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

Journal article

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.

Authors: Schiffner, T; Kong, L; Duncan, C; Back, J; Benschop, J

• Publication status: Published
• Journal: Journal of virology
• Volume: 87
• Issue: 18
• Pages: 10163-10172
• Publication date: 2013-09-01
• DOI: 10.1128/jvi.01161-13
• EISSN: 1098-5514
• ISSN: 0022-538X
• Language: English
• Keywords: AIDS Vaccines; Antibodies, Neutralizing; Rabbits; Animals; Adjuvants, Immunologic; HIV Antigens; HIV Antibodies; env Gene Products, Human Immunodeficiency Virus; Cross-Linking Reagents