Immune focusing and enhanced neutralization induced by HIV-1 gp140 chemical cross-linking

Item Type:	Article
Title:	Immune focusing and enhanced neutralization induced by HIV-1 gp140 chemical cross-linking
Creators Name:	Schiffner, T. and Kong, L. and Duncan, C.J.A. and Back, J.W. and Benschop, J.J. and Shen, X. and Huang, P.S. and Stewart-Jones, G.B. and DeStefano, J. and Seaman, M.S. and Tomaras, G.D. and Montefiori, D.C. and Schief, W.R. and Sattentau, Q.J.
Abstract:	Experimental vaccine antigens based upon the HIV-1 envelope glycoproteins (Env) have failed to induce neutralizing antibodies (NAbs) against the majority of circulating viral strains as a result of antibody evasion mechanisms, including amino acid variability and conformational instability. A potential vaccine design strategy is to stabilize Env, thereby focusing antibody responses on constitutively exposed, conserved surfaces, such as the CD4 binding site (CD4bs). Here, we show that a largely trimeric form of soluble Env can be stably cross-linked with glutaraldehyde (GLA) without global modification of antigenicity. Cross-linking largely conserved binding of all potent broadly neutralizing antibodies (bNAbs) tested, including CD4bs-specific VRC01 and HJ16, but reduced binding of several non- or weakly neutralizing antibodies and soluble CD4 (sCD4). Adjuvanted administration of cross-linked or unmodified gp140 to rabbits generated indistinguishable total gp140-specific serum IgG binding titers. However, sera from animals receiving cross-linked gp140 showed significantly increased CD4bs-specific antibody binding compared to animals receiving unmodified gp140. Moreover, peptide mapping of sera from animals receiving cross-linked gp140 revealed increased binding to gp120 C1 and V1V2 regions. Finally, neutralization titers were significantly elevated in sera from animals receiving cross-linked gp140 rather than unmodified gp140. We conclude that cross-linking favors antigen stability, imparts antigenic modifications that selectively refocus antibody specificity and improves induction of NAbs, and might be a useful strategy for future vaccine design.
Keywords:	AIDS Vaccines, Cross-Linking Reagents, HIV Antibodies, HIV Antigens, Human Immunodeficiency Virus env Gene Products, Immunologic Adjuvants, Neutralizing Antibodies, Animals, Rabbits
Source:	Journal of Virology
ISSN:	1098-5514
Publisher:	American Society for Microbiology
Volume:	87
Number:	18
Page Range:	10163-10172
Date:	15 September 2013
Official Publication:	https://doi.org/10.1128/jvi.01161-13
PubMed:	View item in PubMed

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