Immunogenicity of HIV-1 Vaccines Expressing Chimeric Envelope Glycoproteins on the Surface of Pr55 Gag Virus-Like Particles.

Rosamund Chapman,Michiel Van Diepen,Penny Moore,Edward Rybicki,Tandile Hermanus,Elizabeth Kruse,Shireen Galant,Emmanuel Margolin,Nicola Douglass,Anna-Lise Williamson,Phindile Ximba

doi:10.3390/vaccines8010054

Abstract

The HIV-1 envelope glycoprotein (Env) is present on the surface of the virion at a very low density compared to most other enveloped viruses. Substitution of various parts of the stalk domain of Env (gp41) with the corresponding elements from other viral glycoproteins has been shown to increase Env spike density on the cell membrane and surface of virus-like particles (VLPs). In this study, chimeric Env antigens were generated by replacing the transmembrane and cytoplasmic domains of HIV-1 Env with the corresponding regions from the influenza H5 hemagglutinin (HA) (gp140HA2tr) and by replacing the entire gp41 region of Env with the HA2 subunit of HA (gp120HA2). Recombinant DNA and modified vaccinia Ankara (MVA) vaccines expressing HIV-1 subtype C mosaic Gag and gp150 Env or either of the chimeras were generated. Surprisingly, no significant differences were found in the levels of expression of gp150 Env or either of the chimeras on the surface of cells or on Gag VLPs. Differences were, however, observed in the binding of different monoclonal antibodies to the HIV-1 Env. Monoclonal antibodies, which recognized a V1 / V2 quaternary epitope at the tip of the native Env trimer, bound gp150 and gp140HA2tr chimera but failed to bind to the gp120HA2 chimera. Autologous Tier 2 neutralizing antibodies (NAbs) were produced by rabbits inoculated with DNA and MVA vaccines expressing the gp140HA2tr chimera or gp150 Env, but not those immunized with the gp120HA2 Env. These results showed that the addition of an HA2 stalk to HIV-1 gp120 did not improve immunogenicity, but rather that the full-length gp150 was required for optimal presentation of epitopes for the elicitation of a neutralizing antibody response to HIV-1.

Highlights

There has been a reduction in deaths related to HIV infection in recent years due to the implementation of antiretroviral therapy as well as other measures, the AIDS pandemic continues to grow
We aimed to increase the expression of HIV Env on the surface of virus-like particles by exchanging either the entire gp41 region of the HIV envelope protein or just the transmembrane region (TM) + cytoplasmic tail (CT) region with cognate sequences derived from influenza A H5 HA2 protein
No differences in the ratios of Env:Gag were seen in virus-like particles (VLPs) isolated from cells transfected with DNA or infected with modified vaccinia Ankara (MVA) vaccines expressing the chimeras compared to gp150, as determined by Western blotting

Summary

Introduction

There has been a reduction in deaths related to HIV infection in recent years due to the implementation of antiretroviral therapy as well as other measures, the AIDS pandemic continues to grow. It is thought that an HIV envelope (Env) immunogen that can either elicit broadly neutralizing antibodies (bNAbs) that prevent HIV infection or one that elicits polyfunctional, non-neutralizing antibodies that drive the clearance of the virus are possible approaches to generating a prophylactic HIV vaccine [2]. The envelope glycoproteins of most viruses are present in dense (50–100Å), repetitive arrays on the surface of the virion [3]. This highly ordered, dense spacing of epitopes is not often found on the surface of mammalian cells and is thought to be a key determinant of recognition by the humoral immune system of viruses as being foreign [4]. Influenza virions have 400 to 500 spikes per similar-sized virion

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