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

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

doi:10.1128/jvi.00310-06

Ussama Abdel-Motal, Kim Wigglesworth + Show 3 more

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https://doi.org/10.1128/jvi.00310-06

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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.

Highlights

Many of the studies of recombinant protein and DNA human immunodeficiency virus (HIV) vaccines in primate models or in clinical trials report that these vaccines have not been found as yet to be satisfactory in eliciting a sterilizing protective immune response against infection with HIV or simian immunodeficiency virus (SIV) [3, 22, 31, 40]
A major component on the envelope of HIV, which contributes to the masking of the virus from the immune system and which hinders the effective uptake of gp120 vaccines, is the multiple carbohydrate chains on this envelope glycoprotein [19, 30, 34]
The N-acetyllactosamines exposed on the carbohydrate chains function as an acceptor for recombinant ␣1,3GT, which links to them terminal ␣1-3-galactosyl residues, to form ␣-gal epitopes

Summary

Introduction

Many of the studies of recombinant protein and DNA human immunodeficiency virus (HIV) vaccines in primate models or in clinical trials report that these vaccines have not been found as yet to be satisfactory in eliciting a sterilizing protective immune response against infection with HIV or simian immunodeficiency virus (SIV) [3, 22, 31, 40]. These carbohydrate chains protrude from the gp120 molecule and seem to contribute to the protection of HIV against neutralizing antibodies This protective role of the multiple carbohydrate chains can be inferred from isolate clones of HIV type 1 (HIV-1) in AIDS patients, where at least half of the mutations in gp120 (i.e., the env gene) result in the appearance of new N-glycosylation sites (i.e., Asn-X-Ser/Thr) [58]. These de novo-expressed carbohydrate chains provide a “glycan shield” that protects the virus from neutralizing antibodies [58]. Apes, and Old World monkeys lack an active ␣1,3GT gene but produce the anti-Gal antibody in large amounts [10, 12, 18]

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