Increased Immunogenicity of Human Immunodeficiency Virus gp120 Engineered To Express Galα1-3Galβ1-4GlcNAc-R Epitopes

Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB, Worcester, 01605, USA.
Journal of Virology (Impact Factor: 4.65). 08/2006; 80(14):6943-51. DOI: 10.1128/JVI.00310-06
Source: PubMed

ABSTRACT 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 Galalpha1-3Galbeta1-4GlcNAc-R (alpha-gal) epitopes. These epitopes are ligands for the natural anti-Gal antibody constituting approximately 1% of immunoglobulin G in humans. We hypothesize that vaccination with gp120 expressing alpha-gal epitopes (gp120(alphagal)) 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 Fcgamma 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(alphagal) 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(alphagal) than in mice immunized with gp120. It is suggested that gp120(alphagal) can serve as a platform for anti-Gal-mediated targeting of additional vaccinating HIV proteins fused to gp120(alphagal), thereby creating effective prophylactic vaccines.

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Available from: Shan Lu, Aug 10, 2015
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    • "The enzymatic treatment converted >97% of the gp120 to gp120 αgal , which carried α-gal epitopes (~30 α-gal epitopes per molecule) instead of sialic acid. Immunisation with gp120 αgal led to the production of anti-gp120 antibodies in >100-fold higher titres and also induced a greater T-cell response compared to immunisation with wild-type gp120 [71]. Because HIV-1 gp120 has a high mutation rate and is therefore not particularly suitable for vaccines, Abdel-Motal et al. [72] proposed gp120 αgal as an effective platform for targeting other HIV-1 proteins to APCs. "
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    • "Recently, it was shown that α-Gal conjugation of the HIV gp-120 protein induced high immune responses in α-Gal knockout mice to the gp-120 protein, suggesting an immune-enhancing effect of this carbohydrate residue (Abdel-Motal et al., 2006) in combination with induced preexisting Ab directed to α-Gal residues. Immunization of α(1,3)galactosyltransferase knockout mice (GT0 mice), which, like humans, produce α-Gal-specific Ab binding BSA conjugated to α-Gal (α-Gal-BSA), also led to significant production of anti-BSA IgG Ab without the need for adjuvant, enhancement of BSA-specific cellular immunity , and antiviral T-cell responses after vaccination (Benatuil et al., 2005). "
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