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Title: Effect of trimerization motifs on quaternary structure, antigenicity, and immunogenicity of a noncleavable HIV-1 gp140 envelope glycoprotein

Abstract

The external domains of the HIV-1 envelope glycoprotein (gp120 and the gp41 ectodomain, collectively known as gp140) contain all known viral neutralization epitopes. Various strategies have been used to create soluble trimers of the envelope to mimic the structure of the native viral protein, including mutation of the gp120-gp41 cleavage site, introduction of disulfide bonds, and fusion to heterologous trimerization motifs. We compared the effects on quaternary structure, antigenicity, and immunogenicity of three such motifs: T4 fibritin, a GCN4 variant, and the Escherichia coli aspartate transcarbamoylase catalytic subunit. Fusion of each motif to the C-terminus of a noncleavable JRCSF gp140(-) envelope protein led to enhanced trimerization but had limited effects on the antigenic profile and CD4-binding ability of the trimers. Immunization of rabbits provided no evidence that the trimerized gp140(-) constructs induced significantly improved neutralizing antibodies to several HIV-1 pseudoviruses, compared to gp140 lacking a trimerization motif. However, modest differences in both binding specificity and neutralizing antibody responses were observed among the various immunogens.

Authors:
; ; ;  [1];  [2]; ;  [1]; ;  [3];  [2];  [3];  [4]
  1. Maxygen, Inc., 515 Galveston Drive, Redwood City, CA 94063 (United States)
  2. Torrey Pines Institute for Molecular Studies, San Diego, CA 92121 (United States)
  3. Monogram Biosciences, Inc., San Francisco, CA 94080 (United States)
  4. Aldevron LLC, Fargo, ND 58104 (United States)
Publication Date:
OSTI Identifier:
21357571
Resource Type:
Journal Article
Journal Name:
Virology
Additional Journal Information:
Journal Volume: 395; Journal Issue: 1; Other Information: DOI: 10.1016/j.virol.2009.07.042; PII: S0042-6822(09)00478-4; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0042-6822
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS VIRUS; CLEAVAGE; ENZYMES; ESCHERICHIA COLI; GLYCOPROTEINS; MONOCLONAL ANTIBODIES; RABBITS; ANIMALS; ANTIBODIES; BACTERIA; CARBOHYDRATES; MAMMALS; MICROORGANISMS; MICROSTRUCTURE; ORGANIC COMPOUNDS; PARASITES; PROTEINS; SACCHARIDES; VERTEBRATES; VIRUSES

Citation Formats

Du, Sean X, Idiart, Rebecca J, Mariano, Ellaine B, Chen, Helen, Peifeng, Jiang, Li, Xu, Ostrow, Kristin M, Wrin, Terri, Phung, Pham, Binley, James M, Petropoulos, Christos J, Ballantyne, John A, and Whalen, Robert G., E-mail: robert.whalen@maxygen.co. Effect of trimerization motifs on quaternary structure, antigenicity, and immunogenicity of a noncleavable HIV-1 gp140 envelope glycoprotein. United States: N. p., 2009. Web. doi:10.1016/j.virol.2009.07.042.
Du, Sean X, Idiart, Rebecca J, Mariano, Ellaine B, Chen, Helen, Peifeng, Jiang, Li, Xu, Ostrow, Kristin M, Wrin, Terri, Phung, Pham, Binley, James M, Petropoulos, Christos J, Ballantyne, John A, & Whalen, Robert G., E-mail: robert.whalen@maxygen.co. Effect of trimerization motifs on quaternary structure, antigenicity, and immunogenicity of a noncleavable HIV-1 gp140 envelope glycoprotein. United States. https://doi.org/10.1016/j.virol.2009.07.042
Du, Sean X, Idiart, Rebecca J, Mariano, Ellaine B, Chen, Helen, Peifeng, Jiang, Li, Xu, Ostrow, Kristin M, Wrin, Terri, Phung, Pham, Binley, James M, Petropoulos, Christos J, Ballantyne, John A, and Whalen, Robert G., E-mail: robert.whalen@maxygen.co. 2009. "Effect of trimerization motifs on quaternary structure, antigenicity, and immunogenicity of a noncleavable HIV-1 gp140 envelope glycoprotein". United States. https://doi.org/10.1016/j.virol.2009.07.042.
@article{osti_21357571,
title = {Effect of trimerization motifs on quaternary structure, antigenicity, and immunogenicity of a noncleavable HIV-1 gp140 envelope glycoprotein},
author = {Du, Sean X and Idiart, Rebecca J and Mariano, Ellaine B and Chen, Helen and Peifeng, Jiang and Li, Xu and Ostrow, Kristin M and Wrin, Terri and Phung, Pham and Binley, James M and Petropoulos, Christos J and Ballantyne, John A and Whalen, Robert G., E-mail: robert.whalen@maxygen.co},
abstractNote = {The external domains of the HIV-1 envelope glycoprotein (gp120 and the gp41 ectodomain, collectively known as gp140) contain all known viral neutralization epitopes. Various strategies have been used to create soluble trimers of the envelope to mimic the structure of the native viral protein, including mutation of the gp120-gp41 cleavage site, introduction of disulfide bonds, and fusion to heterologous trimerization motifs. We compared the effects on quaternary structure, antigenicity, and immunogenicity of three such motifs: T4 fibritin, a GCN4 variant, and the Escherichia coli aspartate transcarbamoylase catalytic subunit. Fusion of each motif to the C-terminus of a noncleavable JRCSF gp140(-) envelope protein led to enhanced trimerization but had limited effects on the antigenic profile and CD4-binding ability of the trimers. Immunization of rabbits provided no evidence that the trimerized gp140(-) constructs induced significantly improved neutralizing antibodies to several HIV-1 pseudoviruses, compared to gp140 lacking a trimerization motif. However, modest differences in both binding specificity and neutralizing antibody responses were observed among the various immunogens.},
doi = {10.1016/j.virol.2009.07.042},
url = {https://www.osti.gov/biblio/21357571}, journal = {Virology},
issn = {0042-6822},
number = 1,
volume = 395,
place = {United States},
year = {Sat Dec 05 00:00:00 EST 2009},
month = {Sat Dec 05 00:00:00 EST 2009}
}