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

Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB, Worcester, 01605, USA.
Journal of Virology (Impact Factor: 4.44). 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, Sep 28, 2015
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    • "It has long been known that primary and secondary antibody responses to model antigens can be enhanced by immunization with immune complexes (IC) [2]–[4]. Similar enhancement has also been demonstrated with viral antigens including Venezuelan equine encephalomyelitis virus vaccine [5], Hepatitis B surface antigen [6], HIV gp120 [7], and simian immunodeficiency virus (SIV) gp120 [8]. Importantly, it is now well established that IC can be cross-presented by antigen-presenting cells (APC) and can stimulate potent MHC class I as well as class II – restricted T cell responses [9], [10]. "
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    PLoS ONE 04/2013; 8(4):e60855. DOI:10.1371/journal.pone.0060855 · 3.23 Impact Factor
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    • "Strikingly, anti-OprF IgG was higher following three doses of FG- or HI-modified vector compared to AdOprF, thus highlighting the utility of fiber-modified Ad vectors for vaccine delivery. One of the mechanisms that explains the boosting of humoral response is the Fcγ receptor-mediated uptake of Ad vector-antibody immune complexes by antigen-presenting cells and subsequent increased stimulation of specific immune cells [43]. "
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    PLoS ONE 02/2013; 8(2):e56996. DOI:10.1371/journal.pone.0056996 · 3.23 Impact Factor
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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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    ABSTRACT: The glycan chains attached to cell surfaces or to single proteins are highly dynamic structures with various functions. The glycan chains of mammals and of some microorganisms often terminate in sialic acids or α-1,3-galactose. Although these two sugars are completely distinct, there are several similarities in their biological and medical importance. First, one type of sialic acid, N-glycolylneuraminic acid, and the galactose bound by an α-1,3-linkage to LacNAc, that forms an α-gal epitope, were both eliminated in human evolution, resulting in the production of antibodies to these sugars. Both of these evolutionary events have consequences connected with the consumption of foods of mammalian origin, causing medical complications of varying severity. In terms of ageing, sialic acids prevent the clearance of glycoproteins and circulating blood cells, whereas cryptic α-gal epitopes on senescent red blood cells contribute to their removal from circulation. The efficiency of therapeutic proteins can be increased by sialylation. Another common feature is the connection with microorganisms since sialic acids and α-gal epitopes serve as receptors on host cells and can also be expressed on the surfaces of some microorganisms. Whereas, the sialylation of IgG antibodies may help to treat inflammation, the expression of the α-gal epitope on microbial antigens increases the immunogenicity of the corresponding vaccines. Finally, sialic acids and the α-gal epitope have applications in cancer immunotherapy. N-glycolylneuraminic acid is a powerful target for cancer immunotherapy, and the α-gal epitope increases the efficiency of cancer vaccines. The final section of this article contains a brief overview of the methods for oligosaccharide chain synthesis and the characteristics of sialyltransferases and α-1,3-galactosyltransferase.
    Central European Journal of Biology 10/2012; 7(5). DOI:10.2478/s11535-012-0079-3 · 0.71 Impact Factor
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