Envelope Deglycosylation Enhances Antigenicity of HIV-1 gp41 Epitopes for Both Broad Neutralizing Antibodies and Their Unmutated Ancestor Antibodies

The HIV-1 gp41 envelope (Env) membrane proximal external region (MPER) is an important vaccine target that in rare subjects can elicit neutralizing antibodies. One mechanism proposed for rarity of MPER neutralizing antibody generation is lack of reverted unmutated ancestor (putative naive B cell rec...

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Published in:PLoS pathogens Vol. 7; no. 9; p. e1002200
Main Authors: Ma, Ben-Jiang, Alam, S. Munir, Go, Eden P., Lu, Xiaozhi, Desaire, Heather, Tomaras, Georgia D., Bowman, Cindy, Sutherland, Laura L., Scearce, Richard M., Santra, Sampa, Letvin, Norman L., Kepler, Thomas B., Liao, Hua-Xin, Haynes, Barton F.
Format: Journal Article
Language:English
Published: United States Public Library of Science 01.09.2011
Public Library of Science (PLoS)
Subjects:
Acquired immune deficiency syndrome
AIDS
Animals
Antibodies, Monoclonal - immunology
Antibodies, Neutralizing - immunology
Antigen-antibody reactions
B-Lymphocytes - immunology
Biology
env Gene Products, Human Immunodeficiency Virus - chemistry
env Gene Products, Human Immunodeficiency Virus - immunology
Epitopes - immunology
Experiments
Flow cytometry
Glycosylation
HIV (Viruses)
HIV antibodies
HIV Envelope Protein gp41 - chemistry
HIV Envelope Protein gp41 - immunology
HIV-1 - immunology
Humans
Hypotheses
Immunization
Immunogenicity
Immunology
Macaca mulatta - immunology
Medicine
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase - metabolism
Peptides
Physiological aspects
Proteins
Vaccines
United States
ISSN:1553-7374, 1553-7366, 1553-7374
Online Access:Get full text
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Summary:The HIV-1 gp41 envelope (Env) membrane proximal external region (MPER) is an important vaccine target that in rare subjects can elicit neutralizing antibodies. One mechanism proposed for rarity of MPER neutralizing antibody generation is lack of reverted unmutated ancestor (putative naive B cell receptor) antibody reactivity with HIV-1 envelope. We have studied the effect of partial deglycosylation under non-denaturing (native) conditions on gp140 Env antigenicity for MPER neutralizing antibodies and their reverted unmutated ancestor antibodies. We found that native deglycosylation of clade B JRFL gp140 as well as group M consensus gp140 Env CON-S selectively increased the reactivity of Env with the broad neutralizing human mAbs, 2F5 and 4E10. Whereas fully glycosylated gp140 Env either did not bind (JRFL), or weakly bound (CON-S), 2F5 and 4E10 reverted unmutated ancestors, natively deglycosylated JRFL and CON-S gp140 Envs did bind well to these putative mimics of naive B cell receptors. These data predict that partially deglycoslated Env would bind better than fully glycosylated Env to gp41-specific naïve B cells with improved immunogenicity. In this regard, immunization of rhesus macaques demonstrated enhanced immunogenicity of the 2F5 MPER epitope on deglyosylated JRFL gp140 compared to glycosylated JRFL gp140. Thus, the lack of 2F5 and 4E10 reverted unmutated ancestor binding to gp140 Env may not always be due to lack of unmutated ancestor antibody reactivity with gp41 peptide epitopes, but rather, may be due to glycan interference of binding of unmutated ancestor antibodies of broad neutralizing mAb to Env gp41.
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Conceived and designed the experiments: BFH HXL SMA NLL HD. Performed the experiments: BJM SMA EPG XZL CB LLS RMS SS GDT. Analyzed the data: BJM SMA HD TBK NLL HXL BFH. Contributed reagents/materials/analysis tools: BJM TBK HXL. Wrote the paper: HXL BJM BFH.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1002200