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Title: Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold

Abstract

V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context, and V3 bound to a monoclonal antibody (mAb), we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120 was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high-affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1042308
Report Number(s):
BNL-97986-2012-JA
Journal ID: ISSN 0042-6822; VIRLAX; TRN: US201212%%718
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Virology
Additional Journal Information:
Journal Volume: 405; Journal Issue: 2; Journal ID: ISSN 0042-6822
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AIDS VIRUS; ANTIBODIES; CHOLERA; DESIGN; DNA; PROTEINS; RABBITS; TOXINS

Citation Formats

Totrov, M, Jiang, X, Kong, X, Cohen, S, Krachmarov, C, Salomon, A, Williams, C, Seaman, M, Abagyan, R, and et al. Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold. United States: N. p., 2011. Web.
Totrov, M, Jiang, X, Kong, X, Cohen, S, Krachmarov, C, Salomon, A, Williams, C, Seaman, M, Abagyan, R, & et al. Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold. United States.
Totrov, M, Jiang, X, Kong, X, Cohen, S, Krachmarov, C, Salomon, A, Williams, C, Seaman, M, Abagyan, R, and et al. Sat . "Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold". United States.
@article{osti_1042308,
title = {Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold},
author = {Totrov, M and Jiang, X and Kong, X and Cohen, S and Krachmarov, C and Salomon, A and Williams, C and Seaman, M and Abagyan, R and et al.},
abstractNote = {V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context, and V3 bound to a monoclonal antibody (mAb), we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120 was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high-affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.},
doi = {},
journal = {Virology},
issn = {0042-6822},
number = 2,
volume = 405,
place = {United States},
year = {2011},
month = {12}
}