Article

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 Galα1-3Galβ1-4GlcNAc-R (α-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 α-gal epitopes (gp120αgal) 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 Fcγ 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 α-1,3-galactosyltransferase knockout mice, which
produce anti-Gal. Mice immunized with gp120αgal 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 gp120αgal than in mice immunized with gp120. It is suggested that gp120αgal can serve as a platform for anti-Gal-mediated targeting of additional vaccinating HIV proteins fused to gp120αgal, thereby creating effective prophylactic vaccines.

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    • "Many bacteria generr ate the surface polysaccharide β1166polyyNNacetyllDD glucosamine (PNAG), and production of antibodies against this epitope can generate immunity to a large number of germs[19]. Furthermore, expression of αGal epitopes in inactivated influenza virus vaccine and in gp120 vaccine of HIV produces a prominent increase of the humoral and cellular immune responses generated by the two vaccines[20,21]. Additionally, polyanhydride nanoparticles carrying αGalltransformed antigens induce higher antibody responses with broader epitope recognition compared to other adjuvants[22]. "
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    ABSTRACT: Natural anti-carbohydrate antibodies (NAbC) are antibodies that target glycans and are continuously produced without apparent external antigen stimulation. Clinically, NAbC are recognized by the adverse reactions to ABO mismatched blood transfusions or organ transplantation and the rejection of xenografts. These clinical effects do not reflect the biological functions of NAbC. However, they launch the possibility of using NAbC for boosting immunity in different clinical settings by means of: 1) expression of glycan antigens in elements that do not hold them to allow the binding and reactivity of existing NAbC; 2) removal of existing NAbC; 3) manipulation of the glycosylation pattern of NAbC.
    Preview · Article · Jul 2015 · Biochemistry (Moscow)
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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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    ABSTRACT: Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role.
    Full-text · Article · Apr 2013 · PLoS ONE
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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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    ABSTRACT: Adenovirus (Ad) vector-based vaccines displaying pathogen-derived epitopes on Ad capsid proteins can elicit anti-pathogen immunity. This approach seems to be particularly efficient with epitopes incorporated into the Ad fiber protein. Here, we explore epitope insertion into various sites of the Ad fiber to elicit epitope-specific immunity. Ad vectors expressing the 14-mer Pseudomonas aeruginosa immune-dominant outer membrane protein F (OprF) epitope 8 (Epi8) in five distinct sites of the Ad5 fiber, loops CD (AdZ.F(CD)Epi8), DE (AdZ.F(DE)Epi8), FG (AdZ.F(FG)Epi8), HI (AdZ.F(HI)Epi8) and C terminus (AdZ.F(CT)Epi8), or the hexon HVR5 loop (AdZ.HxEpi8) were compared in their capacity to elicit anti-P. aeruginosa immunity to AdOprF, an Ad expressing the entire OprF protein. Intramuscular immunization of BALB/c mice with AdZ.F(FG)Epi8 or AdZ.F(HI)Epi8 elicited higher anti-OprF humoral and cellular CD4 and CD8 responses as well as enhanced protection against respiratory infection with P. aeruginosa compared to immunization with AdZ.F(CD)Epi8, AdZ.F(DE)Epi8, AdZ.F(CT)Epi8 or AdZ.HxEpi8. Importantly, repeat administration of the fiber- and hexon-modified Ad vectors boosted the OprF-specific humoral immune response in contrast to immunization with AdOprF. Strikingly, following three doses of AdZ.F(FG)Epi8 or AdZ.F(HI)Epi8 anti-OprF immunity surpassed that induced by AdOprF. Furthermore, in the presence of anti-Ad5 immunity, immunization with AdZ.F(FG)Epi8 or AdZ.F(HI)Epi8, but not with AdOprF, induced protective immunity against P. aeruginosa. This suggests that incorporation of epitopes into distinct sites of the Ad fiber is a promising vaccine strategy.
    Preview · Article · Feb 2013 · PLoS ONE
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