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Title: Effect of glycosylation on an immunodominant region in the V1V2 variable domain of the HIV-1 envelope gp120 protein

Heavy glycosylation of the envelope (Env) surface subunit, gp120, is a key adaptation of HIV-1; however, the precise effects of glycosylation on the folding, conformation and dynamics of this protein are poorly understood. Here we explore the patterns of HIV-1 Env gp120 glycosylation, and particularly the enrichment in glycosylation sites proximal to the disulfide linkages at the base of the surface-exposed variable domains. To dissect the influence of glycans on the conformation these regions, we focused on an antigenic peptide fragment from a disulfide bridge-bounded region spanning the V1 and V2 hyper-variable domains of HIV-1 gp120. We used replica exchange molecular dynamics (MD) simulations to investigate how glycosylation influences its conformation and stability. Simulations were performed with and without N-linked glycosylation at two sites that are highly conserved across HIV-1 isolates (N156 and N160); both are contacts for recognition by V1V2-targeted broadly neutralizing antibodies against HIV-1. Glycosylation stabilized the pre-existing conformations of this peptide construct, reduced its propensity to adopt other secondary structures, and provided resistance against thermal unfolding. Simulations performed in the context of the Env trimer also indicated that glycosylation reduces flexibility of the V1V2 region, and provided insight into glycan-glycan interactions in this region. These stabilizing effectsmore » were influenced by a combination of factors, including the presence of a disulfide bond between the Cysteines at 131 and 157, which increased the formation of beta-strands. Together, these results provide a mechanism for conservation of disulfide linkage proximal glycosylation adjacent to the variable domains of gp120 and begin to explain how this could be exploited to enhance the immunogenicity of those regions. Furthermore, these studies suggest that glycopeptide immunogens can be designed to stabilize the most relevant Env conformations to focus the immune response on key neutralizing epitopes.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [2] ;  [2] ;  [6]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Emory Univ., Atlanta, GA (United States)
  4. Univ. of California, Berkeley, CA (United States)
  5. Rutgers Univ., Newark, NJ (United States)
  6. National Cancer Institute - Frederick, Frederick, MD (United States)
Publication Date:
Report Number(s):
LA-UR-16-26334
Journal ID: ISSN 1553-7358
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 12; Journal Issue: 10; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science
OSTI Identifier:
1338782

Tian, Jianhui, Lopez, Cesar Augusto, Derdeyn, Cynthia A., Jones, Morris S., Pinter, Abraham, Korber, Bette Tina Marie, Gnanakaran, Sandrasegaram, and Rein, Alan. Effect of glycosylation on an immunodominant region in the V1V2 variable domain of the HIV-1 envelope gp120 protein. United States: N. p., Web. doi:10.1371/journal.pcbi.1005094.
Tian, Jianhui, Lopez, Cesar Augusto, Derdeyn, Cynthia A., Jones, Morris S., Pinter, Abraham, Korber, Bette Tina Marie, Gnanakaran, Sandrasegaram, & Rein, Alan. Effect of glycosylation on an immunodominant region in the V1V2 variable domain of the HIV-1 envelope gp120 protein. United States. doi:10.1371/journal.pcbi.1005094.
Tian, Jianhui, Lopez, Cesar Augusto, Derdeyn, Cynthia A., Jones, Morris S., Pinter, Abraham, Korber, Bette Tina Marie, Gnanakaran, Sandrasegaram, and Rein, Alan. 2016. "Effect of glycosylation on an immunodominant region in the V1V2 variable domain of the HIV-1 envelope gp120 protein". United States. doi:10.1371/journal.pcbi.1005094. https://www.osti.gov/servlets/purl/1338782.
@article{osti_1338782,
title = {Effect of glycosylation on an immunodominant region in the V1V2 variable domain of the HIV-1 envelope gp120 protein},
author = {Tian, Jianhui and Lopez, Cesar Augusto and Derdeyn, Cynthia A. and Jones, Morris S. and Pinter, Abraham and Korber, Bette Tina Marie and Gnanakaran, Sandrasegaram and Rein, Alan},
abstractNote = {Heavy glycosylation of the envelope (Env) surface subunit, gp120, is a key adaptation of HIV-1; however, the precise effects of glycosylation on the folding, conformation and dynamics of this protein are poorly understood. Here we explore the patterns of HIV-1 Env gp120 glycosylation, and particularly the enrichment in glycosylation sites proximal to the disulfide linkages at the base of the surface-exposed variable domains. To dissect the influence of glycans on the conformation these regions, we focused on an antigenic peptide fragment from a disulfide bridge-bounded region spanning the V1 and V2 hyper-variable domains of HIV-1 gp120. We used replica exchange molecular dynamics (MD) simulations to investigate how glycosylation influences its conformation and stability. Simulations were performed with and without N-linked glycosylation at two sites that are highly conserved across HIV-1 isolates (N156 and N160); both are contacts for recognition by V1V2-targeted broadly neutralizing antibodies against HIV-1. Glycosylation stabilized the pre-existing conformations of this peptide construct, reduced its propensity to adopt other secondary structures, and provided resistance against thermal unfolding. Simulations performed in the context of the Env trimer also indicated that glycosylation reduces flexibility of the V1V2 region, and provided insight into glycan-glycan interactions in this region. These stabilizing effects were influenced by a combination of factors, including the presence of a disulfide bond between the Cysteines at 131 and 157, which increased the formation of beta-strands. Together, these results provide a mechanism for conservation of disulfide linkage proximal glycosylation adjacent to the variable domains of gp120 and begin to explain how this could be exploited to enhance the immunogenicity of those regions. Furthermore, these studies suggest that glycopeptide immunogens can be designed to stabilize the most relevant Env conformations to focus the immune response on key neutralizing epitopes.},
doi = {10.1371/journal.pcbi.1005094},
journal = {PLoS Computational Biology (Online)},
number = 10,
volume = 12,
place = {United States},
year = {2016},
month = {10}
}