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Journal of Virology, July 2006, p. 6943-6951, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00310-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Increased Immunogenicity of Human Immunodeficiency Virus gp120 Engineered To Express Gal{alpha}1-3Galß1-4GlcNAc-R Epitopes

Ussama Abdel-Motal, Shixia Wang, Shan Lu, Kim Wigglesworth, and Uri Galili*

Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Received 13 February 2006/ Accepted 1 May 2006

The glycan shield comprised of multiple carbohydrate chains on the human immunodeficiency virus (HIV) envelope glycoprotein gp120 helps the virus to evade neutralizing antibodies. The present study describes a novel method for increasing immunogenicity of gp120 vaccine by enzymatic replacement of sialic acid on these carbohydrate chains with Gal{alpha}1-3Galß1-4GlcNAc-R ({alpha}-gal) epitopes. These epitopes are ligands for the natural anti-Gal antibody constituting ~1% of immunoglobulin G in humans. We hypothesize that vaccination with gp120 expressing {alpha}-gal epitopes (gp120{alpha}gal) results in in vivo formation of immune complexes with anti-Gal, which targets vaccines for effective uptake by antigen-presenting cells (APC), due to interaction between the Fc portion of the antibody and Fc{gamma} receptors on APC. This in turn results in effective transport of the vaccine to lymph nodes and effective processing and presentation of gp120 immunogenic peptides by APC for eliciting a strong anti-gp120 immune response. This hypothesis was tested in {alpha}-1,3-galactosyltransferase knockout mice, which produce anti-Gal. Mice immunized with gp120{alpha}gal produced anti-gp120 antibodies in titers that were >100-fold higher than those measured in mice immunized with comparable amounts of gp120 and effectively neutralized HIV. T-cell response, measured by ELISPOT, was much higher in mice immunized with gp120{alpha}gal than in mice immunized with gp120. It is suggested that gp120{alpha}gal can serve as a platform for anti-Gal-mediated targeting of additional vaccinating HIV proteins fused to gp120{alpha}gal, thereby creating effective prophylactic vaccines.

* Corresponding author. Mailing address: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB, Worcester, MA 01605. Phone: (508) 856-4188. Fax: (508) 856-4106. E-mail: Uri.Galili{at}umassmed.edu.

Journal of Virology, July 2006, p. 6943-6951, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00310-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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