
authors.initials: C
authors.lastname: Sulli
authors.affiliation: Integral Molecular, Inc., Philadelphia, Pennsylvania, United States of America.
authors.forename: Trevor
authors.initials: T
authors.lastname: Barnes
authors.affiliation: Integral Molecular, Inc., Philadelphia, Pennsylvania, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Goodman
authors.affiliation: Departments of Pediatrics, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Hakimuddin
authors.initials: H
authors.lastname: Sojar
authors.affiliation: Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Briney
authors.affiliation: The Program in Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Jordan
authors.initials: J
authors.lastname: Willis
authors.affiliation: Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Valentine U
authors.initials: VU
authors.lastname: Chukwuma
authors.affiliation: Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|The Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Spyros A
authors.initials: SA
authors.lastname: Kalams
authors.affiliation: Integral Molecular, Inc., Philadelphia, Pennsylvania, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.affiliation: Departments of Pediatrics, Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.affiliation: Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D000072417:Protein Domains / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D016056:Immunodominant Epitopes; D011994:Recombinant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1